04 intravenous immune globulin clinical applications in the newborn

DOI: 10.1542/neo.11-7-e370 2010;11;e370-e378 NeoReviewsVento

Mariel Navarro, Sergio Negre, Sergio Golombek, María L. Matoses and Máximo Intravenous Immune Globulin: Clinical Applications in the Newborn

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Intravenous Immune Globulin:Clinical Applications in the NewbornMariel Navarro, MD,*

Sergio Negre, MD,*

Sergio Golombek, MD,

MPH,† Marıa L. Matoses,

MD,* Maximo Vento,

PhD, MD*

Author Disclosure

Drs Navarro, Negre,

Golombek, Matoses,

and Vento have

disclosed no financial

relationships relevant

to this article. This

commentary does

contain a discussion

of an unapproved/

investigative use of a

commercial

product/device.

AbstractIntravenous immune globulin (IVIG) is manufactured from plasma isolated from healthyblood donors and includes mostly immunoglobulin G (IgG). IVIG is approved by theUnited States Food and Drug Administration (FDA) for use in a variety of diseases inadults and children, although there are no FDA-approved uses of IVIG in newborns.Off-label use of IVIG in newborns includes prophylaxis against infections in low-birthweight infants and treatment of neonatal alloimmune diseases such as hemolyticdisease of the newborn (HDN) and neonatal alloimmune thrombocytopenia (NAIT).More recently, IVIG has been used in parvovirus B19 infection, hemochromatosis, andneonatal Kawasaki disease. The mechanism of action of IVIG includes antibody-specificimmunity as well as mechanisms triggered via IgG binding to fragment crystallizable (Fc)receptors on phagocytes, natural killer (NK) cells, and reticuloendothelial cells locatedthroughout the body. Adverse effects of IVIG in adults and children are well recognizedand include anaphylaxis, thromboembolism, renal failure, and aseptic meningitis. Theadverse effects of IVIG in the newborn are less well described but include severe diseasessuch as necrotizing enterocolitis (NEC). Hence, although IVIG may be indicated as anadjunct for the prevention and treatment of infectious and certain alloimmune-mediateddiseases in infants, it should be used with caution in the newborn period.

Objectives After completing this article, readers should be able to:

1. List the common indications and complications of IVIG treatment in adults, children,and neonates.

2. Describe the properties of IVIG.3. Review uses of IVIG in neonates.

IntroductionIVIG is manufactured from plasma pooled from more than1,000 healthy blood donors and includes mostly IgG, al-though trace IgA also may be present. (1) In adults andchildren, the FDA has approved IVIG for the treatment ofprimary immunodeficiency, idiopathic thrombocytopenicpurpura, Kawasaki disease, chronic lymphocytic leukemia,pediatric human immunodeficiency virus (HIV) infection,and in bone marrow transplantation. (2)(3)(4)(5) In thenewborn, off-label indications include HDN, (6) NAIT,(7)(8)(9) and as prophylaxis/therapy against sepsis in low-birthweight or preterm infants. (10)(11)(12) IVIG also hasbeen used in the treatment of parvovirus B19 infection,(13)(14) neonatal hemochromatosis, (15)(16) neonatalneutropenia, (17)(18) and in rare cases of neonatal Kawasakidisease (Table 1). (19)

The complications of IVIG administration in adults andchildren include acute adverse effects that generally are mild

*Division of Neonatology, University Hospital La Fe, Valencia, Spain.†Regional Neonatal Center, Maria Fareri Children’s Hospital, Westchester Medical Center, New York Medical College, Valhalla,NY.

Abbreviations

ANN: alloimmune neutropeniaELBW: extremely low birthweightFab: fragment of antibody bindingFc: fragment crystallizableFDA: Food and Drug AdministrationHDN: hemolytic disease of the newbornHIV: human immunodeficiency virusIg: immunoglobulinIVIG: intravenous immune globulinNAIT: neonatal alloimmune thrombocytopeniaNEC: necrotizing enterocolitisNH: neonatal hemochromatosisNK: natural killer

Article hematology

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and transient and likely are due to the flow rate of IVIGadministration. Chronic adverse effects may be moresevere and include thromboembolic complications dueto hyperviscosity, renal failure, neutropenia, aseptic men-ingitis, skin reactions, hemolytic anemia, arthritis, andpseudohyponatremia. (4)(20) In the newborn, recentstudies suggest that its use in the treatment of HDN maybe associated with the development of NEC. (21)(22)Although the mechanism of NEC in these infants is notknown, similar to adverse effects in adults and in chil-dren, close attention to flow rate and dosage may limitadditional hyperviscosity or thromboembolism, whichmay function in the pathophysiology of NEC develop-ment in these infants. Accordingly, IVIG should be usedcautiously in the newborn period.

Physiologic Functions of ImmunoglobulinsIgs (antibodies) comprise the humoral arm of the adap-tive immune system and together with T cells, the cellu-lar arm of the adaptive immune system, are essentialcomponents of the human immune system. Deficienciesin either Igs or T cells result in an increased susceptibilityto infection. The humoral immune system is composedof B cells that are clonally selected during maturation inthe bone marrow to secrete antibody. After maturationand on encountering their specific antigen, B cellsclonally expand and differentiate into antibody-secretingB cells called plasma cells. B cells and plasma cells expressone class of Ig. IgG is the predominant antibody foundin serum and the major antibody class in IVIG. IgG ispredominantly active against bacteria, is responsible forthe opsonization of microbes, and facilitates their uptakeand elimination by phagocytic cells in the immune sys-tem. IgM is effective in killing bacteria, IgE functions inthe elimination of parasites as well as atopic reactions inallergy, and IgA is the predominant Ig subtype in secre-

tions at the mucosal interfaces of the body. IgD is pre-dominantly a receptor on early B cells and plays a role intheir activation.

All classes of Ig are formed from two protein chainsthat create a Y-shaped structure in three dimensions.Each protein chain is composed of a light and a heavychain (Fig. 1). Each light and heavy chain is composed ofa variable and a constant region. In its three dimensionalstructure, the light and heavy chains are held together bydisulfide bonds. The variable region forms the uniqueantigen-binding site or fragment of antigen-binding(Fab) region. The constant region, when free in solution,crystallizes (due to homogeneity) and, therefore, isnamed the fragment crystallizable (Fc) region. The Fcportion of Ig binds Fc receptors expressed on reticuloen-dothelial cells throughout the body as well as on phago-cytes and NK cells. The binding of IgG to its respectiveantigen or microbe mediates the immune protectionafforded by IVIG. The binding of IgG via its Fc receptorstriggers most Ig-mediated events in the immune system,leading to phagocytosis of microbes, antibody-mediatedcell killing, the secretion of cytokines and chemokines,and the activation of reticuloendothelial cells, NK cells,and the complement cascade (Table 2). (2)

Plasma cells secrete antibodies with specificity againstforeign antigens as well as antibodies that recognize theFab-binding site of other antibodies, called anti-idiotypeantibodies. The antigen repertoire of most antibodiesincludes Ig with specificity for both foreign and self-proteins. Hence, although a primary function of anti-bodies is the elimination of foreign material (harmful

Table 1. Clinical Uses ofIntravenous Immune Globulinin the Neonatal Period● Hemolytic disease of the newborn● Neonatal alloimmune thrombocytopenia● Prophylaxis and treatment of septicemia in preterm

infants● Coadjuvant therapy in parvovirus B19 infection● Neonatal hemochromatosis● Neonatal alloimmune neutropenia● Neonatal Kawasaki disease

Figure 1. Standard form of immunoglobulins.

hematology intravenous immune globulin

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bacteria and antigens), they also function in the elimina-tion of senescent and altered self-proteins and cells,such as self-proteins that may be modified on tumor cells.Anti-idiotypic antibodies likely play a role in the suppres-sion of autoantibody responses and function in main-taining tolerance in the avoidance of autoimmune dis-ease. (2)

Transport of Maternal IgG Across thePlacentaThe immune system of the fetus and newborn is imma-ture and, therefore, the newborn and, more significantly,the preterm infant are highly susceptible to infections. Ofthe four classes of Ig, only IgG is actively transportedacross the placenta, particularly during the latter weeks ofgestation. Because the repertoire of IgG in the newbornmirrors the spectrum of IgG in the mother, a tremendousprotective advantage is bestowed on the infant from themother (23) IgG is actively transported across the pla-centa into the fetal circulation using IgG Fc receptorspresent on placental cells. Active transport increases be-

ginning at about 16 weeks of gestation and progressivelybecomes more active until term. (23) Circulating IgG inthe fetus is almost completely derived from the mother.In fact, concentrations of IgG in the last month ofgestation approach 1,000 mg/dL and may exceed theconcentrations of circulating maternal IgG at term, al-though the concentration of IgG in preterm infants isonly 500 mg/dL. The active transport of maternal IgGto the fetus also contributes to the pathophysiology ofred blood cell hemolysis in alloimmune sensitization inHDN as well as in the loss of platelets following NAIT.

Properties of IVIGIVIG is prepared from plasma pooled from a minimum of1,000 but often 3,000 to 100,000 healthy blood donors,giving it broad immune specificity against a variety ofpathogens and antigens. Such specificity not only isuseful as an adjunct to prophylaxis against infections inpreterm and low-birthweight infants but also may con-tribute to its role in immune modulation in alloimmunediseases of the newborn. All preparations of IVIG con-tain a high concentration of IgG (90% to 98%), with thesame distribution of IgG subclasses found in normalserum (IgG1, 60% to 70%; IgG2, 20% to 30%; IgG3, 0%to 6%; IgG4, 0% to 4%). Although the World HealthOrganization Committee on Biologic Standardizationmandated that all IVIG preparations be as unmodifiedas possible to maintain biologic functions (Fc receptorbinding, complement fixation, and opsonic activity) andantigen repertoire and meet safety standards for admin-istration to humans, (24) impurities may develop or notbe removed during preparation that account for most ofthe adverse effects. For example, IgG tends to aggregate,forming high-molecular weight complexes that may beresponsible for the adverse reactions. (1) Minor contam-inants of IVIG include trace amounts of IgA, cytokines,soluble forms of cell surface human leukocyte molecules,T-cell surface molecules CD4 and CD8, and IgG withspecificity for self-proteins and anti-idiotypic IgG. (3)In fact, previous manufacturing techniques allowed agreater proportion of contaminants and aggregates ofIgG, resulting in the inadvertent activation of comple-ment and anaphylaxis. Processing modifications that pre-vent or remove IgG aggregates and increase the purity ofIVIG have reduced the incidence of such adverse events.

IVIG has been marketed commercially since the early1980s, with varying production processes for pathogensafety. Most inter-product variations are not clinicallyrelevant, although some affect efficacy, tolerability, andespecially convenience of usage, making certain IVIGproducts inappropriate for specific patient populations.

Table 2. Biologic ImmunomodulatoryFunctions of IgGT cells

● May inactivate, silence, or bring about programmedT cell death

Cytokines

● Restore balance between pro- and anti-inflammatorycytokines.

B Cells

● Downregulate production of antibodies by B cells● Contain abundant anti-idiotypes to neutralize

autoantibodies (factor VIII, DNA, thyroglobulin,neuroblastoma, laminin)

● Anti-CD5 block activity of specific B subpopulationproven to release naturally occurring autoantibodies

● Block receptors on B cell surface responsible forstimulating their proliferation

Complement system

● Interrupts complement system activation cascade● Prevents the assembly of terminal complement

complex

Fc receptor

● Downregulates damaging effect of macrophagesblocking activating receptors and inducing inhibitoryfactors




Adverse reactions in the newborn potentially are relatedto volume overload, viscosity and osmolarity, pH, andsodium and sugar content. IVIG products produced athigher concentrations may reduce the volume requiredfor a specified dose but also may increase the viscosity andosmolarity of the solution and trigger significant adverseevents such as thromboembolic episodes or renal com-plications. In contrast to plasma osmolarity of 280 to296 mOsm/L, the osmolality of commercial IVIG mayexceed 1,000 mOsm/L. Hyperosmolar solutions maycause fluid shifts and adverse events related to hemody-namic changes. (1)(3)(25)

The optimal pH for stability of IVIG solutions is4.0 to 4.5. At this pH, the content of aggregates issubstantially limited. Therefore, low pH-formulatedIVIG solutions do not need stabilizers and products at aphysiologic pH require addition of these agents to main-tain stability. (26) Of note, the addition of stabilizersis associated with significant adverse effects. (27) IVIGsolutions containing sucrose as stabilizer have the great-est risk of causing renal impairment. (28)(29)

Current forms of IVIG have a shelf life of 24 to 36months that varies according to their stability. Liquidpreparations are easier to use than lyophilized (whichrequire time for reconstitution) and are linked with feweradverse effects. Selection of donors and screening of viralmarkers have diminished viral load entering the manu-facturing process, which includes a stage of viral inacti-vation. This manufacturing process can alter the proteinstructure, reducing biologic activity. Thus, the efficacyamong commercial IVIG products can be defined ac-cording to parameters such as percentage of monomers,circulating half-life, percentage of IgG, and subclass dis-tribution. (1)(3)(20)(25)(26)(27)

On-label and Off-label Uses of IVIG inNeonatologyIVIG products have received FDA approval only forsix indications: primary immunodeficiency, idiopathicthrombocytopenic purpura, Kawasaki disease, chroniclymphocytic leukemia, pediatric HIV infection, and bonemarrow transplantation (allogenic). Gamimune N,which no longer is manufactured, was approved for thetwo last indications. (3)(5)(24)(30) Currently, off-labeluses of IVIG products exceed on-label uses. Althoughhigh-dose IVIG initially was used for immune thrombo-cytopenic purpura, it currently is employed as an immu-nomodulatory agent in many immune and inflammatorydiseases. (3)(4) A replacement dose is used essentially asthe treatment of choice for patients who have antibodydeficiencies. (25)(30) All current commercial IVIG

products are approved for use in immunodeficient pa-tients but not for immunomodulatory indications. Be-cause of differences in the opsonic activity, Fc receptorfunction, and complement fixation, all IVIG prepara-tions cannot be considered as a generic product. (4)

In neonatology, conditions that are susceptible toIVIG treatment are related to the transplacental passageof fetal cells to the maternal circulation and formation ofspecific antibodies by the mother that cross the placentaand reach the fetal circulation, where they cause specificactivation of macrophages that destroy fetal cells (Table3). In the presence of IVIG, macrophage receptors areblocked, substantially preventing hemolysis (Fig. 2).

Hemolytic Disease of the NewbornHyperbilirubinemia results from an imbalance betweenproduction and excretion of bilirubin. Among the mostfrequent and severe conditions causing hyperbiliru-binemia in the neonatal period are blood group incom-patibilities. Rh incompatibility represents the principalcause of severe isoimmune HDN, but with the use ofanti-D immunoglobulin, immunization of O againstA or B blood group now is the most frequent causeof mild-to-moderate hyperbilirubinemia. Importantly,newborns whose serum bilirubin is more than 23.5 to

Table 3. ImmunomodulatoryActions of IVIGActions Mediated by the Variable Regions

● Natural antibodies● Effects on cytokine concentrations● Antibodies to immunoregulatory molecules (eg,

cytokines, toll-like receptors)● Antibodies to pathogens and superantigens● Effects on cell adhesion● Activation of specific cells● Modulation of apoptosis and cell cycle● Antiproliferative effects

Actions of Fc Region on a Range of Fc Receptors

● Inhibition of phagocytosis● Effects on antibody production and recycling● Effects on glucocorticoid receptor binding affinity

Actions Mediated by Complement Binding Within theFc Fragment

● Inhibition of deposition of activated complement.

Immunomodulatory Substances Other Than Antibody inthe IVIG Preparation

● For example: cytokines, cytokine receptors, CD4




29.4 mg/dL (400 to 500 mcmol/L) are at severe riskof hyperbilirubinemia-induced neurologic dysfunction.Under these circumstances, phototherapy may be con-sidered the cornerstone of treatment. (31)(32) How-ever, in severe cases, when phototherapy is insufficient,exchange transfusion is used to remove antibody-coatederythrocytes and unbound maternal antibodies. Ex-change transfusion is not free of severe complications,the most relevant of which are thrombocytopenia, apnea,pulmonary hemorrhage, hemodynamic instability, co-agulopathy, hypertension, arrhythmias, septicemia, andNEC. (33)

To reduce/eliminate the need for exchange transfu-sion and its associated morbidity and mortality, therapywith high-dose IVIG was introduced in the early 1990s.Clinical studies have shown that high-dose IVIG pre-vents or decreases hemolysis, as reflected by a rapiddecline of carboxyhemoglobin values. Two recent re-views concluded that early administration of IVIG is themost relevant factor in reducing hyperbilirubinemia andavoiding exchange transfusion. (34)(35) Moreover, asingle 0.5-g/kg dose on day 1 is as effective as otherproposed therapeutic schemes that have used higher

IVIG doses. Thus, in patients in whom total serum bili-rubin is rising despite intensive phototherapy or its con-centration is within 2 to 3 mg/dL (34 to 51 mcmol/L)of the exchange level, 0.5 to 1 g/kg IVIG can beadministered over 2 hours and repeated in 12 hours, ifnecessary (34)(35)(36) However, the American Acad-emy of Pediatrics states that IVIG must not be offeredroutinely as prophylaxis against hyperbilirubinemia inthose who have HDN and should be regarded as anoption for hyperbilirubinemia refractory to phototherapythat reaches values that put the patient at risk of neuro-logic damage. (32)

The reduced rate of hemolysis with the use of IVIGhas decreased the rate of exchange transfusions substan-tially. Patra (33) showed that 74% of exchange transfu-sions were associated with adverse events such as throm-bocytopenia (44%), hypocalcemia (29%), and metabolicacidosis (24%) as well as a mortality rate of 2%. Despitethe declining use of this procedure, the rates of associatedmorbidity and mortality have not changed substantially.(33) In fact, most of the complications are mild andtransient and affect patients who have pre-existing andsignificant comorbidities. Authors of a recent review

Figure 2. Mechanism of maternal-fetal immunization and IVIG antibody blockage.




article stated that “the use of high-dose intravenousimmunoglobulin therapy brings about, with no undesir-able side effects, a significant decrease in exchange trans-fusion number as well as significant reduction in thelength of phototherapy and hospitalization.” (37)

Neonatal Alloimmune ThrombocytopeniaNAIT is the most common cause of early isolated severethrombocytopenia in otherwise healthy newborns, af-fecting 1 in 800 to 1,000 newborns. NAIT is believed tobe caused by maternal alloimmunization against fetalplatelet antigens, although the intrinsic pathophysiologicmechanisms have not yet been elucidated fully. NAITfrequently (10% to 30%) is associated with intracranialhemorrhage, which confers a somber prognosis. Approx-imately 10% to 15% of affected babies die, and 20% ofsurvivors have severe neurodevelopmental sequelae.

The cornerstone of NAIT treatment is early provisionof antigen-negative compatible platelets. The efficacy ofIVIG as an adjunct for the treatment of NAIT lackssufficient evidence, and experts differ in their recommen-dations for the neonatal period. Some indicate IVIG as acomplement to antigen-negative compatible platelets,and others reject its systematic use. The dose of IVIGrecommended for NAIT is 1 g/kg on 2 consecutive days,based on the platelet response. (7)(8)(9)

Neonatal Sepsis in the Preterm InfantLate-onset sepsis (a nosocomial infection) is very com-mon in extremely low-birthweight (ELBW) infants, whospend long periods of time in the neonatal intensive careunit. Mortality ranges from 5 to 30 per 100 admittedpatients. Interestingly, transport of Igs from the motherto the fetus occurs primarily after 32 weeks’ gestation,and infants do not begin to produce Igs until severalmonths after birth. Theoretically, the adverse effects ofinfections, especially in very preterm infants, could bereduced by the preventive administration of IVIG. IVIGinfusion has been associated with a 3% to 4% reductionin sepsis or any serious infection. However, it has notinfluenced other important outcomes, such as incidenceof NEC or intraventricular hemorrhage and length ofhospital stay or mortality. From a clinical perspective, a3% to 4% reduction in nosocomial infections without areduction in mortality or other important clinical out-comes is of marginal importance, as underscored by arecent Cochrane Review. (11)

Parvovirus B19 InfectionParvovirus B19 is a small, nonenveloped DNA virus thatexclusively infects humans. After infection, parvovirus

B19 replicates primarily in erythrocytes and erythro-blasts, leading to anemia in predisposed individuals. In-fection transmitted in utero from a susceptible mother toan immunocompromised fetus is an infrequent cause offetal morbidity and mortality. (13) Although adult dis-ease generally is mild, fetal parvovirus B19 infection cancause spontaneous abortion in the early part of preg-nancy and aplastic anemia, nonimmune hydrops fetalis,and in utero fetal demise. IVIG treatment of parvovirusB19 infection in neonates is controversial, (14) althoughcommercially available products carry antibodies againstthis pathogen, and some authors have reported success-ful treatment of anemia, with prompt resolution of clin-ical symptoms and signs, using commercially availableIVIG. However, evidence is insufficient that IVIG treat-ment can influence the rate of severe sequelae or deathamong patients who have encephalopathy, encephalitis,or meningoencephalitis due to parvovirus B19 infection.(38)

Neonatal HemochromatosisNeonatal hemochromatosis (NH) is a severe neonatalliver disease associated with siderosis of tissues outside ofthe liver that leads to cirrhosis and liver failure duringgestation and clinical manifestations in the neonatal pe-riod. The rate of occurrence in the offspring of womenwho have had one affected infant may reach 60% to 80%.Therefore, avoidance of new pregnancies often is advisedduring genetic counseling. It has been proposed that NHcould be the result of maternal alloimmunity directedagainst the fetal liver. (39) Based on this concept, IVIGcould be indicated in an attempt to prevent recurrentsevere NH. In a recent prospective, multicenter, interna-tional trial, weekly doses of IVIG beginning at the 18thweek of gestation were administered to women at highrisk for NH. (15)(16) Following the intervention, 94.5%of the babies in the IVIG group had intact survivalcompared with 97.1% in the nontreated group beingseverely affected and needing liver transplantation. Theseresults suggest that NH can be treated successfully withhigh doses of IVIG during gestation without apparentsignificant adverse effects to the women or fetuses.

Neonatal Alloimmune NeutropeniaNeonatal alloimmune neutropenia (ANN) is a rare butpotentially life-threatening disorder that results frommaternal alloimmunization to granulocyte antigens. (40)The incidence of ANN has been estimated to be 1 per1,000 to 6,000 live births, and it accounts for 1.5% of allneonatal intensive care unit admissions. Interestingly,the course of pregnancy generally is uneventful. (17) The




diagnosis is based on the demonstration of the presenceof alloantibodies against granulocyte-specific antigenshared by neonatal and paternal granulocytes in thematernal serum. Antibodies to granulocyte-specific anti-gens HNA-1a and HNA-1b have been reported mostcommonly to cause ANN. Anti HNA-2a and antibodiesto gamma Fc receptor (CD16), if the mother is a HNA-null phenotype, rarely are involved in neonatal neutrope-nia. Neutropenia usually lasts only a few weeks or monthsand is self-limiting. (17) ANN remits when maternalantineutrophil antibodies diminish to a critically lowconcentration in the neonate’s marrow and blood. Treat-ment usually includes antibiotics, IVIG, and granulocytecolony-stimulating factor, with variable success. (18)The use of IVIG in ANN has not been tested in prospec-tive, randomized clinical trials; its use has been limited toisolated cases or for the treatment of neutropenia inELBW infants. Until more information is available, theuse of IVIG in ANN is not warranted.

Kawasaki Disease in NeonatesKawasaki disease is extremely unusual in the newbornperiod, representing only 0.005% of a Japanese cohortthat covered a 25-year period. Only four patients havebeen described to date in the neonatal period whoseclinical, ultrasonographic, and pathologic features co-incided with the diagnosis, and only one survived. Themedical literature contains only 10 cases of neonatalKawasaki disease, and most infants died due to severecardiac involvement unresponsive to treatment withIVIG. (19)

Safety of IVIG Therapy in the NewbornThe clinical decision to use IVIG in neonates must beweighed carefully against its potential adverse effects.Christensen and associates (34) included preterm neo-nates in a randomized study of IVIG versus placebo thatcompared a series of laboratory and clinical effects of itsadministration. They suggested that IVIG can be admin-istered safely to preterm neonates, with postinfusionserum IgG concentrations comparable to those of terminfants. Various reports and a recent review showed noincreased adverse reactions compared with control in-fants. (37)(41)(42)(43) A Cochrane review (44) re-vealed some isolated cases of hypertension and hypogly-cemia after exchange transfusion but no differences inthe incidence between the IVIG and the control groups.

The most frequent indication for IVIG in the neonatalperiod is as an adjunct to the treatment of hyperbiliru-binemia refractory to phototherapy from HDN eitherdue to anti-D or ABO incompatibility. ABO incompati-

bility, which is the most common cause of hyperbiliru-binemia in the early neonatal period after the introduc-tion of anti-D immune globulin treatment for Rh-sensitized women, is not preventable and occasionallyrequires double-volume exchange transfusion, which canbe associated with severe risk. Monpoux and colleagues(37) concluded that high-dose IVIG is effective in reduc-ing the number of exchange transfusions, the hours ofphototherapy, and the length of hospital stay. However,episodes of NEC after the administration of IVIG havebeen reported in neonates who had isoimmune throm-bocytopenia (7)(45) Because NEC also has been re-ported in term neonates who had HDN, the risk of NECmay be independent of IVIG and rather be associatedwith exchange transfusion. Two very recent clinical re-ports (21)(22) have described additional cases of NEC interm and preterm infants associated with the use of IVIGfor the treatment of hyperbilirubinemia. Navarro andassociates (21) described three babies (two term and onelate preterm) who developed severe NEC shortly afterreceiving 0.5 to 2 g/kg of IVIG at a slow rate (4 to8 hours) to prevent exchange transfusion. In two of thepatients, who required surgery, pathology studies re-vealed microthrombi in the mesenteric vessels. Figueras-Aloy and colleagues (22) published a retrospective studyincluding neonates of at least 34 weeks’ gestation whohad severe isoimmune hemolytic jaundice due to Rh/ABO incompatibility. Thirty-four percent of the infantsreceived IVIG (0.5 g/kg) over 2 to 4 hours, and NECwas diagnosed in 2.2% of these babies compared with0.3% of those that did not receive IVIG. In the multivar-iate analysis, IVIG was considered an independent vari-able in the development of NEC. In the Navarro study,(21) the IVIG employed was identified as Flebogamma®(Instituto Grifols SA/Grifols USA); no specific brandwas identified in the Figueras-Aloy study. (22) The roleof IVIG in the pathogenesis of NEC is not clear. Severalfactors in addition to IVIG may have promoted thedevelopment of NEC, including hyperviscosity leadingto intestinal ischemia and disruption of the epithelialbarrier initiating the inflammatory cascade characteristicof NEC.

ConclusionThe clinical use of IVIG in newborns has increasedsubstantially in the last few years, although the FDA hasnot approved its use in newborns. The immunomodula-tory, anti-inflammatory, and anti-infectious properties ofIVIG may be of benefit for diseases in the newborn, butthe dose and volume and rate of infusion should bemonitored to avoid acute adverse effects, such as NEC.




The use of IVIG in the treatment and prophylaxis ofdisease in the newborn deserves further study.

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15. Whitington PF, Kelly S. Outcome of pregnancies at risk forneonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics. 2008;121:e1615–e162116. Rand EB, Karpen SJ, Kelly S, et al. Treatment of neonatalhemochromatosis with exchange transfusion and intravenous im-munoglobulin. J Pediatr. 2009;155:566–57117. Christensen RD, Henry E, Wiedmeier SE, Stoddard RA, Lam-bert DK. Low blood neutrophil concentrations among extremelylow birth weight neonates: data from a multihospital health-caresystem. J Perinatol. 2006;26:682–68718. Buenz EJ, Howe CL. Appropriate use of intravenous immu-noglobulin in neonatal neutropenia. J Perinatol. 2007;27:196–19719. Stanley TV, Grimwood K. Classical Kawasaki disease in aneonate. Arch Dis Child Fetal Neonatal Ed. 2002;86:135–13620. Pierce LR, Jain N. Risks associated with the use of intravenousimmunoglobulin. Transfus Med Rev. 2003;17:241–25121. Navarro M, Negre S, Matoses ML, Golombek S, Vento M.Necrotising enterocolitis as a consequence of the use of intravenousimmune globulin for newborn hyperbilirubinemia. Acta Paediatr.2009;98:1214–121722. Figueras-Aloy J, Rodriguez-Miguelez JM, Iriondo-Sanz M,Salvia-Roiges MD, Botet-Mussons F, Carbonell-Estrany X. Intra-venous immunoglobulin and necrotizing enterocolitis in newbornwith hemolytic disease. Pediatrics. 2010;125:139–14423. Saji F, Samejima Y, Kamiura S, Koyama M. Dynamics ofimmunoglobulins at the feto-maternal interface. Rev Reprod. 1999;4:81–8924. IUIS/WHO notice. Appropriate uses of human immunoglob-ulin in clinical practice. Clin Exp Immunol. 1983;52:471–42225. Ballow M. Clinical and investigational considerations for theuse of IGIV therapy. Am J Health-Syst Pharm. 2005;62:S12–S1826. Ameratunga R, Sinclair J, Kolbe J. Increased risk of adverseevents when changing intravenous immunoglobulin preparations.Clin Exp Immunol. 2004;136:111–11327. Shah S. Pharmacy considerations for the use of IVIG therapy.Am J Health-Syst Pharm. 2005;62:S5–S1128. Chapman SA, Gilkerson KL, Davin TD, Pritzker MR. Acuterenal failure and intravenous immune globulin: occurs with sucrose-stabilized, but not with D-sorbitol-stabilized, formulation. AnnPharmacother. 2004;38:2059–206729. United States Food and Drug Administration. Dear DoctorLetter – Important Drug Warning: Immune Globulin Intravenous(Human). 1998. Accessed April 2010 at: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm105914.htm30. Anderson D, Ali K, Blanchette V, et al. Guidelines on the use ofintravenous immune globulin for hematologic conditions. TransfusMed Rev. 2007;21:9–5631. American Academy of Pediatrics Subcommittee on Hyperbil-irubinemia. Management of hyperbilirubinemia in the newborninfant 35 or more weeks of gestation. Pediatrics. 2004;114:297–31632. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaun-dice. N Engl J Med. 2008;358:920–92833. Patra K. Adverse events associated with neonatal exchangetransfusion in the 1990. J Pediatr. 2004;144:626–63134. Christensen RD, Hardman T, Thornton J, Hill HR. A ran-domized, double-blind, placebo-controlled investigation of thesafety of intravenous immune globulin administration to pretermneonates. J Perinatol. 1989;9:126–13035. Steiner LA, Bizzarro MJ, Ehrenkranz RA, Gallagher PG. A de-cline in the frequency of neonatal exchange transfusions and its

American Board of Pediatrics Neonatal-PerinatalMedicine Content Specifications• Know the function of immunoglobulins.• Know the mechanisms and know the

gestational timing of the placental transferof immunoglobulins.

• Know the effects of drugs and othertherapeutic agents in the treatment of hyperbilirubinemia.




effect on exchange-related morbidity and mortality. Pediatrics.2007;120:27–3236. Huizing KMN, Roislien J, Hansen TWR. Intravenous immuneglobulin reduces the need for exchange transfusions in Rhesus andABO incompatibility. Acta Paediatr. 2008;97:1362–136537. Monpoux F, Dageville C, Maillotte AM, De Smet FS, Casa-grande F, Boutte P. Immunoglobulines polyvalentes intraveineuseset ictere neonatal par alloimmunisation erythrocytaire. Arch Pedi-atr. 2009;16:1289–129438. Douvoyiannis M, Litman N, Goldman DL. Neurologic mani-festations associated with parvovirus B19 infection. Clin Infect Dis.2009;48:1713–172339. Whitington PF. Fetal and infantile hemochromatosis. Hepatol-ogy. 2006;43:654–66040. Kaplan C. Foetal and neonatal alloimmune thrombocytopenia.Orphanet J Rare Diseases. 2006;1:39

41. Walsh SA, Yao N, El-Khuffash A, Twomey A, Molloy EJ.Efficacy of intravenous immunoglobulin in the management ofhaemolytic disease of the newborn. Ir Med J. 2008;101:46–4842. Girish G, Chawla D, Agarwal R, Paul VK, Deoraci AK. Efficacyof two dose regimes of intravenous immunoglobulin in Rh hemo-lytic disease of newborn – a randomized controlled trial. IndianPediatr. 2008;45:653–65943. Kaplan M, Merlob P, Regev R. Israel guidelines for the man-agement of neonatal hyperbilirubinemia and prevention of ker-nicterus. J Perinatol. 2008;28:389–39744. Alcock GS, Liley H. Immunoglobulin infusion for isoimmunehaemolytic jaundice in neonates. Cochrane Database Syst Rev.2002;3:CD00331345. Marshall LR, Barr AL, French NP, Lown JA, Knowles S. A fatalcase of necrotizing enterocolitis in a neonate with polyagglutinationof red blood cells. J Paediatr Child Health. 1993;29:63–65

NeoReviews Quiz

8. Intravenous immunoglobulin (IVIG) is derived from plasma pooled from more than 1,000 healthy blooddonors and is approved by the United States Food and Drug Administration for the treatment of variousdisorders in children and adults. Of the following, the most frequent off-label use of IVIG treatment inthe newborn is:

A. Hemolytic disease of the newborn.B. Neonatal hemochromatosis.C. Neonatal Kawasaki disease.D. Parvovirus B19 infection.E. Prophylaxis against sepsis.

9. The use of IVIG in children and adults is associated with generally mild and transient acute adverse effectsas well as more severe and persistent chronic adverse effects. Of the following, the most common chronicadverse effect of IVIG in the newborn is:

A. Aseptic meningitis.B. Hyperviscosity-related thromboembolism.C. Necrotizing enterocolitis.D. Pseudohyponatremia.E. Skin reactions.

10. Immunoglobulins comprise the humoral arm of the adaptive immune system that, together with T cells inthe cellular arm of the adaptive immune system, are essential components of the human immune system.There are five classes of immunoglobulins. Of the following, the immunoglobulin (Ig) class most associatedwith B-cell activation in the immune response is:

A. IgA.B. IgD.C. IgE.D. IgG.E. IgM.




DOI: 10.1542/neo.11-7-e370 2010;11;e370-e378 NeoReviewsVento

Mariel Navarro, Sergio Negre, Sergio Golombek, María L. Matoses and Máximo Intravenous Immune Globulin: Clinical Applications in the Newborn

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