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Alloimmune thrombocytopenia: State of the art 2006
American Journal of Obstetrics and Gynecology (2006) 195, 907–13
www.ajog.org
REVIEW ARTICLES
Alloimmune thrombocytopenia: State of the art 2006 Richard L. Berkowitz, MD,a,* James B. Bussel, MD,b Janice G. McFarland, MDc Department of Obstetrics and Gynecology, Columbia Presbyterian Medical Center a; Department of Pediatrics, Division of Hematology-Oncology, Weill Medical College of Cornell University,b New York, NY; and the BloodCenter of Wisconsin,c Milwaukee, WI Received for publication March 28, 2006; revised April 26, 2006; accepted May 4, 2006
KEY WORDS Antibody Platelets Intracranial hemorrhage Antepartum fetal hemorrhage
In alloimmune thrombocytopenia maternal immunoglobulin G anti-platelet alloantibodies cross the placenta and cause fetal thrombocytopenia. The diagnosis requires laboratory demonstration of incompatibility between a maternal and paternal platelet alloantigen, and detection of maternal antibody to the discordant paternal alloantigen. This disorder should be treated in utero because of its propensity to cause fetal intracranial bleeding. Administration of intravenous immunoglobulin 1 gm/kg/wk to the mother is successful in substantially raising the platelet count in many fetuses, but this is most successful if the count is O20,000/mL3 at the time that the therapy is initiated. The addition of prednisone administered daily to the mother and/or increasing the dose of intravenous immunoglobulin has a therapeutic benefit in cases that have failed to respond to initial therapy with intravenous immunoglobulin alone. The only reliable noninvasive indicator of the potential for severe fetal thrombocytopenia is a history of an antenatal intracranial hemorrhage in a prior affected sibling. Because fetal blood sampling to determine the fetal platelet count may be associated with significant fetal morbidity, attempts are being made to derive a rational, non-invasive, stratified approach to patient-specific therapy of this disorder in affected pregnancies. Ó 2006 Mosby, Inc. All rights reserved.
In alloimmune thrombocytopenia (AIT) maternal immunoglobulin G (IgG) alloantibodies to major platelet antigens cross the placenta and bind to fetal platelets.1-4 * Reprint requests: Richard L. Berkowitz, MD, Department of Obstetrics and Gynecology, Columbia Presbyterian Medical Center, 622 West 168th St, PH 16-66, New York, NY 10032. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2006.05.001
The antibody-coated platelets are subsequently removed from the fetal circulation by the reticuloendothelial system, which results in fetal thrombocytopenia. These same antibodies also may inhibit platelet production. The disorder can be considered the platelet equivalent of Rh alloimmunization, where the offending antigen is located on red cells and which results in fetal anemia by the same mechanism.5 Because screening for sensitization
908 Table AIT
Berkowitz, Bussel, and McFarland Platelet-specific alloantigens that are associated with
HPA system name
Antigen
Familiar name
Polymorphisms of glycoprotein IIIa HPA-1 HPA-1a HPA-1b HPA-4 HPA-4a HPA-4b HPA-6 HPA-6bw HPA-7 HPA-7bw HPA-8 HPA-8bw HPA-10 HPA-10bw HPA-11 HPA-11bw HPA-14 HPA-14bw HPA-16 HPA-16bw
P1A1, Zwa P1A2, Zwb Pena, Yukb Penb, Yuka Ca, Tu Mo Sr-a La(a) Gro(a) Oe(a) Duv(a)
Polymorphisms of glycoprotein IIb HPA-3 HPA-3a HPA-3b HPA-9 HPA-9bw
Baka, Lek Bakb Maxa
Polymorphisms of glycoprotein Ia HPA-5 HPA-5a HPA-5b HPA-13 HPA-13bw
Brb, Zavb Bra, Zava Sit(a)
Polymorphisms of glycoprotein Ib HPA-2 HPA-2b HPA-12 HPA-12bw
Koa, Sib-a Ly(a)
Other probable platelet alloantigen specificities HPA-15 HPA-15a Gov a HPA-15b Gov-b Modified from Mark E. Brecher, editor. Platelet and granulocyte antigens and antibodies in Technical Manual. 15th ed. Bethesda (MD): American Association of Blood Banks; 2005. p. 367-8.
to platelet antigens is rarely performed, couples are usually not known to be at risk for the disorder until they have delivered an affected child. Unlike Rh sensitization, AIT can be very severe in the first affected pregnancy. Sensitization to O15 platelet antigens can be associated with fetal/neonatal thrombocytopenia, but sensitization to the HPA-1a antigen is by far the most common cause of severe alloimmune thrombocytopenia and results in the most significant sequelae.6,7 The incidence of this disorder varies by ethnicity, with rates among the white population in Europe and North America estimated to be between 0.2 and 1 per thousand.8 The African-American population appears to have a lower incidence of the disease, and, since the HPA-1a/1b polymorphism is rarely seen in Asian people, testing for other polymorphisms is important in that population. AIT is one of the most frequent causes of both severe thrombocytopenia and intracranial hemorrhage (ICH) in fetuses and term neonates. Therefore, testing for this disorder should be performed for any neonate with unexplained thrombocytopenia or a platelet count
of !50,000/mL3, regardless of the presumed cause.9,10 A recent series has demonstrated that one third of neonates with laboratory confirmation of AIT had other medical issues that might have seemed to explain the thrombocytopenia.9 Presentation of the first affected child can range from mild thrombocytopenia detected in a complete blood count that was drawn for reasons unrelated to bleeding to a massive ICH occurring in utero. Ten percent to 20% of infants who are severely affected by AIT have an intracranial bleed, and as many as 75% of those hemorrhages occur before delivery.11 Like Rh alloimmunization, this disorder tends to worsen in subsequent pregnancies and as an affected gestation progresses.6,12,13 Coupled with the unpredictable propensity of severely affected fetuses to suffer ICHs before the onset of labor, these factors provide the rationale for antenatal treatment that is intended to increase the platelet count in utero.
Making the diagnosis The laboratory diagnosis of AIT requires that the father of the affected proband be positive for a platelet alloantigen that is lacking in the mother and to which she has made detectable antibodies. In the most common scenario, the mother has the platelet alloantigen genotype HPA 1b/1b, and the father is either homozygous (HPA 1a/1a) or heterozygous (HPA 1a/1b) for the incompatible allele. Approximately 75% of white men are homozygous for that antigen, and all of their progeny will inherit the gene. In that situation, the couple will always produce HPA 1a/1b children who will be affected by the disorder. If the father is heterozygous for the antigen (ie, HPA 1a/1b), 50% of his sperm will carry the gene for the HPA 1b antigen, and those offspring will have the same genotype as the mother and be unaffected. The other 50% of his children, however, will be HPA 1a/1b and be at risk. Although offspring of homozygous fathers can be assumed to be obligate heterozygotes (HPA-1a/1b), genotypes of the fetuses of heterozygous fathers must be determined by DNA testing. Amniocentesis is preferable to chorionic villus sampling for obtaining fetal tissue for genotyping because of the presumed increased potential of the latter to increase maternal sensitization in cases in which the fetus is affected.14 When the disorder involves parental incompatibility of HPA-1a with maternal sensitization to that antigen, an experienced laboratory can readily provide the diagnosis. However, other cases may result in serologic ambiguity for several reasons. Not all cases of AIT involve sensitization to HPA-1a; many other platelet alloantigens have been implicated in the disorder (Table).15 Reference laboratories vary in the number of additional platelet-specific alloantigens that are
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evaluated, and none of the laboratories routinely test for them all. Moreover, if the AIT is due to the mother’s sensitization to a rare platelet polymorphism present in the father, the mother’s antibody will not be detected by screening her serum against laboratory control platelets that are unlikely to express extremely rare alleles. Testing of maternal serum against the paternal platelets is necessary to detect such rare antibodies. If the father is unavailable, blood from the fetus or a previously affected sibling can be used for this testing. Finally, if testing is performed against whole platelets, other maternal antibodies that are not thought to cause AIT, such as those directed against human leukocyte antigens (HLA) or ABO antigens, may be detected. This, in turn, might obscure reactivity to the more relevant plateletspecific antigens. Because most of the important antigens reside on the platelet glycoprotein complex GPIIb/IIIa, performing a crossmatch test with maternal serum and paternal GPIIb/IIIa is a reasonable strategy for the detection of rare alloantibody specificities. This type of testing, however, cannot detect antibodies directed at rare polymorphisms that may reside on non-GPIIb/IIIa paternal platelet structures. In the Modified Antigen Capture ELISA (MACE) test, maternal serum is incubated with either control platelets of known antigen type or paternal platelets that were isolated from EDTA whole blood. After washing and solubilizing the sensitized platelets, the lysates are added to microtiter wells that are precoated with murine monoclonal antibodies specific for platelet glycoprotein (GP) complexes (eg, IIb/ IIIa, Ia/IIa, etc). Anti-GP antibodies are detected with a standard ELISA procedure. A confusing result occurs when only anti-HLA or ABO antibodies are identified through testing of intact platelet targets. Class I HLA and ABO antigens are expressed on platelets, albeit at lower levels than on white blood cells or red blood cells, respectively. Antibody to these antigens can be detected in platelet antibody tests. This has raised the still unresolved question of whether HLA or ABO incompatibilities ever cause AIT. Families do exist with O1 thrombocytopenic neonate in which only maternal HLA sensitization or ABO antibody reactive with paternal platelets has been identified.
initial platelet counts were not low enough to warrant therapy at the time of the initial sampling were subsequently shown to have platelet counts that fell at a rate of O10,000/mL3 per week, which is consistent with a small number of other reported untreated cases.13 At a mean of 25 weeks of gestation, 41 fetuses had initial platelet counts that were already lower than those measured at birth in a previously affected sibling. The only variable that reliably predicted greater severity of fetal thrombocytopenia in the current pregnancy was a history of antenatal hemorrhage in the affected sibling. In this study, the neonatal platelet count of the previous sibling was not predictive of more severe fetal thrombocytopenia in the current pregnancy, but in a smaller series by Birdsall et al,16 it was. These studies clearly indicate that AIT causes severe thrombocytopenia in utero, its onset may be quite early in gestation, and untreated it will inevitably remain severe or worsen as the pregnancy progresses. Sensitization to the HPA-1a antigen is the most common cause of the disorder and, unfortunately, is responsible for the greatest degree of thrombocytopenia. Finally, the only non-invasive indicator of severe disease in utero is a history of a sibling having had an antenatal ICH in a previous pregnancy.
Natural history
Medical therapy
In a study of 107 fetuses with AIT who underwent fetal blood sampling before receiving any antenatal therapy, 53 (50%) had initial platelet counts of !20,000/mL3, including 21 of 46 fetuses (46%) sampled before 24 weeks of gestation.6 There were 97 cases of HPA-1a incompatibility in this series, and those fetuses had more severe thrombocytopenia than the 10 who were sensitized to other platelet antigens. Seven fetuses whose
In 1984 Daffos et al19 reported the first antenatal treatment of AIT when they transfused a fetus with platelets immediately prior delivery. In the same year our group was confronted with a pregnant woman whose husband was a homozygote for HPA-1a and whose previous fetus had suffered an ICH in utero at 32 weeks of gestation. Antenatal treatment with IVIG and steroids was given to the mother, which led to the birth of a
Antenatal treatment The optimal antenatal management for all cases of AIT has not been defined and remains controversial. Nevertheless, a number of studies have clarified some issues and highlighted others as requiring further study. General approaches that have been used include serial fetal platelet transfusions and the administration of intravenous immunoglobulin (IVIG) and/or steroids to the mother. The following discussion pertains to cases in which a definitive laboratory diagnosis for the disorder has been made, and is almost entirely based on studies of cases of HPA-1a incompatibility. It is important to recognize that other platelet incompatibilities, such as those that involved HPA-3a17 and HPA-4b,18 carry a risk for ICH which is similar to that for HPA1a. However, incompatibility to HPA-5b, another relatively common cause of AIT, appears to cause milder disease.7
910 thrombocytopenic but healthy baby.12 A subsequent study of 18 affected pregnancies suggested that the antenatal administration of IVIG to the mother, with or without supplemental steroids, could increase the fetal platelet count and avoid the recurrence of in utero ICH. However, in that series, it was also learned that IVIG in combination with high-dose dexamethasone could lead to the development of oligohydramnios, and that prednisone combined with IVIG seemed more efficacious than the use of IVIG alone.12,20 These results led to a randomized controlled study of 55 women with AIT in which 70% of the patients had an adequate birth platelet count response to therapy with IVIG 1 gm/kg/wk. The addition of 1.5 mg dexamethasone per day did not improve the outcome; however, for those who did not respond adequately to the IVIG alone, the addition of ‘‘salvage therapy’’ with 60 mg prednisone/day increased the overall satisfactory birth platelet count rate to 80%. The mean fetal platelet counts for the entire study population doubled following approximately 4 weeks of therapy and tripled by the time of birth (34,300 G 26,700/mL3; 68,900 G 56,500/mL3; 100,600 G 81,700/ mL3, respectively). Furthermore, none of the fetuses in this study suffered an ICH, despite the fact that 10 of their siblings had done so in a previous pregnancy.11 Finally, while 93.5% had a significant fetal platelet response to therapy with IVIG 1 gm/kg/wk alone if the initial platelet count was O20,000/mL3, this only occurred in 43.5% if the initial count was !20,000/mL3.11,21 This study indicated that a substantial number of patients with AIT will respond adequately to weekly infusions of IVIG 1 gm/kg and that prednisone 1 mg/kg/d provides additional improvement in at least half of those who do not respond to the IVIG alone. It was also clear that those who were most severely affected, by virtue of having initial fetal platelet counts !20,000/ mL3, were least likely to respond to therapy with IVIG 1 gm/kg/wk alone.21 In addition, there was the suggestion that this combination of therapeutic agents might protect against ICH, even if the neonate was found to have a very low birth platelet count. We have subsequently learned that this latter supposition was incorrect. The next step was to perform a parallel set of randomized studies.22 Seventy-eight patients in 79 pregnancies were stratified to 2 different treatment arms based on the presence or absence of an ICH discovered during the neonatal period in a previously affected sibling, and/or the initial fetal platelet count. Patients whose previously affected infant had suffered an ICH in utero were excluded. Forty women whose previous child had a neonatal (but not antenatal) ICH, or whose current fetus had an initial platelet count of !20,000/mL3, were randomized to receive IVIG 1 gm/kg/wk plus prednisone 1 mg/kg/d or IVIG 1 gm/kg/wk alone following a fetal blood sampling procedure at approximately 20 weeks. A statistically
Berkowitz, Bussel, and McFarland significant difference in mean fetal platelet count increase was noted in these 2 groups over the following 3 to 8 weeks (an increase of 67,100/mL3 vs 17,300/mL3, respectively; P ! .001). Furthermore, in the subgroup of patients with initial fetal platelet counts of !10,000/mL3, the combination therapy satisfactorily increased the fetal platelet count in 82% of cases, as compared with only 18% when IVIG was administered alone. Thirty-nine patients whose prior affected child did not have an ICH and whose current fetus had an initial fetal platelet count of O20,000/mL3 were randomized to receive solo therapy with either IVIG 1 gm/kg/wk or prednisone 0.5 mg/kg/d. Both groups did well, and there were no significant differences noted in the fetal platelet count response to these 2 therapeutic regimens, although it appeared that IVIG might be superior in avoiding the need for salvage therapy later in the pregnancy.22 The authors of the aforementioned randomized trials also empirically treated 3 patients whose prior affected infant had suffered an ICH in utero before 28 weeks of gestation, and 12 patients whose previous fetus had an antepartum ICH between 28 weeks of gestation and delivery. Treatment with IVIG 1 or 2 gm/kg/wk was started at 12 weeks of gestation and was followed by intensified therapy, if necessary, after fetal blood sampling was performed at approximately 20 weeks. All but 1 of these patients had an adequate response to intensified therapy. The only non-responder was a fetus who had an ICH at 19 weeks while receiving IVIG 1 gm/kg/wk plus prednisone 1 mg/kg/d. In all of our series, we have advocated elective cesarean delivery prior to the onset of labor unless the platelet count is known, or thought very likely to be O50,000/mL3 at that time. We currently do not know the minimal fetal platelet count that must be present in this disorder at the time of fetal blood sampling at 32 weeks to be certain that a level in excess of 50,000/ mL3 will be maintained 4 to 6 weeks later.
Platelet transfusion therapy The invasive approach to therapy involves serial intrauterine transfusions of platelets directly into the fetal circulation, which in the past has been used more widely in Europe than in the United States.23,24 Multiple different regimens have been described, but all require frequent transfusions because of the short half-life of circulating platelets. In a series of 84 fetal platelet transfusions performed in 12 pregnancies that were complicated by AIT at a single institution over a 10-year period, Overton et al25 reported procedure related fetal loss rates of 1.2% per transfusion and 8.3% per pregnancy. Pooling these data with those from 139 other reported platelet transfusions in patients with AIT revealed an overall fetal loss rate of 1.3% per procedure and 5.5% per affected pregnancy. Based on their own
Berkowitz, Bussel, and McFarland experience and review of the literature, Overton et al recommended that when severe AIT is managed with serial transfusions, the procedures should be performed weekly and the patient should be delivered electively at approximately 32 weeks, within 24 hours of the final transfusion. The high rate of morbidity and mortality outlined above has resulted in this approach being relegated to ‘‘salvage therapy’’ in most institutions, ie, used only if medical therapy administered to the mother has failed to increase the fetal platelet count.
Fetal blood sampling In 1995 Paidas et al26 reported that patients with AIT undergoing fetal blood sampling prior to receiving any therapy were at increased risk for fetal exsanguination at the time of the procedure. This was demonstrated to be due, at least in part, to the profound fetal thrombocytopenia that may be associated with this disorder. These authors recommended that when fetal blood sampling is performed in patients with AIT, transfusion with maternal-compatible platelets should be administered before extracting the sampling needle in cases where the fetal platelet count is determined to be !50,000/mL3 by a count done while the procedure is in progress. When a fetal platelet count cannot be obtained within 1 to 2 minutes after the sample has been aspirated, some clinicians slowly administer up to 10 mL of previously prepared platelets while awaiting the results of the count. Most studies of medical therapy for AIT that have been performed to date have utilized serial fetal blood sampling procedures to initially assess the severity of fetal thrombocytopenia and then follow the effectiveness of the treatment being administered. There is no question, however, that the performance of this invasive procedure can be associated with increased fetal morbidity and death. In the parallel randomized series of 79 pregnancies cited earlier, there were 11 significant complications following a total of 175 fetal blood sampling procedures (6%), 2 of which led to fetal or neonatal deaths.22 Awareness of the potential for inflicting morbidity with fetal blood sampling has led some practitioners to treat AIT empirically. Although one study has demonstrated that this may be feasible in some cases, there are drawbacks to that approach. It is well established that AIT varies enormously in severity and that fetuses with platelet counts of !20,000/mL3 at %20 weeks are far less likely to respond to therapy with IVIG 1 gm/kg/wk than those fetuses with higher numbers of circulating platelets.22 At least one such fetus has been documented to have had an ICH, despite ongoing maternal treatment with IVIG at that dose. The only reliable clue to the degree of thrombocytopenia in the middle portion of the second trimester is a
911 history of either an antepartum or neonatal ICH that occurred in a sibling from a prior affected pregnancy. Intravenous gamma globulin is very expensive to administer weekly, and both IVIG and, especially prednisone, can cause varying degrees of maternal side effects. We feel, therefore, that it is important to treat each woman with a regimen that is appropriate for her fetusdnot too little or too much. The question, then, is what the safest way to determine how to choose an optimal treatment plan. It is clear that stratification by the history of the previous sibling(s) is critical.
Ongoing trial A multicenter study is currently being performed to more precisely determine optimal therapeutic regimens for the management of 3 different subgroups of women with a history of AIT in a prior pregnancy. Patients in the Very High Risk group have had an infant with an antepartum ICH prior to 28 weeks, and are treated with IVIG 2 gm/kg/wk starting at 12 weeks. Those in the High Risk group have had an infant with an ICH at any time after 28 weeks, and are randomized to receive IVIG 1 gm/kg/wk or 2 gm/kg/wk starting at 12 weeks. Both groups undergo fetal blood sampling at 20 to 24 weeks, and those with a platelet count of !30,000/mL3 either have their dose of IVIG increased to 2 gm/kg/wk, or have prednisone 1 mg/kg/d added to the IVIG therapy if they are already receiving 2 gm/kg/wk. The Standard Risk group has no history of an ICH in any prior affected pregnancies and are randomized to receive IVIG 1 gm/kg/wk plus prednisone 0.5 mg/kg/d or IVIG 2 gm/kg/wk starting as close to 20 weeks as possible. In this group no fetal blood sampling is performed until approximately 32 weeks of gestation at which time therapy is increased to IVIG 2 gm/kg/wk plus prednisone 1 mg/kg/d in any woman whose fetus is found to have a fetal platelet count !30,000/mL3. With this study design, each patient whose previous sibling did not have an antenatal ICH only undergoes one fetal blood sampling procedure, and it is performed at a time in pregnancy when there is the potential to deliver a viable infant by emergency cesarean delivery if fetal distress is encountered. The ultimate objective, of course, is to derive recommendations for the therapy of each subset that does not require any invasive procedures but that allows maximum coverage of every fetus while minimizing the potential for maternal morbidity.
HLA sensitization Women who are delivered of thrombocytopenic neonates are sometimes found to have antibodies that react
912 to class I HLA on their husband’s platelets but not to the platelet-specific antigens (HPA) that are associated with classic AIT. These HLA antibodies are estimated to occur in 10% to 30% of pregnant women, and their role in causing fetal or neonatal thrombocytopenia is unclear. We know of no cases in which these antibodies alone have been thought to be responsible for a fetal or neonatal ICH, and neonatal thrombocytopenia rarely recurs in subsequent pregnancies when these antibodies are present. Nevertheless, there have been recurrent cases of low platelet counts in later pregnancies. While the optimal approach to the management of pregnancies in HLA sensitized women who have had a thrombocytopenic fetus is uncertain, it is important to recognize that these women do not have proven AIT. Our current approach to counseling these patients is to reassure them that they are at extremely low risk to have a serious adverse outcome during future pregnancies and to offer them a choice of management options. We do not empirically treat them with either IVIG or corticosteroids and suggest that they either undergo fetal blood sampling at 32 weeks to determine their fetal platelet count at that time, or simply undergo elective cesarean delivery before the onset of labor. This approach allows us to exclude potentially treatable fetal thrombocytopenia at a time when cesarean delivery for complications from the fetal blood sampling would be expected to result in a viable infant. Alternatively, it avoids the potential for fetal injury during the vaginal delivery of an infant who may have a dangerously low platelet count in patients who do not want to risk potential adverse sequelae from a blood sampling procedure. A third alternative, of course, would be to ignore the laboratory results entirely and to allow these patients to simply deliver vaginally without any invasive testing, but we are currently not confident that this is safe for the fetus in all cases. We also suggest that serial testing be obtained in each trimester throughout the pregnancy for antibodies that are directed at platelet antigens, in order to detect an antibody that might have been missed in the earlier gestation that is now strong enough to be identified because of an anamnestic response. This is particularly true for those women who are known to have 1 or more incompatibilities between their HPA antigens and those of their partners. If a woman with HLA antibodies does develop anti-HPA antibodies to an antigen that is carried on her husband’s platelets during the course of the pregnancy, we would treat her as if she had AIT.
The future We believe that the future direction of research in the management of this potentially devastating disorder should primarily focus on two issues. The first is in the
Berkowitz, Bussel, and McFarland area of screening. The problems underlying a financially acceptable, efficient scheme to identify couples at high risk for AIT are formidable. If this were achievable, however, the ultimate objective for the management of this disorder would be its prevention by the platelet equivalent to Rh-immunoglobulin. At the present time, the vast majority of couples at risk for this disorder are only discovered after they have had an affected pregnancy. It obviously would be much better to identify those patients who have severely thrombocytopenic fetuses before that occurred. Three studies evaluating O100,000 couples for HPA-1a incompatibility have been performed with the intent of initiating management when it was discovered. None of these studies have demonstrated significant fetal and neonatal morbidity and mortality at a frequency that is high enough to mandate a national program.8,27,28 The problem is that the disease is relatively rare, and screening is both technically difficult and expensive. Furthermore, not all couples with HPA incompatibilities are at risk to have affected children. A second area of interest for future work in this disorder is the elimination of all invasive procedures from the treatment schema.29 We have already discussed ongoing efforts to remove fetal blood sampling from therapeutic regimens that are tailored to individual patients by placing them in stratified risk groups, but it would certainly be preferable to have a reliable noninvasive form of monitoring to actually follow fetal platelet counts in response to the therapy being administered. Conceivably this could involve the measurement of substances in maternal serum,30 or some currently unavailable form of imaging technology. Finally, it is reasonable to hope that the antigenicity of fetal platelets can be determined by studies of maternal serum, thereby avoiding amniocentesis for this purpose in pregnancies fathered by heterozygote or absent men.
Comment An enormous amount of progress has been made in the management of AIT over the past 2 decades. It is now clear that this disorder can be effectively treated medically in utero in the vast majority of cases, and this stands as one of the major accomplishments in the relatively new science of fetal therapy. However, much remains to be done. The goal for the immediate future is to provide a rational treatment plan that is appropriate for each individual patient and that neither overtreats nor provides inadequate therapy for any fetus. Invasive procedures for the management of this disorder should be kept to a minimum and ideally eliminated. Work should be done to improve the detection of AIT during the first affected pregnancy rather than after it has already occurred, and ultimately, it is hoped that a form of immunoprophylaxis will be discovered that can
Berkowitz, Bussel, and McFarland prevent sensitization to the platelet antigens that lie at the heart of this potentially devastating fetal disorder.
Acknowledgments We thank Jytte Kjaer and Chris Yurchuk for their assistance in the preparation of the manuscript and Megan Wissert for her critical role in the clinical trials.
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30.
thrombocytopenia using allele-specific oligonucleotide probes. Blood 1991;78:2276-82. Santoso S, Kiefel V. Human platelet alloantigens. Wien Klin Wochenschr 2001;113:806-13. Birchall JE, Murphy MF, Kaplan C, Kroll Hfor the European Fetomaternal Alloimmune Thrombocytopenia Study group. European collaborative study of the antenatal management of feto-maternal alloimmune thrombocytopenia. Br J Haematol 2003;122:275-88. Glade-Bender J, McFarland JG, Kaplan C, Porcelijn L, Bussel JB. Anti-HPA-3A induces severe neonatal alloimmune thrombocytopenia. J Pediatr 2001;138:862-7. Friedman JM, Aster RH. Neonatal alloimmune thrombocytopenic purpura and congenital porencephaly in two siblings associated with a ‘‘new’’ maternal antiplatelet antibody. Blood 1985;65: 1412-5. Daffos F, Forestier F, Muller JY, Reznikoff-Etievant M, Habibi B, Capella-Pavlovsky M, et al. Prenatal treatment of alloimmune thrombocytopenia. Lancet 1984;2:632. Lynch L, Bussel JB, McFarland JG, Chitkara U, Berkowitz RL. Antenatal treatment of alloimmune thrombocytopenia. Obstet Gynecol 1992;80:67-71. Gaddipati S, Berkowitz RL, Lembet AA, Lapinski R, McFarland JG, Bussel JB. Initial fetal platelet counts predict the response to intravenous gamma globulin therapy in fetuses that are affected by PLA1 incompatibility. Am J Obstet Gynecol 2001;185: 976-80. Berkowitz RL, Kolb EA, McFarland JG, Wissert M, Primani A, Lesser M, et al. Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia. Obstet Gynecol 2006; 107:91-6. Kroll H, Kiefel V, Giers G, Bald R, Hoch J, Hanfland P, et al. Maternal intravenous immunoglobulin treatment does not prevent intracranial haemorrhage in fetal alloimmune thrombocytopenia. Transfus Med 1994;4:293-6. Murphy MF, Pullon HWH, Metcalfe P, Chapman JF, Jenkins E, Waters AH, et al. Management of fetal alloimmune thrombocytopenia by weekly in utero platelet transfusions. Vox Sanguinis 1990; 58:45-9. Overton TG, Duncan KR, Jolly M, Letsky E, Fisk NM. Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: platelet dynamics and perinatal outcome. Am J Obstet Gynecol 2002;186:826-31. Paidas MJ, Berkowitz RL, Lynch L, Lockwood CJ, Lapinski R, McFarland JG, et al. Alloimmune thrombocytopenia: fetal and neonatal losses related to cordocentesis. Am J Obstet Gynecol 1995; 172:475-9. Turner ML, Bessos H, Fagge T, Harkness M, Rentoul F, Seymour J, et al. Prospective epidemiologic study of the outcome and costeffectiveness of antenatal screening to detect neonatal alloimmune thrombocytopenia due to anti-HPA-1a. Transfusion 2005;45: 1945-56. Kjeldsen-Kraghl J, Killie MK, Aune B, Oian P, Dahl L, Pirhonen J, et al. An intervention program for reducing morbidity and mortality associated with neonatal alloimmune thrombocytopenic purpura. 8th European Symposium on Platelet Granulocyte Immunobiology, Rust, 2004. Radder CM, Brand A, Kanhai HH. A less invasive treatment strategy to prevent intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia. Am J Obstet Gynecol 2001;185: 683-8. Bertrand G, Martageix C, Jallu V, Vitry F, Kaplan C. Predictive value of sequential maternal anti-HPA-1a antibody concentrations for the severity of fetal alloimmune thrombocytopenia. J Thromb Haemostasis 2006;4:628-37.
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REVIEW ARTICLES
Alloimmune thrombocytopenia: State of the art 2006 Richard L. Berkowitz, MD,a,* James B. Bussel, MD,b Janice G. McFarland, MDc Department of Obstetrics and Gynecology, Columbia Presbyterian Medical Center a; Department of Pediatrics, Division of Hematology-Oncology, Weill Medical College of Cornell University,b New York, NY; and the BloodCenter of Wisconsin,c Milwaukee, WI Received for publication March 28, 2006; revised April 26, 2006; accepted May 4, 2006
KEY WORDS Antibody Platelets Intracranial hemorrhage Antepartum fetal hemorrhage
In alloimmune thrombocytopenia maternal immunoglobulin G anti-platelet alloantibodies cross the placenta and cause fetal thrombocytopenia. The diagnosis requires laboratory demonstration of incompatibility between a maternal and paternal platelet alloantigen, and detection of maternal antibody to the discordant paternal alloantigen. This disorder should be treated in utero because of its propensity to cause fetal intracranial bleeding. Administration of intravenous immunoglobulin 1 gm/kg/wk to the mother is successful in substantially raising the platelet count in many fetuses, but this is most successful if the count is O20,000/mL3 at the time that the therapy is initiated. The addition of prednisone administered daily to the mother and/or increasing the dose of intravenous immunoglobulin has a therapeutic benefit in cases that have failed to respond to initial therapy with intravenous immunoglobulin alone. The only reliable noninvasive indicator of the potential for severe fetal thrombocytopenia is a history of an antenatal intracranial hemorrhage in a prior affected sibling. Because fetal blood sampling to determine the fetal platelet count may be associated with significant fetal morbidity, attempts are being made to derive a rational, non-invasive, stratified approach to patient-specific therapy of this disorder in affected pregnancies. Ó 2006 Mosby, Inc. All rights reserved.
In alloimmune thrombocytopenia (AIT) maternal immunoglobulin G (IgG) alloantibodies to major platelet antigens cross the placenta and bind to fetal platelets.1-4 * Reprint requests: Richard L. Berkowitz, MD, Department of Obstetrics and Gynecology, Columbia Presbyterian Medical Center, 622 West 168th St, PH 16-66, New York, NY 10032. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2006.05.001
The antibody-coated platelets are subsequently removed from the fetal circulation by the reticuloendothelial system, which results in fetal thrombocytopenia. These same antibodies also may inhibit platelet production. The disorder can be considered the platelet equivalent of Rh alloimmunization, where the offending antigen is located on red cells and which results in fetal anemia by the same mechanism.5 Because screening for sensitization
908 Table AIT
Berkowitz, Bussel, and McFarland Platelet-specific alloantigens that are associated with
HPA system name
Antigen
Familiar name
Polymorphisms of glycoprotein IIIa HPA-1 HPA-1a HPA-1b HPA-4 HPA-4a HPA-4b HPA-6 HPA-6bw HPA-7 HPA-7bw HPA-8 HPA-8bw HPA-10 HPA-10bw HPA-11 HPA-11bw HPA-14 HPA-14bw HPA-16 HPA-16bw
P1A1, Zwa P1A2, Zwb Pena, Yukb Penb, Yuka Ca, Tu Mo Sr-a La(a) Gro(a) Oe(a) Duv(a)
Polymorphisms of glycoprotein IIb HPA-3 HPA-3a HPA-3b HPA-9 HPA-9bw
Baka, Lek Bakb Maxa
Polymorphisms of glycoprotein Ia HPA-5 HPA-5a HPA-5b HPA-13 HPA-13bw
Brb, Zavb Bra, Zava Sit(a)
Polymorphisms of glycoprotein Ib HPA-2 HPA-2b HPA-12 HPA-12bw
Koa, Sib-a Ly(a)
Other probable platelet alloantigen specificities HPA-15 HPA-15a Gov a HPA-15b Gov-b Modified from Mark E. Brecher, editor. Platelet and granulocyte antigens and antibodies in Technical Manual. 15th ed. Bethesda (MD): American Association of Blood Banks; 2005. p. 367-8.
to platelet antigens is rarely performed, couples are usually not known to be at risk for the disorder until they have delivered an affected child. Unlike Rh sensitization, AIT can be very severe in the first affected pregnancy. Sensitization to O15 platelet antigens can be associated with fetal/neonatal thrombocytopenia, but sensitization to the HPA-1a antigen is by far the most common cause of severe alloimmune thrombocytopenia and results in the most significant sequelae.6,7 The incidence of this disorder varies by ethnicity, with rates among the white population in Europe and North America estimated to be between 0.2 and 1 per thousand.8 The African-American population appears to have a lower incidence of the disease, and, since the HPA-1a/1b polymorphism is rarely seen in Asian people, testing for other polymorphisms is important in that population. AIT is one of the most frequent causes of both severe thrombocytopenia and intracranial hemorrhage (ICH) in fetuses and term neonates. Therefore, testing for this disorder should be performed for any neonate with unexplained thrombocytopenia or a platelet count
of !50,000/mL3, regardless of the presumed cause.9,10 A recent series has demonstrated that one third of neonates with laboratory confirmation of AIT had other medical issues that might have seemed to explain the thrombocytopenia.9 Presentation of the first affected child can range from mild thrombocytopenia detected in a complete blood count that was drawn for reasons unrelated to bleeding to a massive ICH occurring in utero. Ten percent to 20% of infants who are severely affected by AIT have an intracranial bleed, and as many as 75% of those hemorrhages occur before delivery.11 Like Rh alloimmunization, this disorder tends to worsen in subsequent pregnancies and as an affected gestation progresses.6,12,13 Coupled with the unpredictable propensity of severely affected fetuses to suffer ICHs before the onset of labor, these factors provide the rationale for antenatal treatment that is intended to increase the platelet count in utero.
Making the diagnosis The laboratory diagnosis of AIT requires that the father of the affected proband be positive for a platelet alloantigen that is lacking in the mother and to which she has made detectable antibodies. In the most common scenario, the mother has the platelet alloantigen genotype HPA 1b/1b, and the father is either homozygous (HPA 1a/1a) or heterozygous (HPA 1a/1b) for the incompatible allele. Approximately 75% of white men are homozygous for that antigen, and all of their progeny will inherit the gene. In that situation, the couple will always produce HPA 1a/1b children who will be affected by the disorder. If the father is heterozygous for the antigen (ie, HPA 1a/1b), 50% of his sperm will carry the gene for the HPA 1b antigen, and those offspring will have the same genotype as the mother and be unaffected. The other 50% of his children, however, will be HPA 1a/1b and be at risk. Although offspring of homozygous fathers can be assumed to be obligate heterozygotes (HPA-1a/1b), genotypes of the fetuses of heterozygous fathers must be determined by DNA testing. Amniocentesis is preferable to chorionic villus sampling for obtaining fetal tissue for genotyping because of the presumed increased potential of the latter to increase maternal sensitization in cases in which the fetus is affected.14 When the disorder involves parental incompatibility of HPA-1a with maternal sensitization to that antigen, an experienced laboratory can readily provide the diagnosis. However, other cases may result in serologic ambiguity for several reasons. Not all cases of AIT involve sensitization to HPA-1a; many other platelet alloantigens have been implicated in the disorder (Table).15 Reference laboratories vary in the number of additional platelet-specific alloantigens that are
Berkowitz, Bussel, and McFarland
909
evaluated, and none of the laboratories routinely test for them all. Moreover, if the AIT is due to the mother’s sensitization to a rare platelet polymorphism present in the father, the mother’s antibody will not be detected by screening her serum against laboratory control platelets that are unlikely to express extremely rare alleles. Testing of maternal serum against the paternal platelets is necessary to detect such rare antibodies. If the father is unavailable, blood from the fetus or a previously affected sibling can be used for this testing. Finally, if testing is performed against whole platelets, other maternal antibodies that are not thought to cause AIT, such as those directed against human leukocyte antigens (HLA) or ABO antigens, may be detected. This, in turn, might obscure reactivity to the more relevant plateletspecific antigens. Because most of the important antigens reside on the platelet glycoprotein complex GPIIb/IIIa, performing a crossmatch test with maternal serum and paternal GPIIb/IIIa is a reasonable strategy for the detection of rare alloantibody specificities. This type of testing, however, cannot detect antibodies directed at rare polymorphisms that may reside on non-GPIIb/IIIa paternal platelet structures. In the Modified Antigen Capture ELISA (MACE) test, maternal serum is incubated with either control platelets of known antigen type or paternal platelets that were isolated from EDTA whole blood. After washing and solubilizing the sensitized platelets, the lysates are added to microtiter wells that are precoated with murine monoclonal antibodies specific for platelet glycoprotein (GP) complexes (eg, IIb/ IIIa, Ia/IIa, etc). Anti-GP antibodies are detected with a standard ELISA procedure. A confusing result occurs when only anti-HLA or ABO antibodies are identified through testing of intact platelet targets. Class I HLA and ABO antigens are expressed on platelets, albeit at lower levels than on white blood cells or red blood cells, respectively. Antibody to these antigens can be detected in platelet antibody tests. This has raised the still unresolved question of whether HLA or ABO incompatibilities ever cause AIT. Families do exist with O1 thrombocytopenic neonate in which only maternal HLA sensitization or ABO antibody reactive with paternal platelets has been identified.
initial platelet counts were not low enough to warrant therapy at the time of the initial sampling were subsequently shown to have platelet counts that fell at a rate of O10,000/mL3 per week, which is consistent with a small number of other reported untreated cases.13 At a mean of 25 weeks of gestation, 41 fetuses had initial platelet counts that were already lower than those measured at birth in a previously affected sibling. The only variable that reliably predicted greater severity of fetal thrombocytopenia in the current pregnancy was a history of antenatal hemorrhage in the affected sibling. In this study, the neonatal platelet count of the previous sibling was not predictive of more severe fetal thrombocytopenia in the current pregnancy, but in a smaller series by Birdsall et al,16 it was. These studies clearly indicate that AIT causes severe thrombocytopenia in utero, its onset may be quite early in gestation, and untreated it will inevitably remain severe or worsen as the pregnancy progresses. Sensitization to the HPA-1a antigen is the most common cause of the disorder and, unfortunately, is responsible for the greatest degree of thrombocytopenia. Finally, the only non-invasive indicator of severe disease in utero is a history of a sibling having had an antenatal ICH in a previous pregnancy.
Natural history
Medical therapy
In a study of 107 fetuses with AIT who underwent fetal blood sampling before receiving any antenatal therapy, 53 (50%) had initial platelet counts of !20,000/mL3, including 21 of 46 fetuses (46%) sampled before 24 weeks of gestation.6 There were 97 cases of HPA-1a incompatibility in this series, and those fetuses had more severe thrombocytopenia than the 10 who were sensitized to other platelet antigens. Seven fetuses whose
In 1984 Daffos et al19 reported the first antenatal treatment of AIT when they transfused a fetus with platelets immediately prior delivery. In the same year our group was confronted with a pregnant woman whose husband was a homozygote for HPA-1a and whose previous fetus had suffered an ICH in utero at 32 weeks of gestation. Antenatal treatment with IVIG and steroids was given to the mother, which led to the birth of a
Antenatal treatment The optimal antenatal management for all cases of AIT has not been defined and remains controversial. Nevertheless, a number of studies have clarified some issues and highlighted others as requiring further study. General approaches that have been used include serial fetal platelet transfusions and the administration of intravenous immunoglobulin (IVIG) and/or steroids to the mother. The following discussion pertains to cases in which a definitive laboratory diagnosis for the disorder has been made, and is almost entirely based on studies of cases of HPA-1a incompatibility. It is important to recognize that other platelet incompatibilities, such as those that involved HPA-3a17 and HPA-4b,18 carry a risk for ICH which is similar to that for HPA1a. However, incompatibility to HPA-5b, another relatively common cause of AIT, appears to cause milder disease.7
910 thrombocytopenic but healthy baby.12 A subsequent study of 18 affected pregnancies suggested that the antenatal administration of IVIG to the mother, with or without supplemental steroids, could increase the fetal platelet count and avoid the recurrence of in utero ICH. However, in that series, it was also learned that IVIG in combination with high-dose dexamethasone could lead to the development of oligohydramnios, and that prednisone combined with IVIG seemed more efficacious than the use of IVIG alone.12,20 These results led to a randomized controlled study of 55 women with AIT in which 70% of the patients had an adequate birth platelet count response to therapy with IVIG 1 gm/kg/wk. The addition of 1.5 mg dexamethasone per day did not improve the outcome; however, for those who did not respond adequately to the IVIG alone, the addition of ‘‘salvage therapy’’ with 60 mg prednisone/day increased the overall satisfactory birth platelet count rate to 80%. The mean fetal platelet counts for the entire study population doubled following approximately 4 weeks of therapy and tripled by the time of birth (34,300 G 26,700/mL3; 68,900 G 56,500/mL3; 100,600 G 81,700/ mL3, respectively). Furthermore, none of the fetuses in this study suffered an ICH, despite the fact that 10 of their siblings had done so in a previous pregnancy.11 Finally, while 93.5% had a significant fetal platelet response to therapy with IVIG 1 gm/kg/wk alone if the initial platelet count was O20,000/mL3, this only occurred in 43.5% if the initial count was !20,000/mL3.11,21 This study indicated that a substantial number of patients with AIT will respond adequately to weekly infusions of IVIG 1 gm/kg and that prednisone 1 mg/kg/d provides additional improvement in at least half of those who do not respond to the IVIG alone. It was also clear that those who were most severely affected, by virtue of having initial fetal platelet counts !20,000/ mL3, were least likely to respond to therapy with IVIG 1 gm/kg/wk alone.21 In addition, there was the suggestion that this combination of therapeutic agents might protect against ICH, even if the neonate was found to have a very low birth platelet count. We have subsequently learned that this latter supposition was incorrect. The next step was to perform a parallel set of randomized studies.22 Seventy-eight patients in 79 pregnancies were stratified to 2 different treatment arms based on the presence or absence of an ICH discovered during the neonatal period in a previously affected sibling, and/or the initial fetal platelet count. Patients whose previously affected infant had suffered an ICH in utero were excluded. Forty women whose previous child had a neonatal (but not antenatal) ICH, or whose current fetus had an initial platelet count of !20,000/mL3, were randomized to receive IVIG 1 gm/kg/wk plus prednisone 1 mg/kg/d or IVIG 1 gm/kg/wk alone following a fetal blood sampling procedure at approximately 20 weeks. A statistically
Berkowitz, Bussel, and McFarland significant difference in mean fetal platelet count increase was noted in these 2 groups over the following 3 to 8 weeks (an increase of 67,100/mL3 vs 17,300/mL3, respectively; P ! .001). Furthermore, in the subgroup of patients with initial fetal platelet counts of !10,000/mL3, the combination therapy satisfactorily increased the fetal platelet count in 82% of cases, as compared with only 18% when IVIG was administered alone. Thirty-nine patients whose prior affected child did not have an ICH and whose current fetus had an initial fetal platelet count of O20,000/mL3 were randomized to receive solo therapy with either IVIG 1 gm/kg/wk or prednisone 0.5 mg/kg/d. Both groups did well, and there were no significant differences noted in the fetal platelet count response to these 2 therapeutic regimens, although it appeared that IVIG might be superior in avoiding the need for salvage therapy later in the pregnancy.22 The authors of the aforementioned randomized trials also empirically treated 3 patients whose prior affected infant had suffered an ICH in utero before 28 weeks of gestation, and 12 patients whose previous fetus had an antepartum ICH between 28 weeks of gestation and delivery. Treatment with IVIG 1 or 2 gm/kg/wk was started at 12 weeks of gestation and was followed by intensified therapy, if necessary, after fetal blood sampling was performed at approximately 20 weeks. All but 1 of these patients had an adequate response to intensified therapy. The only non-responder was a fetus who had an ICH at 19 weeks while receiving IVIG 1 gm/kg/wk plus prednisone 1 mg/kg/d. In all of our series, we have advocated elective cesarean delivery prior to the onset of labor unless the platelet count is known, or thought very likely to be O50,000/mL3 at that time. We currently do not know the minimal fetal platelet count that must be present in this disorder at the time of fetal blood sampling at 32 weeks to be certain that a level in excess of 50,000/ mL3 will be maintained 4 to 6 weeks later.
Platelet transfusion therapy The invasive approach to therapy involves serial intrauterine transfusions of platelets directly into the fetal circulation, which in the past has been used more widely in Europe than in the United States.23,24 Multiple different regimens have been described, but all require frequent transfusions because of the short half-life of circulating platelets. In a series of 84 fetal platelet transfusions performed in 12 pregnancies that were complicated by AIT at a single institution over a 10-year period, Overton et al25 reported procedure related fetal loss rates of 1.2% per transfusion and 8.3% per pregnancy. Pooling these data with those from 139 other reported platelet transfusions in patients with AIT revealed an overall fetal loss rate of 1.3% per procedure and 5.5% per affected pregnancy. Based on their own
Berkowitz, Bussel, and McFarland experience and review of the literature, Overton et al recommended that when severe AIT is managed with serial transfusions, the procedures should be performed weekly and the patient should be delivered electively at approximately 32 weeks, within 24 hours of the final transfusion. The high rate of morbidity and mortality outlined above has resulted in this approach being relegated to ‘‘salvage therapy’’ in most institutions, ie, used only if medical therapy administered to the mother has failed to increase the fetal platelet count.
Fetal blood sampling In 1995 Paidas et al26 reported that patients with AIT undergoing fetal blood sampling prior to receiving any therapy were at increased risk for fetal exsanguination at the time of the procedure. This was demonstrated to be due, at least in part, to the profound fetal thrombocytopenia that may be associated with this disorder. These authors recommended that when fetal blood sampling is performed in patients with AIT, transfusion with maternal-compatible platelets should be administered before extracting the sampling needle in cases where the fetal platelet count is determined to be !50,000/mL3 by a count done while the procedure is in progress. When a fetal platelet count cannot be obtained within 1 to 2 minutes after the sample has been aspirated, some clinicians slowly administer up to 10 mL of previously prepared platelets while awaiting the results of the count. Most studies of medical therapy for AIT that have been performed to date have utilized serial fetal blood sampling procedures to initially assess the severity of fetal thrombocytopenia and then follow the effectiveness of the treatment being administered. There is no question, however, that the performance of this invasive procedure can be associated with increased fetal morbidity and death. In the parallel randomized series of 79 pregnancies cited earlier, there were 11 significant complications following a total of 175 fetal blood sampling procedures (6%), 2 of which led to fetal or neonatal deaths.22 Awareness of the potential for inflicting morbidity with fetal blood sampling has led some practitioners to treat AIT empirically. Although one study has demonstrated that this may be feasible in some cases, there are drawbacks to that approach. It is well established that AIT varies enormously in severity and that fetuses with platelet counts of !20,000/mL3 at %20 weeks are far less likely to respond to therapy with IVIG 1 gm/kg/wk than those fetuses with higher numbers of circulating platelets.22 At least one such fetus has been documented to have had an ICH, despite ongoing maternal treatment with IVIG at that dose. The only reliable clue to the degree of thrombocytopenia in the middle portion of the second trimester is a
911 history of either an antepartum or neonatal ICH that occurred in a sibling from a prior affected pregnancy. Intravenous gamma globulin is very expensive to administer weekly, and both IVIG and, especially prednisone, can cause varying degrees of maternal side effects. We feel, therefore, that it is important to treat each woman with a regimen that is appropriate for her fetusdnot too little or too much. The question, then, is what the safest way to determine how to choose an optimal treatment plan. It is clear that stratification by the history of the previous sibling(s) is critical.
Ongoing trial A multicenter study is currently being performed to more precisely determine optimal therapeutic regimens for the management of 3 different subgroups of women with a history of AIT in a prior pregnancy. Patients in the Very High Risk group have had an infant with an antepartum ICH prior to 28 weeks, and are treated with IVIG 2 gm/kg/wk starting at 12 weeks. Those in the High Risk group have had an infant with an ICH at any time after 28 weeks, and are randomized to receive IVIG 1 gm/kg/wk or 2 gm/kg/wk starting at 12 weeks. Both groups undergo fetal blood sampling at 20 to 24 weeks, and those with a platelet count of !30,000/mL3 either have their dose of IVIG increased to 2 gm/kg/wk, or have prednisone 1 mg/kg/d added to the IVIG therapy if they are already receiving 2 gm/kg/wk. The Standard Risk group has no history of an ICH in any prior affected pregnancies and are randomized to receive IVIG 1 gm/kg/wk plus prednisone 0.5 mg/kg/d or IVIG 2 gm/kg/wk starting as close to 20 weeks as possible. In this group no fetal blood sampling is performed until approximately 32 weeks of gestation at which time therapy is increased to IVIG 2 gm/kg/wk plus prednisone 1 mg/kg/d in any woman whose fetus is found to have a fetal platelet count !30,000/mL3. With this study design, each patient whose previous sibling did not have an antenatal ICH only undergoes one fetal blood sampling procedure, and it is performed at a time in pregnancy when there is the potential to deliver a viable infant by emergency cesarean delivery if fetal distress is encountered. The ultimate objective, of course, is to derive recommendations for the therapy of each subset that does not require any invasive procedures but that allows maximum coverage of every fetus while minimizing the potential for maternal morbidity.
HLA sensitization Women who are delivered of thrombocytopenic neonates are sometimes found to have antibodies that react
912 to class I HLA on their husband’s platelets but not to the platelet-specific antigens (HPA) that are associated with classic AIT. These HLA antibodies are estimated to occur in 10% to 30% of pregnant women, and their role in causing fetal or neonatal thrombocytopenia is unclear. We know of no cases in which these antibodies alone have been thought to be responsible for a fetal or neonatal ICH, and neonatal thrombocytopenia rarely recurs in subsequent pregnancies when these antibodies are present. Nevertheless, there have been recurrent cases of low platelet counts in later pregnancies. While the optimal approach to the management of pregnancies in HLA sensitized women who have had a thrombocytopenic fetus is uncertain, it is important to recognize that these women do not have proven AIT. Our current approach to counseling these patients is to reassure them that they are at extremely low risk to have a serious adverse outcome during future pregnancies and to offer them a choice of management options. We do not empirically treat them with either IVIG or corticosteroids and suggest that they either undergo fetal blood sampling at 32 weeks to determine their fetal platelet count at that time, or simply undergo elective cesarean delivery before the onset of labor. This approach allows us to exclude potentially treatable fetal thrombocytopenia at a time when cesarean delivery for complications from the fetal blood sampling would be expected to result in a viable infant. Alternatively, it avoids the potential for fetal injury during the vaginal delivery of an infant who may have a dangerously low platelet count in patients who do not want to risk potential adverse sequelae from a blood sampling procedure. A third alternative, of course, would be to ignore the laboratory results entirely and to allow these patients to simply deliver vaginally without any invasive testing, but we are currently not confident that this is safe for the fetus in all cases. We also suggest that serial testing be obtained in each trimester throughout the pregnancy for antibodies that are directed at platelet antigens, in order to detect an antibody that might have been missed in the earlier gestation that is now strong enough to be identified because of an anamnestic response. This is particularly true for those women who are known to have 1 or more incompatibilities between their HPA antigens and those of their partners. If a woman with HLA antibodies does develop anti-HPA antibodies to an antigen that is carried on her husband’s platelets during the course of the pregnancy, we would treat her as if she had AIT.
The future We believe that the future direction of research in the management of this potentially devastating disorder should primarily focus on two issues. The first is in the
Berkowitz, Bussel, and McFarland area of screening. The problems underlying a financially acceptable, efficient scheme to identify couples at high risk for AIT are formidable. If this were achievable, however, the ultimate objective for the management of this disorder would be its prevention by the platelet equivalent to Rh-immunoglobulin. At the present time, the vast majority of couples at risk for this disorder are only discovered after they have had an affected pregnancy. It obviously would be much better to identify those patients who have severely thrombocytopenic fetuses before that occurred. Three studies evaluating O100,000 couples for HPA-1a incompatibility have been performed with the intent of initiating management when it was discovered. None of these studies have demonstrated significant fetal and neonatal morbidity and mortality at a frequency that is high enough to mandate a national program.8,27,28 The problem is that the disease is relatively rare, and screening is both technically difficult and expensive. Furthermore, not all couples with HPA incompatibilities are at risk to have affected children. A second area of interest for future work in this disorder is the elimination of all invasive procedures from the treatment schema.29 We have already discussed ongoing efforts to remove fetal blood sampling from therapeutic regimens that are tailored to individual patients by placing them in stratified risk groups, but it would certainly be preferable to have a reliable noninvasive form of monitoring to actually follow fetal platelet counts in response to the therapy being administered. Conceivably this could involve the measurement of substances in maternal serum,30 or some currently unavailable form of imaging technology. Finally, it is reasonable to hope that the antigenicity of fetal platelets can be determined by studies of maternal serum, thereby avoiding amniocentesis for this purpose in pregnancies fathered by heterozygote or absent men.
Comment An enormous amount of progress has been made in the management of AIT over the past 2 decades. It is now clear that this disorder can be effectively treated medically in utero in the vast majority of cases, and this stands as one of the major accomplishments in the relatively new science of fetal therapy. However, much remains to be done. The goal for the immediate future is to provide a rational treatment plan that is appropriate for each individual patient and that neither overtreats nor provides inadequate therapy for any fetus. Invasive procedures for the management of this disorder should be kept to a minimum and ideally eliminated. Work should be done to improve the detection of AIT during the first affected pregnancy rather than after it has already occurred, and ultimately, it is hoped that a form of immunoprophylaxis will be discovered that can
Berkowitz, Bussel, and McFarland prevent sensitization to the platelet antigens that lie at the heart of this potentially devastating fetal disorder.
Acknowledgments We thank Jytte Kjaer and Chris Yurchuk for their assistance in the preparation of the manuscript and Megan Wissert for her critical role in the clinical trials.
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