ReviewFetal and neonatal alloimmune thrombocytopenia: progress and ongoing debates
Introduction
Fetal and neonatal alloimmune thrombocytopenia (AIT) is the most common cause of severe thrombocytopenia in fetuses and neonates.1 Maternal IgG alloantibodies against paternally derived fetal platelet antigens cross the placenta beginning early in pregnancy and commonly result in severe thrombocytopenia. While the reported incidence varies somewhat with the assigned threshold of thrombocytopenia (50, 100, or 150 × 109/L), in most unselected populations AIT affects 1 in 1000 to 1 in 2000 live births. Severe AIT, however, of the type clinically diagnosed in the newborn nursery is rarer and may only be recognized in 1:10,000 deliveries. Table 1 reports recent studies of AIT in systematically screened, unselected populations, including the Norwegian report of more than 100,000 births2 and one from Scotland of more than 25,000 births.3 At one end of the spectrum, in its most severe form, AIT has the potential for significant morbidity including fetal intracranial hemorrhage (ICH) and in utero death. At the mildest end of the spectrum, a CBC is obtained for another indication or in a screening study (not because of any suspicion of thrombocytopenia or bleeding) and a mild to moderate thrombocytopenia is identified. While there has been considerable progress made in the diagnosis, characterization, and treatment of fetuses and neonates with AIT, strategies for early detection and intervention remain controversial and additional studies are required.
Section snippets
Pathogenesis
There are three requisite components of the pathogenesis of AIT. There must be 1) an incompatibility between maternal and fetal “platelet-specific” antigens (the fetal antigen mismatch is inherited from the father), 2) alloimmunization, a maternal humoral antibody response specific to these “foreign” fetal platelet antigens, and 3) maternal anti-platelet IgG alloantibodies that cross the placenta, bind to fetal platelet antigens, and cause fetal platelet destruction with resultant
Human platelet-specific antigens
Platelets share several antigen systems with other cell types, including the HLA class I antigens, the ABO blood group antigens,4, 5 and even certain VLA antigens, i.e. HPA-5. However, except for the latter, these antigen systems are rarely, if ever, implicated in AIT. AIT secondary to an HLA antigen mismatch remains unproven and controversial.6, 7, 8, 9, 10 Cases of even recurrent transient neonatal thrombocytopenia exist in which only maternal anti-HLA class I antibodies are identified and no
Alloimmunization
AIT has been reported with alloimmunization to numerous platelet antigens (Table 3 and 4). In all large series describing Caucasians, HPA-1a is the most common incompatibility resulting in AIT.15, 16, 17, 18, 19, 20, 21, 22, 23 Newer studies suggest that HPA-5b incompatibility may be relatively common as well, but this is mitigated by the fact that severe thrombocytopenia after HPA-5b alloimmunization is rare.24, 25, 26, 27 Of note, the identification of a new HPA is typically initiated by the
Allo-antibody mediated thrombocytopenia
Maternal alloimmunization to fetal platelet antigens is usually sufficient to result in AIT. However, there are a number of cases of maternal anti-platelet alloantibodies detected in infants with normal platelet counts.21, 25, 44, 45, 59 Maternal alloimmunization without neonatal thrombocytopenia may be as high as 32%. In addition to maternal HLA MHC class II modulation of alloimmunization, there appears to be another regulatory step in AIT. The process of antibody-mediated platelet destruction
Clinical presentation
In general, the clinical presentation begins when a thrombocytopenic neonate is identified in the nursery and serologic testing demonstrates the presence of AIT. The mother or her sister then becomes pregnant with an affected fetus and management of this fetus is instituted based on the estimated risk. Whether and how the clinical presentation will change if screening is instituted remains to be determined.
Fortunately, it is rare that the presentation of the first affected fetus is a result of
Intracranial hemorrhage
The frequency of hemorrhagic symptoms in AIT, including ICH, is likely overestimated in clinical studies not based on population screening; a substantial proportion of patients with AIT either will not have severe thrombocytopenia or will have less severe hemorrhagic events and go undetected. For those patients with clinically significant disease or with neonatal platelet counts less than 100 × 109/L, the incidence of minor hemorrhagic diatheses (petechiae, ecchymoses, or hematomas) is as high as
Predictors of disease
A goal of many recent screening protocols has been to define prognostic factors that may identify those patients at risk for ICH.21, 22, 90, 91 As discussed above, the presence of maternal alloantibody does not clearly predict the degree of thrombocytopenia. However, recent studies have suggested that high (greater that 1:32) third trimester maternal antibody titer21, 22 and high titers of the IgG3 subclass91 may predict severe thrombocytopenia; this remains to be confirmed in other
Diagnosis
The confirmatory diagnosis of AIT in a severely thrombocytopenic infant or fetus requires several laboratory observations. There must be HPA incompatibility between mother and child; often the father’s testing serves as a surrogate for that of the fetus. The identification of maternal anti-platelet alloantibodies is key. Furthermore, these antibodies must bind to paternal, but not maternal, platelets and be specific using appropriate controls to the antigen incompatibility in question.
Antigen testing
Very few laboratories can do DNA-based and serologic testing for both the most frequently and the infrequently encountered HPA antigens. With the development of oligonucleotide probes and the refinement of PCR techniques, platelet antigen typing can routinely be obtained on amniocytes and fetal leukocytes.92, 93, 94 Techniques are also available for platelet antigen genotyping from dried blood spots on cards to aid in rapid perinatal diagnosis.95
Recently, several ELISA-based96, 97 and
Alloantibody testing
In 1987, Kiefel et al.99 reported accurate alloantibody detection with an enzyme immunoassay, the monoclonal antibody immobilization of platelet glycoprotein assay (MAIPA). The MAIPA and similar techniques that focus on recognition antibody to specific platelet glycoproteins allow identification and quantification of glycoprotein-specific alloantibodies.99, 100, 101 These antigen-capture assays can be utilized during pregnancy to monitor antibody levels and have been adapted for large scale
Who to test
We believe that all infants with platelet counts less than 50 × 109/L should be tested for AIT and managed accordingly. Even in patients with mild thrombocytopenia, it is important to identify those with AIT, because of the implication for subsequent offspring, who may be more severely affected and also family members. In general, any thrombocytopenic infant irrespective of the platelet count without an explanation for thrombocytopenia, e.g. without evidence of asphyxia or sepsis or another from
Screening programs
Currently, there is no consensus on the need for routine prenatal, maternal platelet antigen phenotyping or on routinely obtaining neonatal platelet counts. The financial and technical burden of screening for all maternal platelet antigens would certainly exceed the resources of any large-scale screening program. Testing would have to be based on the ethnic distribution of the most likely antigen incompatibilities and the severity of the associated thrombocytopenia. For most populations, this
Management
The goal of the management of AIT is to prevent antenatal or perinatal ICH and the associated neurologic sequelae or mortality. Furthermore, there is a very preliminary suggestion that non-thrombocytopenic fetuses may do better postnatally.106 For those patients diagnosed in the newborn period, prompt diagnosis and treatment is necessary to restore normal hemostasis. However, often the damage is already done and optimal neonatal management merely serves to limit the extent of damage by
Antenatal management
There are a number of important considerations in developing antenatal management strategies for fetuses anticipated to have fetal AIT: the potential severity of the thrombocytopenia including the natural history of fetal AIT, the risk of ICH at a given fetal or neonatal platelet count; the mode of delivery, the morbidity and mortality associated with therapy and therapeutic procedures, and the efficacy of available therapies. The appropriate use of antenatal therapies has been best defined in
Severity of disease
Other than antenatal ICH in an older affected sibling, there are no reliable predictors of severe thrombocytopenia in subsequent pregnancies. However, if an older sibling had severe AIT, subsequent infants will have disease that is at least as severe.58, 82, 84 To our knowledge, there are only very rare reports of untreated fetuses with disease less severe than older affected siblings. As many as 40% of initial fetal platelet counts between 20 and 30 weeks gestation will already be lower than
ICH
“Spontaneous” fetal ICH is rare at platelet counts greater than 20 × 109/L. However, the risk of ICH at a given platelet count after vaginal births and after cesarean section has not been prospectively studied in AIT. Several early reports of ICH in thrombocytopenic infants after vaginal delivery prompted authors to advocate for scheduled “elective” cesarean section in severely thrombocytopenic infants.107, 108 However, it is still not clear if vaginal delivery is an independent risk factor for
Therapeutic procedures
Monitoring the efficacy of therapeutic interventions in fetuses with AIT requires FBS using the technique of cordocentesis. There is a reported fetal loss rate of 0.2%–7.2%, depending on the technique (free-hand technique, fixed-needle technique, or combined technique), operator experience, and underlying fetal disease.91, 111, 112, 113, 114 In otherwise healthy but thrombocytopenic fetuses, the risk of fetal loss is likely closer to 1%,105, 115 but the complication rate is higher.66, 67, 68,
Overall approach to therapy
If a previous fetus had an antenatal ICH, the chances of recurrence are so high that antenatal management (treatment) is mandatory. However, in 70–90% of cases in which an affected neonate is identified in the neonatal nursery, the risk of ICH in a subsequent pregnancy is a) low and b) unknown. The only estimate of which we are aware suggests that the rate of such hemorrhage is 7% but the confidence intervals on this number are wide.117 If this number is approximately correct, then it is
Efficacy of selected therapeutic approaches
a) Blind Treatment: This typically involves IVIG 1 g/kg · week starting as early as 12–20 weeks of gestation but could be any dose starting at any later time and even involve combination with steroid treatment. “Blind” refers to not performing FBS. The two implicit assumptions here are: 1) avoiding the morbidity and mortality of FBS automatically makes this from of treatment superior to other “informed” regimens and 2) blind treatment is sufficiently effective that ICH will not occur. The
Specific management strategies
Our recent study has suggested that, in still unknown ways, the pathobiology of AIT is different in different clinical settings. This distinction is based upon the relationship of response to certain treatments depending upon whether or nor there was an ICH in the previous sibling and, if so, was it perinatal or third trimester or did it occur in the second half of the second trimester. For example, fetuses with a platelet count initially greater than 20 × 109/L and without a history of sibling
Very high risk
Patients are at extremely high risk for an adverse outcome if they are the antigen positive subsequent sibling of a fetus who suffered an antenatal ICH before 28 weeks gestation. For this group, in very limited data, 2g/kg · week (in 2 doses) of maternally-administered IVIG starting at 12 weeks gestation appears to be the optimal treatment. Prednisone 1 mg/kg · d was usually added later.
High risk
Fetuses are at high risk for an adverse outcome if they are antigen positive and have a previous sibling who suffered an antenatal ICH between 28 and 36 weeks gestation or a perinatal ICH. The combination of these two groups is based on two findings: a) it can be difficult to be sure when an ICH that is discovered immediately after birth actually occurred and b) in a recent group of 8 patients with a previous sibling with perinatal ICH, 5 had initial fetal platelet counts less than 10 × 109/L by
Standard risk
Fetuses affected by AIT who have no history of a sibling ICH and have an initial fetal platelet count greater than 20 × 109/L have a lesser risk of an adverse outcome. Treatment (after FBS) was randomized between 1g/kg · week of maternal IVIG and prednisone 0.5 mg/kg · d with essentially equal results. However, without FBS prior to treatment, it is not possible to distinguish those with platelet counts less than 20 × 109/L from those with platelet counts greater than 20 × 109/L. This distinction is
Not well-defined risk
There are several circumstances in which the risk is no clear. The first is when the mother had a thrombocytopenic fetus/neonate who clinically appeared to have AIT but for whom no incompatibility accompanied by sensitization can be demonstrated to establish the probability of recurrence. The second is when there is platelet antigen incompatibility, no antibody detected, and no previous affected sibling of the fetus by which to gauge the likelihood of AIT.
In the first case, before concluding
Long term effects of antenatal management on the treated fetus
Two centers have explored the effects of antenatal management on the long-term outcome of the fetus. One group demonstrated that there were no substantial adverse effects of antenatal management on the immunity of the fetus although a small increase in the CD8% was seen. In addition, in their study, there were no obvious adverse effects on growth and development as well as incidence of infections.133 In our study, matched affected sibling pairs were compared, the older one untreated and the
Treatment in the newborn
Early attempts to treat AIT consisted primarily of transfusion of maternal platelets.137 Maternal platelet transfusion or transfusion of HPA-1a negative platelets are still used in severe cases and are the treatment of choice when available. If HPA-1a negative platelets are not immediately available, random donor platelets may be substituted with frequent assessments of platelet recovery. Two recent studies have demonstrated surprising efficacy of random donor platelets.65, 138 Therefore, the
Conclusions
Alloimmune thrombocytopenia is a disease of varied presentation and course that may have a devastating impact on severely affected fetuses and newborns and their families. While early treatment and intervention may prevent many of the potential adverse sequelae, antenatal management itself is not without risk. The capacity exists to effectively treat a great majority of affected fetuses, but we, unfortunately, lack sensitive and reliable non-invasive indicators of disease severity and response
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