Fetal alloimmune thrombocytopenia is caused by maternal sensitization to paternally-derived antigens on fetal platelets, most commonly HPA-1a.1 It occurs in approximately 1 in 1000 live births and is the commonest cause of severe fetal and neonatal thrombocytopenia, and of intracranial hemorrhage in neonates born at term.2 Since there is currently no routine screening, first-time cases of fetal alloimmune thrombocytopenia are generally identified following the birth of a markedly thrombocytopenic neonate. Antenatal management is thus only possible in subsequent pregnancies.
Intracranial hemorrhage is the most devastating complication of fetal alloimmune thrombocytopenia and often occurs antenatally. Assessment of projected clinical severity is thus based on the development of intracranial hemorrhage in a previous sibling. If there is such a history of intracranial hemorrhage, the chance of this complication occurring again in the next pregnancy is extremely high in an untreated, antigen-positive sibling.3
Administration of intravenous immunoglobulin (IVIG) to the mother, initially given in conjunction with dexamethasone, was first used to prevent recurrence of antenatal intracranial hemorrhage in 1988.4 This approach of providing IVIG-based medical therapy administered to the mother to increase the fetal platelet count has since been extensively investigated in hundreds of maternal-fetal pairs.5 The efficacy of IVIG-based therapy has been supported by numerous studies6–16 (Table 1A) but not by others17–19 (Table 1B). The studies presented in Tables 1A and 1B surprisingly report virtually identical percentages of cases of intracranial hemorrhage: 2.7% versus 2.9%, respectively. However, overall mean birth platelet counts differed markedly between the two groups. While platelet counts are considered to be surrogate markers of intracranial hemorrhage, fortunately, the likelihood of fetal and neonatal intracranial hemorrhage, in the absence of this complication having occurred in a previous sibling, is relatively low.
Over time, a number of considerations have emerged concerning the assessment of the efficacy of maternal IVIG-based therapy in fetal alloimmune thrombocytopenia (Table 2) in addition to the lack of a universally-accepted response criterion.20 A recent randomized study demonstrated that IVIG 1 g/kg/week alone does not work well in more severely affected patients (i.e., those with previous intracranial hemorrhage or whose initial fetal blood platelet count is ≤20×10/L).12 Among patients treated in the standard-risk arm (platelet count at pre-treatment fetal blood sampling > 20×10/L and no history of intracranial hemorrhage in a previous sibling), less intensive therapy was appropriate and prednisone 0.5 mg/kg/day was as good as IVIG. However, among high-risk fetuses, a satisfactory increase in platelets was seen in only 18% of cases treated with maternal IVIG 1 g/kg/week alone versus 82% of those treated with maternal IVIG 1 g/kg/week plus prednisone 1 mg/kg/day. Thus, IVIG 1 g/kg/week alone does not appear to be sufficiently effective for the approximately 50% of severely affected fetuses whose initial fetal platelet count is less than 20×10/L.21 Further studies suggested that IVIG x 2 infusions of 1 g/kg/week combined with 0.5–1.0 mg/kg/day prednisone is the most effective medical regimen for use in the most severely affected fetuses.16 These comparisons demonstrated that risk stratification was essential and that the severity and response to therapy of fetal alloimmune thrombocytopenia was not the same in all cases.
Another management strategy is the use of weekly fetal blood sampling associated with intra-uterine platelet transfusion. Since fetuses with alloimmune thrombocytopenia are vulnerable to compromised hemostasis due to severe thrombocytopenia, impaired platelet function, and endothelial dysfunction; the risks of fetal blood sampling are considerable and well-documented.10–12,14,15,17,18,22,23 Birchall and colleagues from Europe reported a number of procedure-related complications, including exsanguination and emergency Cesarean deliveries attributed to infection, needle dislodgement, severe fetal bradycardia, cord spasm and thrombosis.11 For these reasons, fetal blood sampling is generally coupled with intra-uterine platelet transfusion if platelet counts are low (e.g., < 50×10/L).7,22 In addition, serial fetal blood sampling and intra-uterine platelet transfusions may further sensitize the mother.20,24 Finally, if maternal platelets are used in an intra-uterine transfusion, antiplatelet antibodies may be transfused into the fetus with the platelets.20,25 Overall, as treatment results with maternal IVIG-based therapy have improved substantially6,7,12,14,16 (Table 3), while the morbidity and mortality from fetal blood sampling remain considerable, the consensus at many centers at present is to minimize its use, and, if possible, to avoid fetal blood sampling completely.9,13,15,23 This requires the use of “blind” treatment and, therefore, therapy that will be effective in fetuses with all degrees of severity since; for example, it is unknown whether the fetal platelet count is below or above 20×10/L without pre-treatment fetal blood sampling.
The study by Giers et al.19 in this issue of the journal introduces an entirely novel approach to management in which serial weekly fetal blood samples are taken and intra-uterine platelet transfusions are given only at the final sampling. Twenty-nine pregnancies were studied, 25 of which were from mothers with one to four previously affected children; sibling history was negative for intracranial hemorrhage in all cases. No intra-uterine platelet transfusions were performed except immediately prior to birth, despite the fact that the mean minimal fetal platelet count during pregnancy was 21.5×10/L (range, 4–60×10/L). Maternal therapy was weekly IVIG, 1 g/kg of Endobulin, without steroids (or intra-uterine platelet transfusion). Giers et al. concluded that their data support very limited efficacy of IVIG (mean fetal platelet count at initial intra-uterine platelet transfusion, 56.3×10/L [range, 4–130×10/L]; mean fetal platelet count at final sampling prior to intra-uterine platelet transfusion, 31.3×10/L [range 6–117×10/L]). This 6-year retrospective study included 219 fetal blood sampling procedures (median, 7 per fetus; range, 2–14). Not one procedure-related complication occurred in this study. Because the lack of adverse events associated with fetal blood sampling was attributed to one highly-skilled operator performing all procedures, as in a series of more than 5000 such procedures in France,26 the reproducibility of such a complication-free outcome may not be generalizable to other centers.19 Finally, the overall poor response to IVIG may stem from additional factors beyond the use of a dose of only 1 g/kg/week. These include the brand of IVIG (Endobulin) and the large number of fetal blood sampling procedures performed, as serial sampling may contribute to maternal sensitization, thus masking the therapeutic effects of maternal IVIG.20,24
The management of fetal alloimmune thrombocytopenia has progressed in recent years. Examples of this include implementation of non-invasive approaches, in which fetal blood sampling and intra-uterine platelet transfusion are minimized or eliminated completely, and treatment stratified according to estimated risk.
The current focus on non-invasive approaches9,13,15,23 serves both as a response to the high complication rate of invasive strategies10–12,14,15,17,18,22,23 and as a testament to the efficacy of maternal IVIG-based treatment. In one study Yinon et al. suggested that IVIG without fetal blood sampling is safe and effective in women who, like the subjects featured in the study conducted by Giers et al.,19 lacked a history of fetal or neonatal intracranial hemorrhage in a previous child. The 24 fetuses who underwent this treatment had significantly higher platelet counts at birth compared to their affected siblings and fetuses of mothers who refused treatment (118×10/L versus 25×10/L and 24×10/L, respectively; P<0.05).13 Furthermore, in a group treated with “blind” IVIG, preterm births were significantly less frequent than in groups treated with invasive approaches.23 While avoiding fetal blood sampling entirely is not without its own pitfalls (inability to assess the need for transfusion, determine aspects of severity, etc.), this approach may help to avoid fetal complications ranging from exsanguination to enhanced maternal sensitization and seems feasible in many cases.20,24,25
Recent studies have demonstrated the need to acknowledge variations in severity in treatment protocols.12,16 Severity may be affected by a myriad of factors whose roles in fetal alloimmune thrombocytopenia are not yet understood, such as HLA and, possibly, ABO incompatibility.27,28 It has become clear that fetuses at different risk levels should not be treated identically, and that IVIG 1 g/kg/week alone is not sufficient to treat high-risk cases. Finally, there is now compelling support for the role of a risk-based approach to maternal IVIG-based therapy in the prevention of recurrent intracranial hemorrhage among affected fetuses, again indicating that treatment stratification based on sibling history is appropriate.16
Screening and biomarkers
Screening all pregnancies for fetal alloimmune thrombocytopenia is also a novel approach whose discussion is beyond the scope of this perspective review. Its appropriate implementation remains to be clarified.
Finally, development of biomarkers of severity would be extremely useful. Analogy could be made to the use of middle cerebral artery Doppler studies to predict the severity of fetal anemia.
Non-invasive approaches and the implementation of risk stratification (including combination therapy of IVIG with steroids and/or the use of more than 1 g/kg/week of IVIG) are appropriate in the management of fetal alloimmune thrombocytopenia. The data are equally compelling that fetal blood sampling cannot be considered routine in most centers and that Giers et al.19 were exceptional and fortunate in their skilled performance of this technically-demanding procedure.
- Cheryl Vinograd is a senior medical student from Stony Brook University School of Medicine who is spending one year at Cornell performing research on fetal and neonatal alloimmune thrombocytopenia. James Bussel is a Professor of Pediatrics and Obstetrics at Cornell who has had a 27-year long interest in the treatment of fetal and neonatal alloimmune thrombocytopenia.
- Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are available with the full text of this paper at www.haematologica.org.
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