title: Omission of fetal sampling in treatment of subsequent pregnancies in fetal-neonatal alloimmune thrombocytopenia.
abstract: BACKGROUND
  Fetal-neonatal alloimmune thrombocytopenia affects approximately 1 of 1000 live births, most of which are not severely thrombocytopenic. Despite effective treatment with intravenous gammaglobulin and/or prednisone, antenatal management of a subsequent affected pregnancy is complicated by the risks associated with fetal blood sampling. Furthermore, there are no biomarker(s) of high risk other than the occurrence of intracranial hemorrhage in a previous sibling. Management of these high-risk pregnancies requires intensive treatment initiated at 12 weeks of gestation.
  
  
  OBJECTIVE
  The objective of the study was to evaluate whether empiric escalation of therapy at 32 weeks allows the omission of fetal blood sampling in all fetal-neonatal alloimmune thrombocytopenia-affected patients. Specifically, we sought to determine whether intensive intravenous gammaglobulin-based regimens for the treatment of a subsequent fetal-neonatal alloimmune thrombocytopenia-affected pregnancy followed by empirically escalated intravenous gammaglobulin and prednisone treatment would increase the fetal platelet count and thus safely allow omission of fetal blood sampling in the antepartum management of these patients.
  
  
  METHODS
  In this prospective, multicenter, randomized controlled study, 99 women with fetal-neonatal alloimmune thrombocytopenia whose prior affected child did not have an intracranial hemorrhage were randomized to receive an intensive intravenous gammaglobulin-based regimen: 2 g/kg per week or intravenous gammaglobulin 1 g/kg per week plus prednisone 0.5 mg/kg per day, starting at 20-30 weeks of gestation. Escalated therapy (intravenous gammaglobulin 2 g/kg per week plus prednisone 0.5 mg/kg per day) was recommended and usually initiated at 32 weeks when fetal counts were <50,000/mL(3) or when fetal blood sampling was not performed. The preliminary report of this study from 2007 demonstrated the efficacy of both intravenous gammaglobulin-based regimens in most patients. Most patients who underwent fetal sampling had adequate fetal counts and therefore did not have their treatment escalated. This post hoc analysis describes the 29 fetuses who had their treatment escalated either because they had low counts at 32 weeks or when sampling was not performed. This study explored whether the empiric escalation of treatment at 32 weeks was sufficiently effective in increasing fetal platelet counts in these patients.
  
  
  RESULTS
  Mean fetal and birth counts of fetuses randomized to each of the 2 initial treatment groups were all >100,000/mL(3). Three neonates had an intracranial hemorrhage; all 3 were grade 1 and all had birth platelet counts >130,000/mL(3). In a post hoc analysis, 19 fetuses undergoing fetal blood sampling at 32 weeks had fetal platelet counts <50,000/mL(3) despite their initial treatment. Of these 19, birth platelet counts were >50,000/mL(3) in 11 of 13 fetuses who received escalated treatment compared with only 1 of 6 of those who did not (P = .01); only 3 fetuses that received initial therapy followed by escalated treatment had birth platelet counts <50,000/mL(3) and none had an intracranial hemorrhage. The platelet counts of 14 of 15 fetuses that received empirically escalated treatment without sampling were >50,000/mL(3) at birth. In addition, none of these had an intracranial hemorrhage.
  
  
  CONCLUSIONS
  The 2 recommended protocols of intensive initial treatment followed by empiric escalation of therapy at 32 weeks of gestation are reasonably safe, effective in increasing fetal platelet counts, and allow omission of fetal blood sampling by increasing the fetal platelet count in almost all cases.
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Lakkaraja
authors.affiliation: Department of Obstetrics and Gynecology Columbia University Medical Center, New York, NY.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Berkowitz
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Vinograd
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Manotas
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York.
authors.forename: Polina
authors.initials: P
authors.lastname: Ferd
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York.
authors.forename: Julia
authors.initials: J
authors.lastname: Gabor
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York.
authors.forename: Megan
authors.initials: M
authors.lastname: Wissert
authors.affiliation: Platelet and Neutrophil Immunology Laboratory, Blood Center of Wisconsin, Milwaukee, WI; Department of Medicine, Division of Hematology-Oncology, Medical College of Wisconsin, Wauwatosa, WI.
authors.forename: Janice G
authors.initials: JG
authors.lastname: McFarland
authors.affiliation: Department of Pediatrics, Division of Hematology, Weill Cornell Medicine, New York, New York. Electronic address: jbussel@med.cornell.edu.
authors.forename: James B
authors.initials: JB
authors.lastname: Bussel
mesh_terms: D017218:Cordocentesis / Q000009:adverse effects; D005260:Female; D005312:Fetal Blood; D005865:Gestational Age; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage*; D007155:Immunologic Factors / Q000008:administration & dosage*; D020300:Intracranial Hemorrhages / Q000209:etiology; D010976:Platelet Count; D011241:Prednisone / Q000008:administration & dosage; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy*; D011296:Prenatal Diagnosis; D011446:Prospective Studies; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy*
chemical_list: D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D011241:Prednisone
keywords: fetal hematology; hemorrhage; platelet; steroids