Antepartum Treatment Without Early Cordocentesis for Standard-Risk Alloimmune Thrombocytopenia- A Randomized Controlled Trial Berkowitz, Richard L et al Obstet Gynecol 2007: 11: Elianna Saidenberg February 2008

Case Mrs DA 25 yo G2A1L0 –1 st pregnancy ended by TA at 13 weeks for known trisomy 21 U/S at 33 weeks GA revealed intracranial lesion Follow up U/S 5 days later at TOH and blood bank notified of possible case of NAIT –Maternal samples acquired for maternal Ab testing in Ottawa Strong anti-HPA 1a Abs as well as anti-HLA Abs HPA 1a negative, CMV negative, irradiated apheresis platelets found in Hamilton Ottawa CBS HPA 1a negative donors notified of possible need for donation –Maternal and paternal samples acquired for platelet Ag/ Ab testing in Hamilton

Case-2 MRI confirms 2 right sided intracebral hematomata which appeared to be subacute. The larger of the 2 was 2.2 x 2.4 x 3.3 cm and was surrounded by edema leading to midline shift BPP was normal (8/8) –Dr MFM #1 wishes to deliver baby by C/S ASAP –Dr MFM #2 wishes to perform intra-uterine platelet transfusion –Dr. NICU wishes to give Celestone and deliver baby in 2 days Dr. MFM #1 calls me around 2:30 on Wed to say that based on wishes of Dr NICU he will delay C/S until Friday at 10 am, however, there will be no intra-uterine transfusion Dr, MFM #1 calls me again around 5 pm on Wed to say that Dr. Neurosurgeon has looked at the MRI and insists baby be delivered ASAP. Plan to deliver via C/S next day at 10 am is finalized.

Case -3 Baby Boy A is delivered via C/S and has normal APGAR scores but bleeds when attempts are made to insert lines. Multiple bruises are present. Platelet count at time of delivery: 8 1 pediatric platelet dose given (1/4 of the apheresis unit we had secured) Post-transfusion platelet count: 180 Results from Hamilton: –Mom is HPA 1b/1b and dad is HPA 1a/1a –They also found presence of anti-HPA 1a antibodies in mom –No other incompatibilities detected to date

Background Definition: –Thrombocytopenia due to transplacentally acquired maternal IgG platelet alloantibodies

Epidemiology: –Occurs in approx 1 per 1200 live births in the Caucasian population In Caucasian patients >75% of cases are due to incompatibility for HPA-1a, 2 nd most commonly implicated Ag is HPA-5b and rare causes are incompatibility for HLA, blood group ABO or other platelet specific antigens In non-Caucasian populations other antigens such as HPA- 4b are more commonly implicated –Considered the most common cause of severe thrombocytopenia in fetuses and term neonates; also the most common cause of ICH in term neonates

Diagnosis –Lab criteria include: Low platelet count in fetus or neonate (<100) Evidence of maternal incompatibility for a platelet-associated antigen Evidence of maternal platelet allo-Ab reactive against the fetal platelet antigen Clinical response to antigen-negative platelet transfusion –Clinical features include History of a previously affected pregnancy provides strong support for the diagnosis although 1 st borns can be affected Severe bleeding symptoms

Platelet count by GA GA5th percentileMean95th percentile

Bleeding symptoms in 88 cases of NAIT –None 10% –Petechiae 90% –Hematomas 66% –GI bleeding 30% (melena >> hematemesis) –Hemoptysis8% –Retinal bleeds 7% –CNS bleeds 14% Muller-Eckhardt Lancet 1989 Fetuses/ infants with platelet counts of <20 are at especially high risk of ICH and life-threatening hemorrhage –75% of ICH in NAIT occurs in-utero In-utero ICH most often occurs in the 3 rd trimester but cases of very early ICH have been reported and the bleeding can be recurrent –Most cases of in-utero ICH have been in cases of HPA-1a incompatibility

Postnatal Management Confirm thrombocytopenia Exclude other causes of thrombocytopenia If maternal platelet count is normal, pregnancy and delivery history are normal and no other cause of TP in the infant can be found a diagnosis of NAIT can be presumed until it can be proven otherwise U/S infant’s head Obtain blood samples on both parents for Ag and Ab testing Transfuse antigen-negative platelets, possibly plasma depleted maternal platelets

Antenatal Management IVIg/corticosteroids (The North American Approach) –Given weekly to alloimmunized pregnant patients known to be carrying an antigen-positive fetus with thrombocytopenia –First reported by Bussel et al in alloimmunized HPA-1a negative pregnant women Fetal platelet count determined by percutaneous umbilical vein sampling Treated with 1 g/kg IVIg weekly from ~20 weeks GA mg dexamethasone po Second fetal blood sampling 4-6 weeks later –All fetuses had increases in platelet count with therapy –None of the treated infants had ICH –Bussel et al 1996-Prospective randomized controlled trial of IVIg vs IVIg plus deaxmethasone Addition of dexamethasone provided no additional benefit Increased risk of death at time of fetal blood sampling, presumed due to exsanguination. Antigen negative platelets made available during procedure and no further problems –Recommended that if fetal blood count <30 give platelet transfusion while needle still in

Antenatal Management-2 In-utero platelet transfusion (The European Approach) –Daffos et al First reported maternal platelet transfusion to 36 week GA fetus with thrombocytopenia due to HPA-1a incompatibility 6 hours prior to elective C/S. Infant platelet count at delivery 95 –Murphy et al pregnancies in women with history of previous pregnancy with NAIT and infant with ICH were given repeated in-utero platelet transfusions all with good outcome –Case report by Murphy et al of poor outcome of in-utero transfusion caused by presence of maternal HLA antibodies. Improved outcomes observed when HLA compatible platelets given

A few notes on FBS Bleeding from the puncture site –Most common complication, up to one-half of cases –Puncture of the umbilical artery is associated with a significantly longer duration of bleeding than venipuncture –More ominous prognosis if occurs at less than 21 weeks of gestation –Fetuses with defects in platelet number or function are known to be at significant risk for potentially fatal bleeding from the puncture site Some centres advocate slowly transfusing the fetus with concentrated, washed maternal or compatible donor platelets while awaiting the fetal platelet count when FBS is performed to diagnosis a fetal platelet disorder. Dislodgement of the needle before platelet transfusion can have fatal consequences for the fetus affected with a platelet abnormality Cord hematoma –Generally asymptomatic, but can be associated with a transient or prolonged sudden fetal bradycardia –Seen in 17% of cases

FBS-2 Fetomaternal hemorrhage –A significant fetomaternal transfusion occurs in ~40 percent of cases –The main consequence of fetomaternal hemorrhage is reported to be an increase in maternal antibody titers when the procedure is done for red blood cell isoimmunization –Could this impact on natural history of NAIT? Fetal loss –The risk of fetal loss is substantially higher in the presence of fetal pathology. – The total spontaneous pregnancy loss rate within two weeks of the procedure is 1% when done for genetic diagnosis, 7-13% if structural fetal anomalies, 9-14% among growth restricted fetuses, and 25% in fetuses with nonimmune hydrops –Does ICH count as a structural anomaly? –There is a higher frequency of fetal loss in smaller series, suggesting that operator experience affects the complication rate

The Study- Rationale Berkowitz et al Parallel randomized trials of risk- based therapy for fetal alloimmune thrombocytopenia Patients separated into high risk and standard risk groups –High risk group consisted of patients who had a sibling affected by ICH or had a platelet count less than 20. Within each risk arm patients randomized to IVIg alone or IVIg plus prednisone 1mg/kg/day No significant difference in response to therapy seen between arms in standard risk group In the high risk group better response seen in the combination treatment arm Concluded that fetuses with platelet counts <20 are not likely to respond adequately to IVIg therapy alone Based on these results the authors advocate determining fetal platelet count prior to initiation of therapy and also monitoring platelet count to assess response to treatment and assess need for intensification of therapy

Rationale-2 The data from the parallel randomized study “clearly indicate that patients with milder disease can be successfully treated with less intensive therapy than their more severely affected counterparts….The current study was designed to prospectively identify a group of patients who could be empirically treated with a medical regimen that adequately covers the severely affected fetuses without subjecting the mothers of more mildly affected fetuses to far more therapy than is necessary.”

The Study “Randomized multicentre study to evaluate the effectiveness and safety of two antenatal treatment regimens designed to optimally protect fetuses against having an intracranial hemorrhage resulting from alloimmune thrombocytopenia while minimizing the risks associated with fetal blood sampling.” Evaluated patients with known NAIT but no history of ICH in previous pregnancy Primary outcome: Development of fetal or neonatal ICH Secondary outcomes: Fetal and birth platelet counts, GA at delivery, problems related to FBS and complications of medical therapy

Methods May 2001-June 2006, 73 women enrolled –Diagnosis of AIT based on evidence of HPA incompatibility with father’s platelet and evidence of circulating antibodies to said antigen –If father heterozygous for platelet antigen in question HPA genotype of fetal platelet was confirmed Randomized using computer-generated random numbers

Methods-2 Therapy started ~20 weeks GA –Group A: IVIg 2 g/kg/week (37 women) –Group B: IVIg 1g/kg/week + prednisone 0.5 mg/kg/day (36 women) Cordocentesis performed at ~32 weeks GA after administration of betamethasone –If platelet count <30 or procedure not able to be done “salvage therapy” initiated –Group A: addition of prednisone 0.5 mg/kg/day –Group B: Increase IVIg to 2 g/kg/week –Salvage failure defined as birth platelet count <30

Results ICH: –One neonate in each group suffered ICH in neonatal period –Neither considered due to treatment failure Group A ICH infant: birth platelet count 133 Group B ICH infant: birth platelet count 197 Average platelet counts on FBS: –Group A: fetuses with platelet count <30 1 fetus with platelet count between 30-50, born with platelet count 14 at 36 weeks –Group B: fetuses with platelet count <30 3 fetuses with platelet counts 30-50; all born with platelet count between Salvage therapy: –Group A: 10 (27%) –Group B: 6 (17%) –1 infant in each group delivered with platelet count <30 Average birth platelet counts: –Group A: (14%) neonates with platelet counts <50 –Group B: (11%) neonates with platelet counts <50

Results-2 Complications of cordocentesis –Group A: 2 complications of 39 procedures, both were fetal bradycardia requiring urgent C/S –Group B: 2 complications, both were premature rupture of membranes within 24 hrs

Authors’ conclusions “Statistical analysis of the incidence of intracranial hemorrhage, as well as fetal and birth platelet counts in the two treatment arms, showed neither is demonstrably superior to the other.”

Author’s Recommendations 1) Start empiric therapy with either IVIg 2 mg/kg/week OR IVIg 1 g/kg/week plus prednisone 0.5 mg/kg/week as close to 20 weeks as possible 2) Offer all patients FBS at 32 weeks and institute salvage therapy for fetal platelet counts <50*. If FBS cannot be performed at that time, empirically institute salvage therapy at 32 weeks. 3) Allow vaginal delivery only for those patients whose fetuses were shown to have platelets >100 at 32 weeks and remain compliant with therapy. OR- empirically institute salvage therapy in all patients at 32 weeks and then only perform FBS at 36 weeks in those women who want to deliver vaginally

A few thoughts…. If an average pregnant woman weighs 70 kg 2 g/kg/week of IVIg amounts to 140 grams per week. If therapy starts at 20 weeks and continues to 40 weeks that’s 2800 grams of IVIg per patient If IVIg costs about $70 per gram that equals $196,000 per patient

What’s a girl to do? Ulitmately, the dicision about therapy has to be made by the patient, her husband and their obstetrician. However, perhaps we should evaluate alternative treatment strategies that would cost less and expose the patient to less blood products.