Antepartum Treatment Without Antepartum Treatment Without Early Cordocentesis for Early Cordocentesis for

Standard-Risk Alloimmune Standard-Risk Alloimmune Thrombocytopenia- Thrombocytopenia-

A Randomized Controlled TrialA Randomized Controlled Trial Berkowitz, Richard L et al Obstet Gynecol Berkowitz, Richard L et al Obstet Gynecol

2007: 11:249-552007: 11:249-55

Elianna Saidenberg February 2008Elianna Saidenberg February 2008

CaseCase

Mrs DA 25 yo G2A1L0 Mrs DA 25 yo G2A1L0 – 11stst pregnancy ended by TA at 13 weeks for known trisomy 21 pregnancy ended by TA at 13 weeks for known trisomy 21

U/S at 33 weeks GA revealed intracranial lesionU/S at 33 weeks GA revealed intracranial lesionFollow up U/S 5 days later at TOH and blood bank Follow up U/S 5 days later at TOH and blood bank notified of possible case of NAITnotified of possible case of NAIT– Maternal samples acquired for maternal Ab testing in Ottawa Maternal samples acquired for maternal Ab testing in Ottawa

Strong anti-HPA 1a Abs as well as anti-HLA AbsStrong anti-HPA 1a Abs as well as anti-HLA AbsHPA 1a negative, CMV negative, irradiated apheresis platelets HPA 1a negative, CMV negative, irradiated apheresis platelets found in Hamilton found in Hamilton Ottawa CBS HPA 1a negative donors notified of possible need for Ottawa CBS HPA 1a negative donors notified of possible need for donationdonation

– Maternal and paternal samples acquired for platelet Ag/ Ab Maternal and paternal samples acquired for platelet Ag/ Ab testing in Hamiltontesting in Hamilton

Case-2 Case-2

MRI confirms 2 right sided intracebral hematomata which appeared 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 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 shiftsurrounded by edema leading to midline shiftBPP was normal (8/8)BPP was normal (8/8)– Dr MFM #1 wishes to deliver baby by C/S ASAPDr MFM #1 wishes to deliver baby by C/S ASAP– Dr MFM #2 wishes to perform intra-uterine platelet transfusionDr MFM #2 wishes to perform intra-uterine platelet transfusion– Dr. NICU wishes to give Celestone and deliver baby in 2 daysDr. 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 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, wishes of Dr NICU he will delay C/S until Friday at 10 am, however, there will be no intra-uterine transfusionthere will be no intra-uterine transfusionDr, MFM #1 calls me again around 5 pm on Wed to say that Dr. 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 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.ASAP. Plan to deliver via C/S next day at 10 am is finalized.

Case -3Case -3

Baby Boy A is delivered via C/S and has normal APGAR Baby Boy A is delivered via C/S and has normal APGAR scores but bleeds when attempts are made to insert scores but bleeds when attempts are made to insert lines. Multiple bruises are present.lines. Multiple bruises are present.Platelet count at time of delivery: 8Platelet count at time of delivery: 81 pediatric platelet dose given (1/4 of the apheresis unit 1 pediatric platelet dose given (1/4 of the apheresis unit we had secured)we had secured)Post-transfusion platelet count: 180Post-transfusion platelet count: 180Results from Hamilton:Results from Hamilton:– Mom is HPA 1b/1b and dad is HPA 1a/1aMom is HPA 1b/1b and dad is HPA 1a/1a– They also found presence of anti-HPA 1a antibodies in momThey also found presence of anti-HPA 1a antibodies in mom– No other incompatibilities detected to dateNo other incompatibilities detected to date

BackgroundBackgroundDefinition:Definition:– Thrombocytopenia due Thrombocytopenia due

to transplacentally to transplacentally acquired maternal IgG acquired maternal IgG platelet alloantibodiesplatelet alloantibodies

Epidemiology: Epidemiology: – Occurs in approx 1 per 1200 live births in the Occurs in approx 1 per 1200 live births in the

Caucasian populationCaucasian populationIn Caucasian patients >75% of cases are due to In Caucasian patients >75% of cases are due to incompatibility for HPA-1a, 2incompatibility for HPA-1a, 2ndnd most commonly implicated Ag most commonly implicated Ag is HPA-5b and rare causes are incompatibility for HLA, blood is HPA-5b and rare causes are incompatibility for HLA, blood group ABO or other platelet specific antigensgroup ABO or other platelet specific antigens

In non-Caucasian populations other antigens such as HPA-In non-Caucasian populations other antigens such as HPA-4b are more commonly implicated4b are more commonly implicated

– Considered the most common cause of severe Considered the most common cause of severe thrombocytopenia in fetuses and term neonates; also thrombocytopenia in fetuses and term neonates; also the most common cause of ICH in term neonatesthe most common cause of ICH in term neonates

DiagnosisDiagnosis– Lab criteria include:Lab criteria include:

Low platelet count in fetus or neonate (<100)Low platelet count in fetus or neonate (<100)

Evidence of maternal incompatibility for a platelet-associated Evidence of maternal incompatibility for a platelet-associated antigenantigen

Evidence of maternal platelet allo-Ab reactive against the Evidence of maternal platelet allo-Ab reactive against the fetal platelet antigenfetal platelet antigen

Clinical response to antigen-negative platelet transfusionClinical response to antigen-negative platelet transfusion

– Clinical features includeClinical features includeHistory of a previously affected pregnancy provides strong History of a previously affected pregnancy provides strong support for the diagnosis although 1support for the diagnosis although 1stst borns can be affected borns can be affected

Severe bleeding symptomsSevere bleeding symptoms

Platelet count by GAPlatelet count by GAGA 5th percentile Mean 95th percentile

20 145 219 293

22 148 222 297

24 151 225 300

26 154 229 303

28 157 232 306

30 160 235 310

32 163 238 313

34 166 241 316

36 169 244 319

38 172 247 323

40 175 250 326

Bleeding symptoms in 88 cases of NAITBleeding symptoms in 88 cases of NAIT– None 10%None 10%– Petechiae 90%Petechiae 90%– Hematomas 66%Hematomas 66%– GI bleeding 30% (melena >> hematemesis)GI bleeding 30% (melena >> hematemesis)– Hemoptysis8%Hemoptysis8%– Retinal bleeds 7%Retinal bleeds 7%– CNS bleeds 14%CNS bleeds 14%

Muller-Eckhardt Lancet 1989Muller-Eckhardt Lancet 1989

Fetuses/ infants with platelet counts of <20 are at especially high Fetuses/ infants with platelet counts of <20 are at especially high risk of ICH and life-threatening hemorrhagerisk of ICH and life-threatening hemorrhage– 75% of ICH in NAIT occurs in-utero75% of ICH in NAIT occurs in-utero

In-utero ICH most often occurs in the 3In-utero ICH most often occurs in the 3rdrd trimester but cases of very trimester but cases of very early ICH have been reported and the bleeding can be recurrentearly ICH have been reported and the bleeding can be recurrent– Most cases of in-utero ICH have been in cases of HPA-1a Most cases of in-utero ICH have been in cases of HPA-1a

incompatibility incompatibility

Postnatal ManagementPostnatal Management

Confirm thrombocytopeniaConfirm thrombocytopeniaExclude other causes of thrombocytopeniaExclude other causes of thrombocytopeniaIf maternal platelet count is normal, pregnancy and If maternal platelet count is normal, pregnancy and delivery history are normal and no other cause of TP in delivery history are normal and no other cause of TP in the infant can be found a diagnosis of NAIT can be the infant can be found a diagnosis of NAIT can be presumed until it can be proven otherwisepresumed until it can be proven otherwiseU/S infant’s headU/S infant’s headObtain blood samples on both parents for Ag and Ab Obtain blood samples on both parents for Ag and Ab testingtestingTransfuse antigen-negative platelets, possibly plasma Transfuse antigen-negative platelets, possibly plasma depleted maternal plateletsdepleted maternal platelets

Antenatal ManagementAntenatal ManagementIVIg/corticosteroids (The North American Approach)IVIg/corticosteroids (The North American Approach)– Given weekly to alloimmunized pregnant patients known to be Given weekly to alloimmunized pregnant patients known to be

carrying an antigen-positive fetus with thrombocytopeniacarrying an antigen-positive fetus with thrombocytopenia– First reported by Bussel et al in 1988First reported by Bussel et al in 1988

7 alloimmunized HPA-1a negative pregnant women 7 alloimmunized HPA-1a negative pregnant women Fetal platelet count determined by percutaneous umbilical vein Fetal platelet count determined by percutaneous umbilical vein samplingsamplingTreated with 1 g/kg IVIg weekly from ~20 weeks GA + 3-5 mg Treated with 1 g/kg IVIg weekly from ~20 weeks GA + 3-5 mg dexamethasone podexamethasone poSecond fetal blood sampling 4-6 weeks laterSecond fetal blood sampling 4-6 weeks later

– All fetuses had increases in platelet count with therapyAll fetuses had increases in platelet count with therapy– None of the treated infants had ICH None of the treated infants had ICH

– Bussel et al 1996-Prospective randomized controlled trial of IVIg Bussel et al 1996-Prospective randomized controlled trial of IVIg vs IVIg plus deaxmethasonevs IVIg plus deaxmethasone

Addition of dexamethasone provided no additional benefit Addition of dexamethasone provided no additional benefit Increased risk of death at time of fetal blood sampling, presumed Increased risk of death at time of fetal blood sampling, presumed due to exsanguination. Antigen negative platelets made available due to exsanguination. Antigen negative platelets made available during procedure and no further problemsduring procedure and no further problems

– Recommended that if fetal blood count <30 give platelet transfusion Recommended that if fetal blood count <30 give platelet transfusion while needle still in while needle still in

Antenatal Management-2Antenatal Management-2

In-utero platelet transfusion (The European Approach)In-utero platelet transfusion (The European Approach)– Daffos et al 1984- First reported maternal platelet transfusion to Daffos et al 1984- First reported maternal platelet transfusion to

36 week GA fetus with thrombocytopenia due to HPA-1a 36 week GA fetus with thrombocytopenia due to HPA-1a incompatibility 6 hours prior to elective C/S. Infant platelet count incompatibility 6 hours prior to elective C/S. Infant platelet count at delivery 95at delivery 95

– Murphy et al 1994- 15 pregnancies in women with history of Murphy et al 1994- 15 pregnancies in women with history of previous pregnancy with NAIT and infant with ICH were given previous pregnancy with NAIT and infant with ICH were given repeated in-utero platelet transfusions all with good outcomerepeated in-utero platelet transfusions all with good outcome

– Case report by Murphy et al of poor outcome of in-utero Case report by Murphy et al of poor outcome of in-utero transfusion caused by presence of maternal HLA antibodies. transfusion caused by presence of maternal HLA antibodies. Improved outcomes observed when HLA compatible platelets Improved outcomes observed when HLA compatible platelets givengiven

A few notes on FBSA few notes on FBSBleeding from the puncture site Bleeding from the puncture site – Most common complication, up to one-half of cases Most common complication, up to one-half of cases – Puncture of the umbilical artery is associated with a significantly Puncture of the umbilical artery is associated with a significantly

longer duration of bleeding than venipuncturelonger duration of bleeding than venipuncture– More ominous prognosis if occurs at less than 21 weeks of More ominous prognosis if occurs at less than 21 weeks of

gestation gestation – Fetuses with defects in platelet number or function are known to Fetuses with defects in platelet number or function are known to

be at significant risk for potentially fatal bleeding from the be at significant risk for potentially fatal bleeding from the puncture site puncture site

Some centres advocate slowly transfusing the fetus with Some centres advocate slowly transfusing the fetus with concentrated, washed maternal or compatible donor platelets while concentrated, washed maternal or compatible donor platelets while awaiting the fetal platelet count when FBS is performed to diagnosis awaiting the fetal platelet count when FBS is performed to diagnosis a fetal platelet disorder. a fetal platelet disorder. Dislodgement of the needle before platelet transfusion can have Dislodgement of the needle before platelet transfusion can have fatal consequences for the fetus affected with a platelet abnormalityfatal consequences for the fetus affected with a platelet abnormality

Cord hematomaCord hematoma– Generally asymptomatic, but can be associated with a transient Generally asymptomatic, but can be associated with a transient

or prolonged sudden fetal bradycardia or prolonged sudden fetal bradycardia – Seen in 17% of casesSeen in 17% of cases

FBS-2FBS-2

Fetomaternal hemorrhageFetomaternal hemorrhage– A significant fetomaternal transfusion occurs in ~40 percent of cases A significant fetomaternal transfusion occurs in ~40 percent of cases – The main consequence of fetomaternal hemorrhage is reported to be an The main consequence of fetomaternal hemorrhage is reported to be an

increase in maternal antibody titers when the procedure is done for red increase in maternal antibody titers when the procedure is done for red blood cell isoimmunization blood cell isoimmunization

– Could this impact on natural history of NAIT?Could this impact on natural history of NAIT?Fetal lossFetal loss– The risk of fetal loss is substantially higher in the presence of fetal The risk of fetal loss is substantially higher in the presence of fetal

pathology.pathology.– The total spontaneous pregnancy loss rate within two weeks of the The total spontaneous pregnancy loss rate within two weeks of the

procedure is 1% when done for genetic diagnosis, 7-13% if structural procedure is 1% when done for genetic diagnosis, 7-13% if structural fetal anomalies, 9-14% among growth restricted fetuses, and 25% in fetal anomalies, 9-14% among growth restricted fetuses, and 25% in fetuses with nonimmune hydrops fetuses with nonimmune hydrops

– Does ICH count as a structural anomaly?Does ICH count as a structural anomaly?– There is a higher frequency of fetal loss in smaller series, suggesting There is a higher frequency of fetal loss in smaller series, suggesting

that operator experience affects the complication rate that operator experience affects the complication rate

The Study- RationaleThe Study- Rationale

Berkowitz et al 2006- Parallel randomized trials of risk-Berkowitz et al 2006- Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopeniabased therapy for fetal alloimmune thrombocytopenia

Patients separated into high risk and standard risk groupsPatients separated into high risk and standard risk groups– High risk group consisted of patients who had a sibling High risk group consisted of patients who had a sibling

affected by ICH or had a platelet count less than 20. affected by ICH or had a platelet count less than 20. Within each risk arm patients randomized to IVIg alone or Within each risk arm patients randomized to IVIg alone or IVIg plus prednisone 1mg/kg/dayIVIg plus prednisone 1mg/kg/dayNo significant difference in response to therapy seen No significant difference in response to therapy seen between arms in standard risk groupbetween arms in standard risk groupIn the high risk group better response seen in the In the high risk group better response seen in the combination treatment armcombination treatment armConcluded that fetuses with platelet counts <20 are not likely Concluded that fetuses with platelet counts <20 are not likely to respond adequately to IVIg therapy aloneto respond adequately to IVIg therapy aloneBased on these results the authors advocate determining Based on these results the authors advocate determining fetal platelet count prior to initiation of therapy and also fetal platelet count prior to initiation of therapy and also monitoring platelet count to assess response to treatment monitoring platelet count to assess response to treatment and assess need for intensification of therapyand assess need for intensification of therapy

Rationale-2Rationale-2

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

The StudyThe Study

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

MethodsMethods

May 2001-June 2006, 73 women enrolledMay 2001-June 2006, 73 women enrolled– Diagnosis of AIT based on evidence of HPA Diagnosis of AIT based on evidence of HPA

incompatibility with father’s platelet and incompatibility with father’s platelet and evidence of circulating antibodies to said evidence of circulating antibodies to said antigenantigen

– If father heterozygous for platelet antigen in If father heterozygous for platelet antigen in question HPA genotype of fetal platelet was question HPA genotype of fetal platelet was confirmedconfirmed

Randomized using computer-generated Randomized using computer-generated random numbers random numbers

Methods-2Methods-2

Therapy started ~20 weeks GATherapy started ~20 weeks GA– Group A: IVIg 2 g/kg/week (37 women)Group A: IVIg 2 g/kg/week (37 women)– Group B: IVIg 1g/kg/week + prednisone 0.5 Group B: IVIg 1g/kg/week + prednisone 0.5

mg/kg/day (36 women)mg/kg/day (36 women)

Cordocentesis performed at ~32 weeks GA after Cordocentesis performed at ~32 weeks GA after administration of betamethasoneadministration of betamethasone– If platelet count <30 or procedure not able to be done If platelet count <30 or procedure not able to be done

“salvage therapy” initiated“salvage therapy” initiated– Group A: addition of prednisone 0.5 mg/kg/dayGroup A: addition of prednisone 0.5 mg/kg/day– Group B: Increase IVIg to 2 g/kg/weekGroup B: Increase IVIg to 2 g/kg/week– Salvage failure defined as birth platelet count <30Salvage failure defined as birth platelet count <30

ResultsResultsICH:ICH:– One neonate in each group suffered ICH in neonatal periodOne neonate in each group suffered ICH in neonatal period– Neither considered due to treatment failureNeither considered due to treatment failure

Group A ICH infant: birth platelet count 133Group A ICH infant: birth platelet count 133Group B ICH infant: birth platelet count 197Group B ICH infant: birth platelet count 197

Average platelet counts on FBS:Average platelet counts on FBS:– Group A: 121Group A: 121

9 fetuses with platelet count <309 fetuses with platelet count <301 fetus with platelet count between 30-50, born with platelet count 14 at 36 weeks1 fetus with platelet count between 30-50, born with platelet count 14 at 36 weeks

– Group B: 116Group B: 1165 fetuses with platelet count <305 fetuses with platelet count <303 fetuses with platelet counts 30-50; all born with platelet count between 40-80 3 fetuses with platelet counts 30-50; all born with platelet count between 40-80

Salvage therapy:Salvage therapy:– Group A: 10 (27%)Group A: 10 (27%)– Group B: 6 (17%)Group B: 6 (17%)– 1 infant in each group delivered with platelet count <301 infant in each group delivered with platelet count <30

Average birth platelet counts:Average birth platelet counts:– Group A: 169Group A: 169

5 (14%) neonates with platelet counts <505 (14%) neonates with platelet counts <50– Group B: 134Group B: 134

4 (11%) neonates with platelet counts <504 (11%) neonates with platelet counts <50

Results-2Results-2

Complications of Complications of cordocentesiscordocentesis– Group A: 2 Group A: 2

complications of 39 complications of 39 procedures, both were procedures, both were fetal bradycardia fetal bradycardia requiring urgent C/Srequiring urgent C/S

– Group B: 2 Group B: 2 complications, both complications, both were premature were premature rupture of membranes rupture of membranes within 24 hrswithin 24 hrs

Authors’ conclusionsAuthors’ conclusions

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

Author’s RecommendationsAuthor’s Recommendations

1)1) Start empiric therapy with Start empiric therapy with either either IVIg 2 mg/kg/week OR IVIg 2 mg/kg/week OR IVIg 1 g/kg/week plus prednisone 0.5 mg/kg/week as IVIg 1 g/kg/week plus prednisone 0.5 mg/kg/week as close to 20 weeks as possibleclose to 20 weeks as possible

2)2) Offer all patients FBS at 32 weeks and institute Offer all patients FBS at 32 weeks and institute salvage therapy for fetal platelet counts <50*. If FBS salvage therapy for fetal platelet counts <50*. If FBS cannot be performed at that time, empirically institute cannot be performed at that time, empirically institute salvage therapy at 32 weeks.salvage therapy at 32 weeks.

3)3) Allow vaginal delivery only for those patients whose Allow vaginal delivery only for those patients whose fetuses were shown to have platelets >100 at 32 fetuses were shown to have platelets >100 at 32 weeks and remain compliant with therapy. OR- weeks and remain compliant with therapy. OR- empirically institute salvage therapy in all patients at 32 empirically institute salvage therapy in all patients at 32 weeks and then only perform FBS at 36 weeks in weeks and then only perform FBS at 36 weeks in those women who want to deliver vaginallythose women who want to deliver vaginally

A few thoughts….A few thoughts….

If an average pregnant woman weighs 70 If an average pregnant woman weighs 70 kg 2 g/kg/week of IVIg amounts to 140 kg 2 g/kg/week of IVIg amounts to 140 grams per week. grams per week.

If therapy starts at 20 weeks and If therapy starts at 20 weeks and continues to 40 weeks that’s 2800 grams continues to 40 weeks that’s 2800 grams of IVIg per patient of IVIg per patient

If IVIg costs about $70 per gram that If IVIg costs about $70 per gram that equals $196,000 per patientequals $196,000 per patient

What’s a girl to do?What’s a girl to do?

Ulitmately, the dicision about therapy has Ulitmately, the dicision about therapy has to be made by the patient, her husband to be made by the patient, her husband and their obstetrician. and their obstetrician.

However, perhaps we should evaluate However, perhaps we should evaluate alternative treatment strategies that would alternative treatment strategies that would cost less and expose the patient to less cost less and expose the patient to less blood products.blood products.