Original Presentation Transfusion Medicine by mikeholy


									Antepartum Treatment Without
   Early Cordocentesis for
 Standard-Risk Alloimmune
   A Randomized Controlled Trial
Berkowitz, Richard L et al Obstet Gynecol
            2007: 11:249-55

   Elianna Saidenberg February 2008
Mrs DA 25 yo G2A1L0
– 1st 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
– Maternal and paternal samples acquired for platelet Ag/ Ab
  testing in Hamilton
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
– Thrombocytopenia
  due to transplacentally
  acquired maternal IgG
  platelet alloantibodies
– 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, 2nd 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
– Lab criteria include:
     Low platelet count in fetus or neonate (<100)
     Evidence of maternal incompatibility for a platelet-associated
     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 1st borns can be affected
     Severe bleeding symptoms
     Platelet count by GA
            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 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 3rd 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
     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
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 1988
      7 alloimmunized HPA-1a negative pregnant women
      Fetal platelet count determined by percutaneous umbilical vein
      Treated with 1 g/kg IVIg weekly from ~20 weeks GA + 3-5 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 1984- 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 1994- 15 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
        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
– 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
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
 – 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 2006- 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
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
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
– If father heterozygous for platelet antigen in
  question HPA genotype of fetal platelet was
Randomized using computer-generated
random numbers
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
 – 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: 121
        9 fetuses with platelet count <30
        1 fetus with platelet count between 30-50, born with platelet count 14 at 36 weeks
 – Group B: 116
        5 fetuses with platelet count <30
        3 fetuses with platelet counts 30-50; all born with platelet count between 40-80
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: 169
        5 (14%) neonates with platelet counts <50
 – Group B: 134
        4 (11%) neonates with platelet counts <50
Complications of
– 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.

To top