Transcript Antepartum Treatment Without Early Cordocentesis for

Antepartum Treatment Without
Early Cordocentesis for
Standard-Risk Alloimmune
ThrombocytopeniaA Randomized Controlled Trial
Berkowitz, Richard L et al Obstet Gynecol
2007: 11:249-55
Elianna Saidenberg February 2008
Case
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
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, 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 HPA4b 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 1st borns can be affected
Severe bleeding symptoms
Platelet count by GA
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
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 1988
7 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 + 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
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 2006- Parallel randomized trials of riskbased 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: 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
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)
2)
3)
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
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.
Allow vaginal delivery only for those patients whose
fetuses were shown to have platelets >100 at 32
weeks and remain compliant with therapy. ORempirically 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.