Transcript Slide 1

DEBATE
Role Of IVIG In RH
isoimmunization
Dr. Najat Rooh-Al-Deen
Consultant Hematology
Maternity Hospital
IVIG—Is It the Answer?
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Disease Nature ---Does IVIG has a real role----IUT – related issues-------Maternity Hospital – related issues
Long term outcome in children treated
with IUT d/t RBC alloimmunization
• Research interest in the monitoring and
treatment of fetal anemia
IVIG—Is It the Answer?
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•
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Disease Nature –---Does IVIG has a real role----Maternity Hospital – related issues
IUT – related issues-------Long term l outcome in children treated
with IUT d/t RBC alloimmunization
• Reaserch interest in the monitoring and
treatment of fetal anemia
About 1 in 10 pregnancies involve an Rh-negative
mother and an Rh-positive father
Background
• Hemolytic disease of the newborn (HDN)
-Devastating effects on fetal and maternal
health.
-Clinical management is challenging and
fetal prognosis
# High maternal antibody titer
# Multiple alloantibodies presence
It may start very early in pregnancy in severe
IVIG—Is It the Answer?
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•
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Disease Nature –---IUT – related issues-------Does IVIG has a real role----Maternity Hospital – related issues
Long term l outcome in children treated
with IUT d/t RBC alloimmunization
• Reaserch interest in the monitoring and
treatment of fetal anemia
IVIG—Is It the Answer?
• Disease Nature – related issues----• IUT – related issues-------– is an invasive procedure
– IUT-complication
– IUT- limitation in early severe maternal
isoimmunization
• Does IVIG has a real role----• Maternity Hospital – related issues
IVIG—Is It the Answer?
• Disease – related issues----• IUT – related issues-------– is an invasive procedure
– IUT-complication
– IUT- limitation in early severe maternal
isoimmunization
• Does IVIG has a real role----• Maternity Hospital – related issues
IVIG—Is It the Answer?
• Disease – related issues----• IUT – related issues-------– is an invasive procedure
– IUT-complication
– IUT- limitation in early severe maternal
isoimmunization
• Does IVIG has a real role----• Maternity Hospital – related issues
• 740 transfusions (254
fetuses), median 3 (1-7)
per fetus
• First IUT: 27.1 (16.6-35.6)
wk,
• hydrops 38%,
• Hct 15 (4-38)%
• Survival 89%
Intrauterine transfusions -Complication
• Brady cardia
3.1-12 %
• Preterm labor.
• Excessive bleeding and mixing of fetal and
maternal blood 65% if placenta anterior and
16% if placenta posterior %.
• Amniotic fluid leakage from the uterus.
• Fetal death 2.7%.
• Uterine infection rare.
• Fetal infection rare.
• Abruptio placentae
• Complications associated with intrauterine
procedures such as cord hematoma, hemorrhage,
fetal bradycardia and intrauterine death could
increase in the future
(Illanes S and Soothill PW, 2006).
IVIG—Is It the Answer?
• Disease – related issues----• IUT – related issues-------– is an invasive procedure
– IUT-complication
– IUT- limitation in early severe maternal
isoimmunization
• Does IVIG has a real role----• Maternity Hospital – related issues
severe maternal red cell alloimmunization is
before 20 weeks ’ gestation
a “ challenging ”
due to
•The
access
in fetal intravascular
system
despite
even technically
if the IUT isdifficult
completed
successfully,
the premature
anemic
improved
ultrasound
fetus
will not
tolerate
the
hemodynamic
changes.
The estimated
overallresolution.
IUT acute
procedure-related
fetal
loss rate was 5.6
•The
operator
has toattarget
the umbilical
cord vessels that measure
% when
performed
< 20 weeks
’ gestation
<especially
3 – 5 mmifin
diameter
the
Hgb level is < 5 SD for gestation fetal hydrops
IVIG
IVIG—Is It the Answer?
•
•
•
•
•
Disease Nature -------IUT – related issues-------Does IVIG has a real role----Maternity Hospital – related issues
Long term outcome in children treated
with IUT d/t RBC alloimmunization
• Reaserch interest in the monitoring and
treatment of fetal anemia
Management of severe red cell
alloimmunisation - IV Immune globulin
Landmarks in the History of Immunoglobulin
Replacement Therapy
Janeway and Gitlin prefer IM
injections, and this becomes
standard of care in US2
1952
IVIG introduced and becomes
standard therapy due to
reduction of bacterial and
non-bacterial infections4
1953 1955
Bruton treats first patient diagnosed
with agammaglobulinemia with SC injections of
immune serum globulin (ISG)1
1.
2.
3.
4.
5.
1980
Renewed interest
in SCIG as alternative to
IV therapy, especially for
home use5
1990s
Berger introduces batterypowered pumps to slowly
administer IM ISG by SC route3
Bruton OC. Pediatrics. 1952;9:722-728.
Berger M. Clin Immunol. 2004;112:1-7.
Berger M. et al. Ann Intern Med. 1980;98:55-56.
Quartier P. et al. Jour Pediatrics. 1999;134:5:589-596.
Abrahamsen TG. Et al. Pediatrics. 1996;98:1127-1131.
2006
First Sub-cu
IgG
Licensed in US
Management of severe red cell
alloimmunisation - IV Immune globulin
• Prevent placental Fc-mediated endocytosis
reduce passage maternally-derived
alloantibodies
IVIG and Viral Safety
• No disease transmission by any products
since 1994
• Viral inactivation continue to improve
• Solven/ Detergent remains the most
commonly used method of viral inactivation
Role Of IVIG in
Management of red cell
alloimmunisation
Options for severe early disease
( studies )
Retrospective case series (n=1-30) interpretation difficult;
- Variable severity (pre- or post- first IUT)
- 1g/kg/wk (from as early as 8w)
-Variable effects
Management of severe red cell
alloimmunisation
IV Immune globulin
• IV IG
• IVIG + IUT
• IV IG + plasmaphoresis +/- IUT
Management of severe red cell
alloimmunisation
IV Immune globulin
• IV IG
• IVIG + IUT
• IV IG + plasmaphoresis +/- IUT
Margulies et al. conducted the largest prospective series
to date in which 24 severely Rh-sensitized pregnant women were treated
with IVIG alone until delivery and
Demonstrated that IVIG use should be initiated before 28 weeks or before
the appearence of hydrops.
Management of severe red cell
alloimmunisation
IV Immune globulin
• IV IG
• IVIG + IUT
• IV IG + plasmaphoresis +/- IUT
Voto et al. 1997 IUT vs IUT + IVIG
GA first IUT greater and fetal mortality 36% lower in combined
group
Connan et al. reported a case series of six women at high-risk for severe disease
who were treated with weekly IVIG infusions and were monitored with MCA
Doppler ultrasound to time the required IUTs;
All experienced improved perinatal outcomes
Management of severe red cell
alloimmunisation
IV Immune globulin
• IV IG
• IVIG + IUT
• IV IG + plasmaphoresis +/- IUT
• Management of severe red cell alloimmunisation-IV IG +
plasmaphoresis +/- IUT
in a case series with nine fetuses (fi ve with anti-D and four with anti-K), concluded that the
combined immunomodulation could be theorized a successful treatment modality because all
the fetuses survived, with a mean gestational age at delivery of 34 weeks,
maternal antibody titers were significantly reduced after plasmapheresis and remained stable
during IVIG therapy
Management of severe red cell alloimmunisation
Combined plasmapheresis & IVIG
• Ruma et al. 2007 - 9 severe cases (IUFD 17-31 w or
high titre)
• 3 x single volume plasmaphersis (after 12 w) with
volume replaced with
• 5% albumin then
• IVIG 1g/kg/wk to 20 wk
Management of severe red cell alloimmunisation
Combined plasmapheresis & IVIG
RESULTS
• Fetus : All 9 fetuses subsequently required intrauterine
transfusions (median 4; range 3-8).
• Infant : All infants survived with a mean gestational age at
delivery of 34 weeks (range 26-38 weeks).
• Maternal antired cell titers : were significantly reduced after
plasmapheresis (P <.01) and remained decreased during IVIG
therapy.
• Serial peak middle cerebral artery velocities : remained
below the threshold for moderate to severe fetal anemia
during therapy.
Management of severe red cell alloimmunisation
Combined plasmapheresis & IVIG
• RESULTS
• Fetus : All 9 fetuses subsequently required intrauterine
transfusions (median 4; range 3-8).
• Infant
: All infants survived with a mean gestational age
CONCLUSION
at delivery
ofimmunomodulation
34 weeks (range
26-38
weeks).
Combined
with
plasmapheresis
and IVIG represents
successful
the
• Maternal
antiredacell
titersapproach
: were tosignificantly
reduced
treatment
of severe maternal
red cell
alloimmunization
.
after
plasmapheresis
(P <.01)
and
remained decreased
during IVIG therapy.
• Serial peak middle cerebral artery velocities : remained
below the threshold for moderate to severe fetal anemia
during therapy.
• Management of severe red cell alloimmunisation-IV IG +
plasmaphoresis +/- IUT
Case Report
Management of severe red cell alloimmunisation
Combined plasmapheresis & IVIGCase Report
Successful Management of Severe
Hemolytic Disease of Newborn using a
Combined Immunomodulatory Regimen:
TPE,
IVIG,
Intrauterine Transfusion and
RhIG
Bandarenko N., Stagg K.,Immel Caroline
C., Moise K.M., Moise K
Management of severe red cell alloimmunisation
Combined plasmapheresis & IVIG- Case
Report
First3 TPE
IUT procedures
at 19.2 weeks
sensitized
mother
with other day
performed
every
5 subsequent
successful
IUTs over 3
anti
D,HDN
anti-C and
anti-G Jka
Severe
Loading
dose
of
IVIG
(2
gm/kg)
months
multiple
alloantibodies
markedly
elevated
60% reduction
withwith
each
procedure
Immediately
following
after the 3rd TPE
titers
(Multiple more
1:16000).
Bandarenko N., Stagg K.,Immel Caroline
C., Moise K.M., Moise
RED CELL ALLOIMMUNIZATION
Immune Therapy
• Single volume plasmapheresis in week 10
on M, W, F (5% albumin for replacement)
• 1 gr/kg IVIG load after last plasmapheresis
• 1 gr/kg IVIG load the following day
• 1 gr/kg IVIG weekly until 20 weeks’
gestation
IVIG—Is It the Answer?
•
•
•
•
•
Disease Nature -------IUT – related issues-------Does IVIG has a real role----Maternity Hospital – related issues
Long term outcome in children treated
with IUT d/t RBC alloimmunization
• Reaserch interest in the monitoring and
treatment of fetal anemia
IVIG—Is It the Answer?
•
•
•
•
Disease Nature -------IUT – related issues-------Does IVIG has a real role----Maternity Hospital – related issues
– Absence of highly qualified fetomaternal specialist
• Long term outcome in children treated with IUT
d/t RBC alloimmunization
• Reaserch interest in the monitoring and treatment
of fetal anemia
IVIG—Is It the Answer?
•
•
•
•
•
Disease Nature -------IUT – related issues-------Does IVIG has a real role----Maternity Hospital – related issues
Long term outcome in children treated
with IUT d/t RBC alloimmunization
• Reaserch interest in the monitoring and
treatment of fetal anemia
Long-Term Outcome- the LOTUS study
• Perinatal survival-91% (389/426)
•338 (87%) children were included (age 2-17)
• neurodevelopmental impairment was detected in
9% (31/338):
–Severe developmental delay ( 23)
–Cerebral palsy (5)
–Bilateral deafness (3)
study SMFM 2011
Long-Term Outcome- the LOTUS study
•Risk factors for NDI:
–Hemoglobin at first IUT
–Presence of fetal hydrops
–Number of IUT’s
–Severe neonatal morbidity
SMFM 2011
IVIG—Is It the Answer?
•
•
•
•
•
Disease Nature -------IUT – related issues-------Does IVIG has a real role----Maternity Hospital – related issues
Long term outcome in children treated
with IUT d/t RBC alloimmunization
• Reaserch interest in the monitoring and
treatment of fetal anemia
• The focus of research interest has
shifted from the invasive management
to a non-invasive monitoring and
treatment of fetal anemia
Future Immune Therapy
• Maternal intravenous immune
globulin
• Paternal Leukocyte immunization to
create antibodies
• Intranasal RHD peptides to
desensitize
Whitecar et al. Am J Obstet Gynecol 2002;187:977-80.
Hall et al. Blood 2005;105:2175-9
IVIG—Is It the Answer?
Intravenous
immune
globulin
should
not be
expected
CONCLUSIONS
the
inactivation
IVIg
of
the
may
FcRn
enter
receptor
fetal
blood
(
prevents
circulation
theshow
Immune therapy in established cases of alloimmunisation
IVIG
has been
noted
decrease the passage of
to eliminate
the need
forto
intravascular
promise
but of
has
yetadjust
to
be translated
into routine
clinical
via
catabolism
placenta,
and
IgG,)
resulting
fetal
inimmune
increased
ability
catabolism
to reduce
of
transfusions
but
can
prolong
the
interval
before
the
first
maternal
anti-D
management.
the
degree
harmful
ofantibodies
fetal hemolysis.
as well
procedure
is necessary
Intravenous immunoglobulin
• Early-onset Rh alloimmunization was offered as a
promising therapy
• limited data were available to support it widespread
use.
evaluated in patients with
– Severe Rh immunization,
– High maternal antibody titers, and
– Previous pregnancy with early-onset hydrops and
intrauterine death and has been related to
– Reduction in overall IUT requirements and
– Beneficial effect on pregnancy outcome.
Management of red cell alloimmunisation
Options for severe early disease
• Weekly US (from 14 w) with intravascular
• transfusion if hydropic (from 17 w)
• Intraperitoneal transfusion (from 14 w)
(Howe & Michailidis 2007)
• Plasmapheresis (from 12 w)
• IV immune globulin (1g/kg/wk from 12 wk)
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