1. DEBATE Role Of IVIG In RH isoimmunization
Dr. Najat Rooh-Al-Deen
Consultant Hematology
Maternity Hospital

2. IVIG—Is It the Answer? 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

3. IVIG—Is It the Answer? 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

4. About 1 in 10 pregnancies involve an Rh-negative mother and an Rh-positive father

5. 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

7. IVIG—Is It the Answer? 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

8. 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

9. 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

10. 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

11. Complications of intravascular IUT Leiden Experience
740 transfusions (254 fetuses), median 3 (1-7) per fetus
First IUT: 27.1 ( ) wk,
hydrops 38%,
Hct 15 (4-38)%
Survival 89%

12. Intrauterine transfusions -Complication
Brady cardia %
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

13. 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).

14. 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

15. severe maternal red cell alloimmunization is before 20 weeks ’ gestation
a “ challenging ” due to
even if the IUT is completed successfully, the premature anemic fetus will not tolerate the acute hemodynamic changes.
The technically difficult access in fetal intravascular system despite improved ultrasound resolution.
The operator has to target the umbilical cord vessels that measure < 3 – 5 mm in diameter
The estimated overall IUT procedure-related fetal loss rate was 5.6 % when performed at < 20 weeks ’ gestation
especially if the Hgb level is < 5 SD for gestation fetal hydrops

16. IVIG

17. 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

18. Management of severe red cell alloimmunisation - IV Immune globulin

19. Landmarks in the History of Immunoglobulin Replacement Therapy
IVIG introduced and becomes standard therapy due to reduction of bacterial and non-bacterial infections4
Renewed interest in SCIG as alternative to IV therapy, especially for home use5
Janeway and Gitlin prefer IM injections, and this becomes standard of care in US2
1952
1953
1955
1980
1990s
2006
Bruton treats first patient diagnosed with agammaglobulinemia with SC injections of immune serum globulin (ISG)1
Berger introduces battery-powered pumps to slowly administer IM ISG by SC route3
First Sub-cu
IgG
Licensed in US
Landmarks in the History of Immunoglobulin Replacement Therapy
The era of accurate diagnosis and therapy of immunodeficiency states began in the 1950s. Bruton, Janeway and Gitlin were leaders in the field and treated some of the first patients to be diagnosed with primary immunodeficiency, and established that subcutaneous and IM injections of gammaglobulin were viable methods of treating these patients.1,2
Techniques were improved and in the early 1980s, Berger introduced the battery pump to slowly administer ISG (immune serum globulin).3
In the early 1980s, IVIG replacement therapy became standard of care when preparations with an acceptable incidence of systemic reactions were finally achieved, and it was demonstrated that the incidence of bacterial and non-bacterial infections could be significantly reduced with IVIG treatment.4
In the 1990s there was a renewed interest in the SC method of delivery, especially for home use.5
Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:
Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol ;112:1-7.
Berger M. et al. Immunoglobulin Replacement by Slow Subcutaneous Infusion. Ann Intern Med.1980;98:55-56.
Quartier P. et al. Early and prolonged immunoglobulin replacement therapy in childhood aggamaglobulinemia: A retrospective survey of 31 patients. Journal of Pediatrics. 1999;134:5:
Abrahamsen TG, et al. Sanderson H. Home Therapy With Subcutaneous Immunoglobulin Infusions in Children with Congenital Immunodeficiencies. Pediatrics. 1996;98:
Bruton OC. Pediatrics. 1952;9:
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:
Abrahamsen TG. Et al. Pediatrics. 1996;98:

20. Management of severe red cell alloimmunisation - IV Immune globulin
Prevent placental Fc-mediated endocytosis reduce passage maternally-derived alloantibodies

21. 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
The requirements for donor screening and transmissible disease testing of input plasma are stringent
. In addition, the IVIG manufacturing
process itself includes at least 1 and usually 2 steps of viral inactivation

22. Role Of IVIG in
Management of red cell alloimmunisation Options for severe early disease
( studies )

23. 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

24. Management of severe red cell alloimmunisation IV Immune globulin
IV IG
IVIG + IUT
IV IG + plasmaphoresis +/- IUT

25. Management of severe red cell alloimmunisation IV Immune globulin
IV IG
IVIG + IUT
IV IG + plasmaphoresis +/- IUT

26. 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.

27. Management of severe red cell alloimmunisation IV Immune globulin
IV IG
IVIG + IUT
IV IG + plasmaphoresis +/- IUT

29. GA first IUT greater and fetal mortality 36% lower in combined group
Voto et al IUT vs IUT + IVIG
GA first IUT greater and fetal mortality 36% lower in combined group

30. 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

31. Management of severe red cell alloimmunisation IV Immune globulin
IV IG
IVIG + IUT
IV IG + plasmaphoresis +/- IUT

32. 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

33. Management of severe red cell alloimmunisation Combined plasmapheresis & IVIG
Ruma et al severe cases (IUFD 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

35. 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 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.

36. 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 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.
CONCLUSION
Combined immunomodulation with plasmapheresis and IVIG represents a successful approach to the treatment of severe maternal red cell alloimmunization.

37. Management of severe red cell alloimmunisation-IV IG + plasmaphoresis +/- IUT

38. Case Report

39. Successful Management of Severe Hemolytic Disease of Newborn using a
Management of severe red cell alloimmunisation Combined plasmapheresis & IVIG- Case 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

40. 5 subsequent successful IUTs over 3 months
Management of severe red cell alloimmunisation Combined plasmapheresis & IVIG- Case Report
First IUT at 19.2 weeks
5 subsequent successful IUTs over 3 months
anti D, anti-C and anti-G Jka
60% reduction with each procedure
sensitized mother with
Severe HDN
multiple alloantibodies with markedly elevated titers (Multiple more 1:16000).
3 TPE procedures
performed every other day
Loading dose of IVIG (2 gm/kg)
Immediately following after the 3rd TPE
Bandarenko N., Stagg K.,Immel Caroline C., Moise K.M., Moise

42. 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

43. 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

44. IVIG—Is It the Answer?
Disease Nature
IUT – related issues
Does IVIG has a real role-----
Maternity Hospital – related issues
Absence of highly qualified feto-maternal specialist
Long term outcome in children treated with IUT d/t RBC alloimmunization
Reaserch interest in the monitoring and treatment of fetal anemia

45. 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

47. 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

48. 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

49. 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

52. The focus of research interest has shifted from the invasive management to a non-invasive monitoring and treatment of fetal anemia

54. 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:
Hall et al. Blood 2005;105:2175-9

55. IVIG—Is It the Answer?
Intravenous immune globulin should not be expected
to eliminate the need for intravascular
transfusions but can prolong the interval before the first
procedure is necessary
the inactivation of the FcRn receptor ( prevents the catabolism of IgG,) resulting in increased catabolism of the harmful antibodies as well
IVIG has been noted to decrease the passage of maternal anti-D
CONCLUSIONS IVIg may enter fetal blood circulation via placenta, and adjust fetal immune ability to reduce the degree of fetal hemolysis.
Immune therapy in established cases of alloimmunisation show promise but has yet to be translated into routine clinical management.

56. 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.

57. 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)

58. THANK YOU