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

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Presentation on theme: "DEBATE Role Of IVIG In RH isoimmunization Dr. Najat Rooh-Al-Deen Consultant Hematology Maternity Hospital."— Presentation transcript:

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

2 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?

3 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 IVIG—Is It the Answer?

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

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7 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?

8 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?

9 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?

10 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?

11 740 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 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?

15 severe maternal red cell alloimmunization is before 20 weeks ’ gestation a “ challenging ” due to 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 even if the IUT is completed successfully, the premature anemic fetus will not tolerate the acute hemodynamic changes. 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 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?

18 Management of severe red cell alloimmunisation - IV Immune globulin

19 Landmarks in the History of Immunoglobulin Replacement Therapy 1952 Bruton treats first patient diagnosed with agammaglobulinemia with SC injections of immune serum globulin (ISG) Janeway and Gitlin prefer IM injections, and this becomes standard of care in US 2 Renewed interest in SCIG as alternative to IV therapy, especially for home use 5 1.Bruton OC. Pediatrics. 1952;9: Berger M. Clin Immunol. 2004;112: Berger M. et al. Ann Intern Med. 1980;98: Quartier P. et al. Jour Pediatrics. 1999;134:5: Abrahamsen TG. Et al. Pediatrics. 1996;98: Berger introduces battery- powered pumps to slowly administer IM ISG by SC route s IVIG introduced and becomes standard therapy due to reduction of bacterial and non-bacterial infections 4 First Sub-cu IgG IgG Licensed in US 2006

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

21 No disease transmission by any products since 1994 Viral inactivation continue to improve Solven/ Detergent remains the most commonly used method of viral inactivation IVIG and Viral Safety

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. 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

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

30 Connan et al 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 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 IV IG + plasmaphoresis +/- IUT Management of severe red cell alloimmunisation-IV IG + plasmaphoresis +/- IUT

33 Management of severe red cell alloimmunisation Combined plasmapheresis & IVIG Ruma et al 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

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35 RESULTS Fetus Fetus : All 9 fetuses subsequently required intrauterine transfusions (median 4; range 3-8). Infant Infant : All infants survived with a mean gestational age at delivery of 34 weeks (range weeks). Maternal antired cell titers : Maternal antired cell titers : were significantly reduced after plasmapheresis (P <.01) and remained decreased during IVIG therapy. Serial peak middle cerebral artery velocities : 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

36 RESULTS RESULTS Fetus Fetus : All 9 fetuses subsequently required intrauterine transfusions (median 4; range 3-8). Infant Infant : All infants survived with a mean gestational age at delivery of 34 weeks (range weeks). Maternal antired cell titers : Maternal antired cell titers : were significantly reduced after plasmapheresis (P <.01) and remained decreased during IVIG therapy. Serial peak middle cerebral artery velocities : 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. Management of severe red cell alloimmunisation Combined plasmapheresis & IVIG

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

38 Case Report

39 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

40 Bandarenko N., Stagg K.,Immel Caroline C., Moise K.M., Moise Management of severe red cell alloimmunisation Combined plasmapheresis & IVIG- Case Report 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 anti D, anti-C and anti-G Jka 60% reduction with each procedure 60% reduction with each procedure First IUT at 19.2 weeks 5 subsequent successful IUTs over 3 months

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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 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?

44 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 IVIG—Is It the Answer?

45 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?

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47 Long-Term Outcome- the LOTUS study Perinatal survival-91% (389/426) 338 (87%) children were included (age 2-17) 9% (31/338 neurodevelopmental impairment was detected in 9% (31/338): – Severe developmental delay ( 23) –Cerebral palsy (5) –Bilateral deafness (3) study SMFM 2011

48 Risk factors for NDI: –Hemoglobin at first IUT –Presence of fetal hydrops –Number of IUT’s –Severe neonatal morbidity SMFM 2011 Long-Term Outcome- the LOTUS study

49 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?

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

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54 Future Immune Therapy Maternal intravenous immune globulin Maternal intravenous immune globulin Paternal Leukocyte immunization to create antibodies Paternal Leukocyte immunization to create antibodies Intranasal RHD peptides to desensitize 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? CONCLUSION CONCLUSIONS IVIg may enter fetal blood circulation via placenta, and adjust fetal immune ability to reduce the degree of fetal hemolysis. IVIG has been noted to decrease the passage of maternal anti-D increased catabolism of the harmful antibodies as well the inactivation of the FcRn receptor ( prevents the catabolism of IgG,) resulting in increased catabolism of the harmful antibodies as well 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 Immune therapy in established cases of alloimmunisation show promise but has yet to be translated into routine clinical management.

56 Intravenous immunoglobulin promising therapy Early-onset Rh alloimmunization was offered as a promising therapy limited limited data were available to support it widespread use. evaluated in patients with 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) (H owe & Michailidis 2007) Plasmapheresis (from 12 w) IV immune globulin (1g/kg/wk from 12 wk)

58 THANK YOU


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