DEBATE Role Of IVIG In RH isoimmunization

DEBATERole Of IVIG In RH isoimmunization Dr. NajatRooh-Al-Deen Consultant Hematology Maternity Hospital

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

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

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? • 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

Complications of intravascular IUTLeiden Experience • 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. • Abruptioplacentae

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 isbefore 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

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 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 1953 1955 1980 1952 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 • 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.

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 alloimmunisationOptions 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 alloimmunisationIV 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.

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 IG + plasmaphoresis +/- IUT • Management of severe red cell alloimmunisation-IV IG + plasmaphoresis +/- IUT in a case series with nine fetuses (five 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 alloimmunisationCombined 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 alloimmunisationCombined 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 alloimmunisationCombined 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. 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-IV IG + plasmaphoresis +/- IUT

Case Report

Management of severe red cell alloimmunisationCombined 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

Management of severe red cell alloimmunisationCombined plasmapheresis & IVIG- Case Report Bandarenko N., Stagg K.,Immel Caroline C., Moise K.M., Moise 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

RED CELL ALLOIMMUNIZATIONImmune 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 • 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

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

DEBATE Role Of IVIG In RH isoimmunization