Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn


      Intrauterine transfusion for severe alloimmunization in pregnancy performed <20 weeks’ gestation is associated with a higher fetal death rate. Intravenous immunoglobulins may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions.


      We evaluated whether maternal treatment with intravenous immunoglobulins defers the development of severe fetal anemia and its consequences in a retrospective cohort to which 12 fetal therapy centers contributed.

      Study Design

      We included consecutive pregnancies of alloimmunized women with a history of severe hemolytic disease and by propensity analysis compared index pregnancies treated with intravenous immunoglobulins (n = 24) with pregnancies managed without intravenous immunoglobulins (n = 28).


      In index pregnancies with intravenous immunoglobulin treatment, fetal anemia developed on average 15 days later compared to previous pregnancies (8% less often <20 weeks’ gestation). In pregnancies without intravenous immunoglobulin treatment anemia developed 9 days earlier compared to previous pregnancies (10% more <20 weeks), an adjusted 4-day between-group difference in favor of the immunoglobulin group (95% confidence interval, –10 to +18; P = .564). In the subcohort in which immunoglobulin treatment was started <13 weeks, anemia developed 25 days later and 31% less <20 weeks’ gestation (54% compared to 23%) than in the previous pregnancy. Fetal hydrops occurred in 4% of immunoglobulin-treated pregnancies and in 24% of those without intravenous immunoglobulin treatment (odds ratio, 0.03; 95% confidence interval, 0–0.5; P = .011). Exchange transfusions were given to 9% of neonates born from pregnancies with and in 37% without immunoglobulin treatment (odds ratio, 0.1; 95% confidence interval, 0–0.5; P = .009).


      Intravenous immunoglobulin treatment in mothers pregnant with a fetus at risk for hemolytic disease seems to have a potential clinically relevant, beneficial effect on the course and severity of the disease. Confirmation in a multicenter randomized trial is needed.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • de Haas M.
        • Thurik F.F.
        • Koelewijn J.M.
        • van der Schoot C.E.
        Hemolytic disease of the fetus and newborn.
        Vox Sang. 2015; 109: 99-113
        • Abbasi N.
        • Johnson J.A.
        • Ryan G.
        Fetal anemia.
        Ultrasound Obstet Gynecol. 2017; 50: 145-153
        • van Kamp I.L.
        • Klumper F.J.
        • Meerman R.H.
        • Oepkes D.
        • Scherjon S.A.
        • Kanhai H.H.
        Treatment of fetal anemia due to red-cell alloimmunization with intrauterine transfusions in The Netherlands, 1988-1999.
        Acta Obstet Gynecol Scand. 2004; 83: 731-737
        • Zwiers C.
        • Lindenburg I.T.M.
        • Klumper F.J.
        • de Haas M.
        • Oepkes D.
        • Van Kamp I.L.
        Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures.
        Ultrasound Obstet Gynecol. 2017; 50: 180-186
        • Yinon Y.
        • Visser J.
        • Kelly E.N.
        • et al.
        Early intrauterine transfusion in severe red blood cell alloimmunization.
        Ultrasound Obstet Gynecol. 2010; 36: 601-606
        • Canlorbe G.
        • Mace G.
        • Cortey A.
        • et al.
        Management of very early fetal anemia resulting from red-cell alloimmunization before 20 weeks of gestation.
        Obstet Gynecol. 2011; 118: 1323-1329
        • Poissonnier M.H.
        • Picone O.
        • Brossard Y.
        • Lepercq J.
        Intravenous fetal exchange transfusion before 22 weeks of gestation in early and severe red-cell fetomaternal alloimmunization.
        Fetal Diagn Ther. 2003; 18: 467-471
        • Howe D.T.
        • Michailidis G.D.
        Intraperitoneal transfusion in severe, early-onset Rh isoimmunization.
        Obstet Gynecol. 2007; 110: 880-884
        • Fox C.
        • Martin W.
        • Somerset D.A.
        • Thompson P.J.
        • Kilby M.D.
        Early intraperitoneal transfusion and adjuvant maternal immunoglobulin therapy in the treatment of severe red cell alloimmunization prior to fetal intravascular transfusion.
        Fetal Diagn Ther. 2008; 23: 159-163
        • Voto L.S.
        • Mathet E.R.
        • Zapaterio J.L.
        • Orti J.
        • Lede R.L.
        • Margulies M.
        High-dose gammaglobulin (IVIG) followed by intrauterine transfusions (IUTs): a new alternative for the treatment of severe fetal hemolytic disease.
        J Perinat Med. 1997; 25: 85-88
        • Connan K.
        • Kornman L.
        • Savoia H.
        • Palma-Dias R.
        • Rowlands S.
        IVIG–is it the answer? Maternal administration of immunoglobulin for severe fetal red blood cell alloimmunization during pregnancy: a case series.
        Aust N Z J Obstet Gynaecol. 2009; 49: 612-618
        • Gelfand E.W.
        Intravenous immune globulin in autoimmune and inflammatory diseases.
        N Engl J Med. 2012; 367: 2015-2025
        • van den Akker E.S.
        • Oepkes D.
        Fetal and neonatal alloimmune thrombocytopenia.
        Best Pract Res Clin Obstet Gynaecol. 2008; 22: 3-14
        • Margulies M.
        • Voto L.S.
        • Mathet E.
        • Margulies M.
        High-dose intravenous IgG for the treatment of severe rhesus alloimmunization.
        Vox Sang. 1991; 61: 181-189
        • Clark A.L.
        Clinical uses of intravenous immunoglobulin in pregnancy.
        Clin Obstet Gynecol. 1999; 42: 368-380
        • Thung S.F.
        • Grobman W.A.
        The cost effectiveness of empiric intravenous immunoglobulin for the antepartum treatment of fetal and neonatal alloimmune thrombocytopenia.
        Am J Obstet Gynecol. 2005; 193: 1094-1099
        • Kriplani A.
        • Malhotra Singh B.
        • Mandal K.
        Fetal intravenous immunoglobulin therapy in rhesus hemolytic disease.
        Gynecol Obstet Invest. 2007; 63: 176-180
        • Moise Jr., K.J.
        Management of rhesus alloimmunization in pregnancy.
        Obstet Gynecol. 2002; 100: 600-611
        • Mari G.
        • Deter R.L.
        • Carpenter R.L.
        • et al.
        Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses.
        N Engl J Med. 2000; 342: 9-14
        • Nicolaides K.H.
        • Soothill P.W.
        • Clewell W.H.
        • Rodeck C.H.
        • Mibashan R.S.
        • Campbell S.
        Fetal hemoglobin measurement in the assessment of red cell isoimmunization.
        Lancet. 1988; 1: 1073-1075
        • Austin P.C.
        An introduction to propensity score methods for reducing the effects of confounding in observational studies.
        Multivariate Behav Res. 2011; 46: 399-424
        • Lindenburg I.T.
        • Smits-Wintjens V.E.
        • van Klink J.M.
        • et al.
        Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study.
        Am J Obstet Gynecol. 2012; 206: 141.e1-141.e8
        • Santos M.C.
        • Sa C.
        • Gomes Jr., S.C.
        • Camacho L.A.
        • Moreira M.E.
        The efficacy of the use of intravenous human immunoglobulin in Brazilian newborns with rhesus hemolytic disease: a randomized double-blind trial.
        Transfusion. 2013; 53: 777-782
        • Smits-Wintjens V.E.
        • Walther F.J.
        • Rath M.E.
        • et al.
        Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial.
        Pediatrics. 2011; 127: 680-686
        • Steiner L.A.
        • Bizzarro M.J.
        • Ehrenkranz R.A.
        • Gallagher P.G.
        A decline in the frequency of neonatal exchange transfusions and its effect on exchange-related morbidity and mortality.
        Pediatrics. 2007; 120: 27-32
        • Orchard C.
        Comparing healthcare outcomes.
        BMJ. 1994; 308: 1493-1496
        • Austin P.C.
        • Stuart E.A.
        Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
        Stat Med. 2015; 34: 3661-3679