HIP (HPA-screening in pregnancy) study: protocol of a nationwide, prospective and observational study to assess incidence and natural history of fetal/neonatal alloimmune thrombocytopenia and identifying pregnancies at risk

Dian Winkelhorst, Thijs W de Vos, Marije M Kamphuis, Leendert Porcelijn, Enrico Lopriore, Dick Oepkes, C Ellen van der Schoot, Masja de Haas, Dian Winkelhorst, Thijs W de Vos, Marije M Kamphuis, Leendert Porcelijn, Enrico Lopriore, Dick Oepkes, C Ellen van der Schoot, Masja de Haas

Abstract

Introduction: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may lead to severe fetal or neonatal bleeding and/or perinatal death. Maternal alloantibodies, targeted against fetal human platelet antigens (HPAs), can result thrombocytopenia and bleeding complications. In pregnancies with known immunisation, fetal bleeding can be prevented by weekly maternal intravenous immunoglobulin infusions. Without population-based screening, immunisation is only detected after birth of an affected infant. Affected cases that might have been prevented, when timely identified through population-based screening. Implementation is hampered by the lack of knowledge on incidence, natural history and identification of pregnancies at high risk of bleeding. We designed a study aimed to obtain this missing knowledge.

Methods and analysis: The HIP (HPA-screening in pregnancy) study is a nationwide, prospective and observational cohort study aimed to assess incidence and natural history of FNAIT as well as identifying pregnancies at high risk for developing bleeding complications. For logistic reasons, we invite rhesus D-negative or rhesus c-negative pregnant women, who take part in the Dutch population-based prenatal screening programme for erythrocyte immunisation, to participate in our study. Serological HPA-1a typing is performed and a luminex-based multiplex assay will be performed for the detection of anti-HPA-1a antibodies. Results will not be communicated to patients or caregivers. Clinical data of HPA-1a negative women and an HPA-1a positive control group will be collected after birth. Samples of HPA-1a immunised pregnancies with and without signs of bleeding will be compared with identify parameters for identification of pregnancies at high risk for bleeding complications.

Ethics and dissemination: Ethical approval for this study has been obtained from the Medical Ethical Committee Leiden-The Hague-Delft (P16.002). Study enrolment began in March 2017. All pregnant women have to give informed consent for testing according to the protocol. Results of the study will be disseminated through congresses and publication in relevant peer-reviewed journals.

Trial registration number: NCT04067375.

Keywords: fetal medicine; neonatology; prenatal diagnosis.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Schedule of selection, enrolment and tests in the HIP study. HIP, HPA-screening in pregnancy; HPA, human platelet antigen; PSIE, prenatal screening of infectious diseases and erythrocyte immunisation; RhD, rhesus D; Rhc, rhesus c.
Figure 2
Figure 2
Clinical parameters. These clinical parameters will be collected in the human platelet antigen-screening in pregnancy study. CRP, C-reactive protein.

References

    1. Burrows RF, Kelton JG. Thrombocytopenia at delivery: a prospective survey of 6715 deliveries. Am J Obstet Gynecol 1990;162:731–4. 10.1016/0002-9378(90)90996-K
    1. Dreyfus M, Kaplan C, Verdy E, et al. . Frequency of immune thrombocytopenia in newborns: a prospective study. Immune thrombocytopenia working group. Blood 1997;89:4402–6.
    1. Winkelhorst D, Kamphuis MM, de Kloet LC, et al. . Severe bleeding complications other than intracranial hemorrhage in neonatal alloimmune thrombocytopenia: a case series and review of the literature. Transfusion 2016;56:1230–5. 10.1111/trf.13550
    1. Tiller H, Kamphuis MM, Flodmark O, et al. . Fetal intracranial haemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry. BMJ Open 2013;3:002490. 10.1136/bmjopen-2012-002490
    1. Winkelhorst D, Murphy MF, Greinacher A, et al. . Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review. Blood 2017;129:1538–47. 10.1182/blood-2016-10-739656
    1. Mueller-Eckhardt C, Kiefel V, Grubert A, et al. . 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet 1989;1:363–6. 10.1016/s0140-6736(89)91733-9
    1. Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PIA2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest 1989;83:1778–81. 10.1172/JCI114082
    1. Davoren A, Curtis BR, Aster RH, et al. . Human platelet antigen-specific alloantibodies implicated in 1162 cases of neonatal alloimmune thrombocytopenia. Transfusion 2004;44:1220–5. 10.1111/j.1537-2995.2004.04026.x
    1. Campbell S, Swann HR, Seif MW, et al. . Cell adhesion molecules on the oocyte and preimplantation human embryo. Hum Reprod 1995;10:1571–8. 10.1093/humrep/10.6.1571
    1. Sajid M, Stouffer GA. The role of alpha(v)beta3 integrins in vascular healing. Thromb Haemost 2002;87:187–93.
    1. de Haas M, Thurik FF, Koelewijn JM, et al. . Haemolytic disease of the fetus and newborn. Vox Sang 2015;109:99–113. 10.1111/vox.12265
    1. Husebekk A, Killie MK, Kjeldsen-Kragh J, et al. . Is it time to implement HPA-1 screening in pregnancy? Curr Opin Hematol 2009;16:497–502. 10.1097/MOH.0b013e3283317be9
    1. Kjeldsen-Kragh J, Ni H, Skogen B. Towards a prophylactic treatment of HPA-related foetal and neonatal alloimmune thrombocytopenia. Curr Opin Hematol 2012;19:469–74. 10.1097/MOH.0b013e328358f86c
    1. Murphy MF, Williamson LM. Antenatal screening for fetomaternal alloimmune thrombocytopenia: an evaluation using the criteria of the UK national screening committee. Br J Haematol 2000;111:726–32.
    1. Blanchette VS, Chen L, de Friedberg ZS, et al. . Alloimmunization to the PlA1 platelet antigen: results of a prospective study. Br J Haematol 1990;74:209–15. 10.1111/j.1365-2141.1990.tb02567.x
    1. Durand-Zaleski I, Schlegel N, Blum-Boisgard C, et al. . Screening primiparous women and newborns for fetal/neonatal alloimmune thrombocytopenia: a prospective comparison of effectiveness and costs. immune thrombocytopenia Working group. Am J Perinatol 1996;13:423–31. 10.1055/s-2007-994382
    1. Davoren A, McParland P, Crowley J, et al. . Antenatal screening for human platelet antigen-1a: results of a prospective study at a large maternity hospital in Ireland. BJOG 2003;110:492–6. 10.1046/j.1471-0528.2003.02335.x
    1. Maslanka K, Guz K, Zupanska B. Antenatal screening of unselected pregnant women for HPA-1a antigen, antibody and alloimmune thrombocytopenia. Vox Sang 2003;85:326–7. 10.1111/j.0042-9007.2003.00363.x
    1. Kjeldsen-Kragh J, Killie MK, Tomter G, et al. . A screening and intervention program aimed to reduce mortality and serious morbidity associated with severe neonatal alloimmune thrombocytopenia. Blood 2007;110:833–9. 10.1182/blood-2006-08-040121
    1. Zwiers C, van Kamp I, Oepkes D, et al. . Intrauterine transfusion and non-invasive treatment options for hemolytic disease of the fetus and newborn - review on current management and outcome. Expert Rev Hematol 2017;10:337–44. 10.1080/17474086.2017.1305265
    1. Hamberg-van Reenen L, van den Berg HH, van den Berg M, et al. . Kosteneffectiviteit van preventie. Rijksinstituut voor Volksgezondheid en Milieu (RIVM), 2009.
    1. SY VderLAMA, Oomen P, Vos K. Prenatale screening Infectieziekten en Erytrocytenimmunisatie (PSIE. TNO/RIVM, 2018.
    1. van der Ploeg K, Schönbeck Y, Oomen P, et al. . Prenatale screening Infectieziekten en Erytrocytenimmunisatie (PSIE, 2018.
    1. Kapur R, Kustiawan I, Vestrheim A, et al. . A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy. Blood 2014;123:471–80. 10.1182/blood-2013-09-527978
    1. Kapur R, Heitink-Pollé KMJ, Porcelijn L, et al. . C-Reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia. Blood 2015;125:1793–802. 10.1182/blood-2014-05-579110
    1. Sonneveld ME, Natunen S, Sainio S, et al. . Glycosylation pattern of anti-platelet IgG is stable during pregnancy and predicts clinical outcome in alloimmune thrombocytopenia. Br J Haematol 2016;174:310–20. 10.1111/bjh.14053
    1. L'Abbé D, Tremblay L, Filion M, et al. . Alloimmunization to platelet antigen HPA-1a (PIA1) is strongly associated with both HLA-DRB3*0101 and HLA-DQB1*0201. Hum Immunol 1992;34:107–14. 10.1016/0198-8859(92)90036-M
    1. Metcalfe P, Allen D, Chapman J, et al. . Interlaboratory variation in the detection of clinically significant alloantibodies against human platelet alloantigens. Br J Haematol 1997;97:204–7. 10.1046/j.1365-2141.1997.9992647.x
    1. Kamphuis MM, Paridaans N, Porcelijn L, et al. . Screening in pregnancy for fetal or neonatal alloimmune thrombocytopenia: systematic review. BJOG 2010;117:1335–43. 10.1111/j.1471-0528.2010.02657.x
    1. Gupta SN, Kechli AM, Kanamalla US. Intracranial hemorrhage in term newborns: management and outcomes. Pediatr Neurol 2009;40:1–12. 10.1016/j.pediatrneurol.2008.09.019
    1. Winkelhorst D, Loeff RM, van den Akker-Van Marle ME, et al. . Women's attitude towards routine human platelet antigen-screening in pregnancy. Acta Obstet Gynecol Scand 2017;96:991–7. 10.1111/aogs.13150
    1. Koelewijn JM, Vrijkotte TGM, van der Schoot CE, et al. . Effect of screening for red cell antibodies, other than anti-D, to detect hemolytic disease of the fetus and newborn: a population study in the Netherlands. Transfusion 2008;48:941–52. 10.1111/j.1537-2995.2007.01625.x
    1. Winkelhorst D, Kamphuis MM, Steggerda SJ, et al. . Perinatal outcome and long-term neurodevelopment after intracranial haemorrhage due to fetal and neonatal alloimmune thrombocytopenia. Fetal Diagn Ther 2019;45:184–91. 10.1159/000488280
    1. Williamson LM, Hackett G, Rennie J, et al. . The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as determined by antenatal screening. Blood 1998;92:2280–7. 10.1182/blood.V92.7.2280
    1. Porcelijn L, Huiskes E, Comijs-van Osselen I, et al. . A new bead-based human platelet antigen antibodies detection assay versus the monoclonal antibody immobilization of platelet antigens assay. Transfusion 2014;54:1486–92. 10.1111/trf.12509

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