Transfus Clin Biol 2001 ; 8 : 311-4 2001 ditions scientiques et mdicales Elsevier SAS.

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Immune thrombocytopenia in the foetus and the newborn: diagnosis and therapy
C. Kaplan*
Unit dImmunologie Plaquettaire, INTS, 6 rue Alexandre Cabanel, 75015 Paris, France

Summary Thrombocytopenia is a common condition in intensive care units. However the frequency of neonatal thrombocytopenia in all newborns (< 150109/L) has been estimated at 14%. Foetal/neonatal immune thrombocytopenia due to the transplacental passage of maternal antiplatelet IgG is a transient passive disease in an otherwise healthy newborn. The major risk of severe thrombocytopenia is intracranial haemorrhage (ICH) leading to death or neurological impairment. The principal aim in the management of the affected infants is to prevent the deleterious consequences of severe thrombocytopenia. Autoimmune thrombocytopenic purpura (AITP) in pregnant women can induce moderate or severe thrombocytopenia in the foetus or the newborn whatever the mothers disease status. Foetal thrombocytopenia can occur as early as 20 weeks of gestation. The frequency of ICH has been estimated to be 13% of cases. Foetal thrombocytopenia cannot be prevented. After birth, thrombocytopenia usually worsens during the first days of life. Postnatal management is usually ly of intravenous immunoglobulins. Neonatal alloimmune thrombocytopenia is considered to be the platelet counterpart of haemolytic disease of the newborn. Severe bleeding in the central nervous system and death (10% of cases) or neurological sequelae (20% of cases) may occur. The incidence of neonatal alloimmune thrombocytopenia has been estimated at 1 per 8001 000 live births. After birth, maternal platelet transfusion is the treatment of choice. Due to the high risk of recurrence of foetal thrombocytopenia in subsequent pregnancies, protocols for antenatal management including maternal therapy with intravenous immunoglobulins and/or corticosteroids, or in utero transfusion have been proposed. 2001 ditions scientifiques et mdicales Elsevier SAS alloimmunisation / autoimmunity / foetus / newborn / thrombocytopenia

Thrombocytopenia is a common condition in intensive care units [1]. However the frequency of neonatal thrombocytopenia in all newborns (< 150109/L) has been estimated at 14% [2]. The major risk of severe thrombocytopenia is intracranial haemorrhage (ICH), leading to death or neurological impairment. Moreover, foetal intracranial haemorrhage may be responsible for porencephaly and in utero death. At birth, in most instances neonatal thrombocytopenia is the only sign that draws attention to several possible aetiologies and thus to specic management of the infant, or to that of a subsequent pregnancy.

Immune foetal or neonatal thrombocytopenia results from platelet destruction by maternal antibodies crossing the placenta. In all cases immune thrombocytopenia is a transient passive disease in an otherwise healthy newborn. The principal aim in the management of affected infants is to prevent the deleterious consequences of severe thrombocytopenia. Foetal or neonatal immune thrombocytopenias are due either to maternal autoimmune thrombocytopenic purpura (AITP) or materno-foetal antiplatelet alloimmunisation.

*Correspondence and reprints. E-mail address: cecile.kaplan@teaser.fr (C. Kaplan).

312 MATERNAL AUTOIMMUNE THROMBOCYTOPENIC PURPURA AND FOETAL/NEONATAL THROMBOCYTOPENIA

C. Kaplan

Neonatal thrombocytopenia Neonatal thrombocytopenia usually worsens during the rst days of life with a nadir on day 3 to 5, and lasts from 10 to 60 days. Diagnosis The diagnosis is straightforward when the mother is known to have AITP. Maternal thrombocytopenia could suggest AITP. Laboratory testing for platelet autoantibodies should be performed even in a mother with normal platelet counts due to compensated thrombocytolysis. In many cases, the diagnosis of maternal AITP is completed during the post-partum period Therapy Postnatal management includes IVIgG, which has been shown to be effective in most cases, and low dose steroid therapy which may be prescribed as a haemostatic agent. Exchange transfusion has only a moderate and transient effect, but can be proposed in case of emergency. FOETAL/NEONATAL ALLOIMMUNE THROMBOCYTOPENIA Neonatal alloimmune thrombocytopenia (NAIT) results from maternal allo-immunisation against foetal platelet antigens inherited from the father, which the mother herself lacks. The incidence of foeto-maternal alloimmunisation (FMAIT) is estimated to be 1 per 800 to 1 000 live births [2, 7]. NAIT is considered to be the counterpart of Rh haemolytic disease in the newborn (HDN). In contrast to HDN, NAIT may affect the rst child. It is due to alloantibodies against platelet specic alloantigens. Five platelet specic alloantigen systems (HPA) [8] are mainly implicated in NAIT. In some cases, rare or private antigens have been described (table I). Foetal thrombocytopenia Severe thrombocytopenia can occur very early during gestation, and in utero ICH has been observed whatever the platelet alloantigens implicated with a reported frequency of 10% cases some of them occur before 20 weeks of gestation. When serial platelet counts are
Transfus Clin Biol 2001 ; 8 : 3114

AITP in pregnant women can induce moderate or severe thrombocytopenia in the foetus or in the newborn whatever the mothers disease status. It is an unpredictable disorder and occurs in 3040% of cases. None of the mothers clinical or biological parameters can predict the risk of thrombocytopenia in the newborn [3, 4]. However, more recent studies have shown that severe neonatal thrombocytopenias are more often found in the offspring of women with previous splenectomy [5]. Furthermore, mothers with AITP and an HLA DRB3* phenotype seem to be protected against giving birth to a thrombocytopenic newborn, in contrast to those with HLA DR02, DR5* which could carry a higher risk [6]. Foetal thrombocytopenia Thrombocytopenia can be observed as early as 20 weeks of gestational age and increases as gestation proceeds. The frequency of ICH has been estimated at 13% of the cases. Foetal thrombocytopenia cannot be prevented: intravenous immunoglobulins (IVIgG) or steroids, even if effective in raising the mothers platelet counts, do not appear to be able to decrease foetal platelet destruction [3]. The mode of delivery of mothers with AITP has evolved during the past years. Caesarean section has been advocated to avoid potential intracranial haemorrhage in severely thrombocytopenic foetuses, whereas it has been suggested that vaginal delivery bears a higher risk. Recently the rationale for the assessment of foetal platelet counts has been subject to controversy, as there is no prospective study showing that caesarean section is more effective in preventing intracranial haemorrhage than vaginal delivery. Moreover, severe foetal thrombocytopenia is observed in only 1015% of cases, and not all of these foetuses will suffer intracranial bleeding (13%). As percutaneous umbilical blood sampling (PUBS) has a 0.51.5% complication rate, it is not recommended in this situation unless there has been a history of severe bleeding in the siblings. In the case of obstetrical complications and suspicion of severe foetal thrombocytopenia, we propose caesarean delivery as an alternative. After birth, close monitoring of the newborn platelet count is recommended.

Immune thrombocytopenia in the foetus and newborn Table I. Specific platelet alloantigens implicated in NAIT. Systems HPA-1 (= Zw = PlA) HPA-2 (Ko) HPA-3 (= Bak = Lek) HPA-4(= Yuk = Pen) HPA-5 (= Br = Hc = Zav) HPA-6w (= Ca = Tu) HPA-6wb* HPA-7w (= Mo) HPA-7wb* HPA-8w (= Sr) HPA-8wb* HPA-9w (Max) HPA-9wb* HPA-10w (= La) HPA10wb* HPA-11w (= Gro) HPA11wb* HPA-12w (= Iy) HPA12wb* HPA-13w (= Sit) HPA13bw* * Rare or private antigens. GPIa IIIa GPIb IIIa IIb IIIa IIIa Antigens HPA-1a HPA-1b HPA-2a HPA-2b HPA-3a HPA-3b HPA-4a HPA-4b HPA-5a HPA-5b Glycoproteins IIIa Ib IIb IIIa Ia IIIa Amino-acid substitution Leu33 Pro33 Thr145 Met145 Ile843 Ser843 Arg143 Gln143 Glu505 Lys505 Gln489 Atg489 Ala407 Pro407 Cys636 Arg636 Met837 Val837 Gln62 Arg62 His633 Arg633 Glu15 Gly15 Met799 Thr799

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mangioma, absence of radii). Visceral haemorrhages such as gastrointestinal bleeding or haematuria are less common than purpura or haematoma. The maternal history should be taken into account to eliminate the effect of drugs during pregnancy, maternal autoimmune thrombocytopenia or familial thrombocytopenia. However, one should be aware that NAIT may also be associated with other causes of neonatal thrombocytopenia, especially with maternal AITP [2]. If the infant is not rst-born, attention should be paid to the history of previous siblings during the neonatal period; thrombocytopenia when present is a strong argument for the diagnosis. The most serious complication is ICH (1030% of cases) leading to death in up to 10% of reported cases, or neurological sequelae in 20% of cases [10, 11] . ICH may be present at birth or can occur as long as the newborn remains thrombocytopenic. Conversely, the infant may be nonsymptomatic, with thrombocytopenia discovered incidentally and which hitherto had passed unnoticed. The risk of life-threatening haemorrhage necessitates prompt diagnosis and effective therapy. Diagnosis The diagnosis of NAIT is made initially on clinical grounds and depends upon the exclusion of other causes of neonatal thrombocytopenia. The neonatal platelet count is low and anaemia is only observed when secondary to bleeding. Platelet immunological investigations must be performed by an experienced laboratory in order to avoid erroneous diagnosis. The testing involves the detection of maternal circulating antibodies and the identication of the offending platelet antigen with the determination of the parents platelet genotype. Detection of antibodies is usually performed with antigen capture ELISA [12]. Molecular techniques are used for genotyping [13]. The diagnosis is straightforward when parental antigen incompatibility with a corresponding maternal antibody is present. However, it could be equivocal in the absence of such an antibody or when a new, rare or private antigen is implicated. In these cases, it is recommended that the parents and child be tested later on, especially when improved methods of detection become available. Any difficulties in conrming the diagnosis should not delay therapy when there are sufficient grounds for a provisional diagnosis to be made.

available, the platelet count falls as gestation progresses and there is no spontaneous correction of thrombocytopenia [9]. As the recurrence of NAIT is estimated to be over 90% in subsequent pregnancies with incompatible foetuses at least as severely affected as the previous foetus, the management of these high-risk pregnancies must take place in referral centres. Considerable efforts have been made to prevent foetal bleeding and to avoid birth trauma. Neonatal thrombocytopenia The usual presentation is that of a healthy mother, who gives birth to a full-term neonate which exhibits widespread purpura at birth or a few hours afterwards. Otherwise this infant is well, with no clinical signs of infection (hepatosplenomegaly) or malformation (haeTransfus Clin Biol 2001 ; 8 : 3114

314 Therapy

C. Kaplan

REFERENCES
1 Castle V, Andrew M, Kelton JG, Giron D, Johnston M, Carter C. Frequency and mechanism of neonatal thrombocytopenia. J Pediatr 1986 ; 108 : 749-55. 2 Dreyfus M, Kaplan C, Verdy E, Schlegel N, Durand-Zaleski I, Tchernia G, et al. Frequency of immune thrombocytopenia in newborns: a prospective study. Blood 1997 ; 89 : 4402-6. 3 Kaplan C, Daffos F, Forestier F, Tertian G, Catherine N, Pons JC, et al. Fetal platelet counts in thrombocytopenic pregnancy. Lancet 1990 ; 336 : 979-82. 4 Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in pregnancy. Semin Hematol 2000 ; 37 : 275-89. 5 Valat AS, Caulier MT, Devos P, Rugeri L, Wibaut B, Vaast P, et al. Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia. Br J Haematol 1998 ; 103 : 397-401. 6 Gandemer V, Kaplan C, Quelvennec E, Poulain P, Laurent MC, Semana G, et al. Pregnancy-associated autoimmune neonatal thrombocytopenia: role of maternal HLA genotype. Br J Haematol 1999 ; 104 : 878-85. 7 Durand-Zaleski I, Schlegel N, Blum-Boisgard C, Uzan S, Dreyfus M, Kaplan C, et al. Screening primiparous women and newborns for fetal/neonatal alloimmune thrombocytopenia: a prospective comparison of effectiveness and costs. Am J Perinatol 1996 ; 13 : 423-31. 8 von dem Borne AEGK, Decary F. Nomenclature of platelet specic antigens. Br J Haematol 1990 ; 74 : 2039-40. 9 Bussel J, Kaplan C. The fetal and neonatal consequences of maternal alloimmune thrombocytopenia. In: Michiels JJ, Ed. Acquired disorders of haemostasis: pathophysiology,clinical practice and basic research. London: Bailliere Tindall; 1998. p. 391-408. 10 Mueller-Eckhardt C, Kiefel V, Grubert A, Kroll H, Weisheit M, Schmidt S, et al. 348 cases of suspected neonatal allo-immune thrombocytopenia. Lancet 1989 ; i : 363-6. 11 Kaplan C, Morel-Kopp MC, Clemenceau S, Daffos F, Forestier F, Tchernia G. Fetal and neonatal alloimmune thrombocytopenia: current trends in diagnosis and therapy. Transfus Med 1992 ; 2 : 265-71. 12 Kiefel V, Santoso S, Weisheit M, Mueller-Eckhardt C. Monoclonal antibody-specic immobilization of platelet antigens (MAIPA): a new tool for the identication of platelet-reactive antibodies. Blood 1987 ; 70 : 1722-6. 13 Kroll H, Kiefel V, Santoso S. Clinical aspects and typing of platelet alloantigens. Vox Sang 1998 ; 74 (Suppl 2) : 345-54. 14 Bussel JB, Kaplan C. McFarland JG, and the Working Party on Neonatal Immune Thrombocytopenia of the Neonatal Hemostasis Subcommittee of the Scientic and Standardization Committee of the ISTH. Recommendations for the evaluation and treatment of neonatal autoimmune and alloimmune thrombocytopenia. Thromb Haemost 1991 ; 65 : 631-4. 15 Massey GV, McWilliams NB, Mueller DG, Napolitano A, Maurer HM. Intravenous immunoglobulin in treatment of neonatal isoimmune thrombocytopenia. J Pediatr 1987 ; 111 : 133-5. 16 Kaplan C, Murphy MF, Kroll H, Waters AH. Feto-maternal alloimmune thrombocytopenia: antenatal therapy with IvIgG and steroids more questions than answers. Br J Haematol 1998 ; 100 : 62-5.

The treatment of choice is the transfusion of platelets compatible with the maternal alloantibody. The most reliable donor is the mother. The maternal platelets must be washed to remove the maternal plasma containing the antibody, and irradiated to eliminate the risk of graft-versus-host-disease. If the mothers platelets are not available, considering that most cases of NAIT are linked with anti HPA-1a, some blood banks can provide phenotyped HPA-1b/1b donor platelets. In an emergency, exchange immunization transfusion, which removes part of the circulating antibodies, may be considered [14]. IVIgG administration can be considered only when haemorrhage is not obvious, because the effect is delayed for 1218 hours after injection [15]. In any case of NAIT, the platelet counts should be closely monitored and cranial and abdominal ultrasounds are required. Nevertheless, it is mandatory to monitor all infants with NAIT for at least 2 years after birth for evidence neurological impairment due to clinically silent ICH unless nuclear magnetic resonance (NMR) imaging has been performed. At the moment the preferred current management of subsequent pregnancies after an index case is aimed at preventing ICH during pregnancy and delivery. The optimal antenatal therapy to reverse foetal thrombocytopenia is still a matter of debate [16]. At present, alternatives include weekly maternal injection of high doses of immunoglobulins (IVIgG) with or without corticosteroids, or weekly intrauterine platelet transfusions with antigen-negative platelets. The results obtained by different groups in Europe and in the United States vary however so far no randomised trials have been performed [9, 16]. Thus, denite recommendations cannot be provided. In any case, pregnant women are advised to avoid vigorous exercise, trauma, and drugs that interfere with platelet function (e.g., aspirin, antibiotics). We also recommend the screening of the female siblings of the affected woman in order to detect at-risk individuals. In conclusion, unexpected or unexplained neonatal thrombocytopenia or severe early onset thrombocytopenia in both pre-term and full-term infants should raise the possibility of immune thrombocytopenia and guide investigations accordingly.

Transfus Clin Biol 2001 ; 8 : 3114