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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki City Maternity Hospital, and Finnish Red Cross Blood Transfusion Service, Helsinki, Finland.
Address reprint requests to: Susanna Sainio, MD Department of Obstetrics and Gynecology Helsinki University Central Hospital Haartmaninkatu 2 Hyks FIN-00029 Finland
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Abstract |
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Methods: We conducted a 1-year, population-based surveillance study involving all full-term infants (at least 37 weeks’ gestation) born to native Finnish women in Helsinki. In cases of thrombocytopenia (cord platelet count less than 150 x 109/L) clinical risk factors were evaluated and immunologic studies were performed on both parents and on the infant; 95% confidence intervals (CIs) were calculated on the basis of binomial distribution.
Results: Platelet counts were done in cord blood from 4489 infants, 84.9% of the study population. Eighty-nine infants had platelet counts below 150 x 109/L (2.0%; 95% CI 1.5, 2.3) in cord blood and 11 were less than 50 x 109/L (0.24%; 95% CI 0.10, 0.38). All causes of clinically important thrombocytopenia, those presenting with bleeding and requiring treatment, were related to fetomaternal alloimmune thrombocytopenia. The incidence of severe alloimmune thrombocytopenia was one in 1500 live births and one in 900 of all thrombocytopenia. An immunologic mechanism was involved in ten of 65 (15.4%; 95% CI 6.6, 24.2) infants studied and in four of 15 (26.7%; 95% CI 4.3, 49.1) cases of severe thrombocytopenia.
Conclusion: Immunologic studies should be considered in all cases of severe neonatal thrombocytopenia for careful monitoring and prevention of potentially severe complications in subsequent pregnancies.
Thrombocytopenia is common in low-birth-weight (LBW) preterm infants, occurring in 15–20% of infants in intensive care units.1–5 It is an independent risk factor for intraventricular hemorrhage and contributes to the high neurologic morbidity in those infants.5 In term infants, frequency of thrombocytopenia is less well documented. Recent studies of unselected newborns report incidence, defined as platelet count less than 150 x 109/L, to be 0.5–0.9%, and less than 50 x 109/L 0.12%.6–9
Causes of neonatal thrombocytopenia include infections, hypoxia, LBW, disseminated intravascular coagulation, and chromosomal and congenital abnormalities. In sick infants, thrombocytopenia is most severe several days after delivery.2,4 When present at birth, 30% of cases of thrombocytopenia are caused by maternal antiplatelet alloantibodies or autoantibodies that have crossed the placenta,6–8 the most serious consequence of which is intracranial hemorrhage.
In fetomaternal alloimmune thrombocytopenia, intracranial hemorrhage affects 15–20% of cases, up to half antenatally.10,11 In cases of autoimmune thrombocytopenia, the risk is estimated to be significantly lower, around 1%.9,12 It was suggested that the only neonates with severe thrombocytopenia leading to morbidity and mortality are those born to mothers with antiplatelet alloantibodies.9 At present, prenatal screening for fetomaternal alloimmune thrombocytopenia is not routine. Diagnosing the first affected child is often difficult. A term neonate typically exhibits purpura associated with severe thrombocytopenia. Platelet counts might continue to decrease after birth, and infants remain at risk for intracranial hemorrhage. Recognition of the disease and appropriate therapy are important to the affected child and in subsequent pregnancies.
Our aim in this prospective study was to assess the prevalence and causes of thrombocytopenia among full-term infants in a homogenous population. Special attention was paid to immune mechanisms of thrombocytopenia.
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Methods |
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Cord-blood samples were collected from 4588 infants. Each mother’s platelet count was measured at delivery. In 691 infants (13.1%), samples were not collected because of refusal of mothers or inability of midwives to collect samples owing to technical reasons. In 99 cases (2.2%), samples were clotted or microscopy showed aggregation. The final study group consisted of 4489 infants (84.9% of the original study population). All mothers were white; the mean (± standard deviation [SD]) maternal age was 30.4 ± 5.2 years. Half the mothers were nulliparous, and 33% had one, and 17% two or more previous deliveries. To exclude any possible bias in the selection of cord-blood samples, infants from whom no sample was collected or whose samples were clotted were compared for maternal age, maternal parity, birth weight, and Apgar scores with infants from whom counts were collected, and there were no significant differences between groups.
Cord platelet counts were done on ethylenediaminetetra-acetic acid anticoagulated blood with standard automatic blood cell counters (Advia 120, Bayer Diagnostics, Tarrytown, NY; and Celldyn 1600 or 3500, Abbot Laboratories, Santa Clara, CA). Platelet counts lower than 150 x 109/L or counts in which the instrument generated platelet-associated alarms, such as for clumping, were verified by microscopy.
In cases of neonatal thrombocytopenia (cord platelet count less than 150 x 109/L), platelet typing studies were done on both parents and the infant. The platelet alloantigens HPA-1, -2, -3, -5, and -6b were determined by polymerase chain reaction (PCR) amplification. Maternal samples were tested for glycoprotein-specific platelet-associated and serum platelet-reactive antibodies to paternal antigens and platelets of known phenotypes with a monoclonal antibody-immobilized platelet antigen assay.13,14
The diagnosis of fetomaternal alloimmune thrombocytopenia was confirmed by the specific antibody detected in the mother of an antigen-incompatible infant. In mothers with no detectable antibody, diagnosis was considered possible, although owing to the relative insensitivity of the antiplatelet antibody tests,8,10 some of those infants might still have had alloimmune thrombocytopenia. Because of nonspecificity of general antiplatelet autoantibodies, only glycoprotein-specific (anti-GPIbIX or IIbIIa) autoantibodies were considered significant in relation to neonatal thrombocytopenia.
Ultrasonography was used to identify intracranial hemorrhage or hematoma of the adrenal gland in infants with cord platelet counts less than 50 x 109/L. Statistical analysis was done with SPSS 7.5 software (SPSS Inc., Chicago, IL). Confidence intervals (CIs) (95%) were done based on binomial distribution. One-way analysis of variance and 
2 test were used to determine differences between groups.
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Results |
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). Results from the two study hospitals were similar. A total of 89 newborns (2.0%, 95% CI 1.5, 2.3) had cord platelet counts less than 150 x 109/L. The count was less than 100 x 109/L in 33 cases (0.67%, 95% CI 0.44, 0.90) and less than 50 x 109/L in 11 (0.24%, 95% CI 0.10, 0.38). Data on the severely thrombocytopenic infants are given in Table 1.
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Thirty-six of 89 infants appeared ill and were small for gestational age (SGA) (birth weight less than -2 SD for gestational age) (17), had perinatal asphyxia (5-minute Apgar scores less than 7 or umbilical artery pH less than 7.15) (five), hemolytic disease due to ABO incompatibility (two), signs of bacterial infection (two), congenital cytomegalovirus infection (one), congenital heart defect (three), chromosomal abnormalities (trisomy 21, Turner syndrome, and ring chromosome 15) (three), and hydrocephaly (one). Two infants (cases 1 and 8 in Table 1
) had petechiae at delivery or the following day, but were otherwise healthy and of normal birth weight. Neonatal-associated illnesses and their overlaps between the immunologic studies are shown in Figure 2.
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) developed severe and long-lasting thrombocytopenia during the first week.
Adequate samples were available from 65 of 89 cases of thrombocytopenia in cord blood (73%). No samples were available in 24 owing to breach of study protocol (15), ambulatory delivery (six), refusal (two), and infant death from chromosomal abnormality (one). Fetomaternal alloimmune thrombocytopenia was confirmed in four cases of HPA-1a immunization and one case of HPA-1b immunization. We considered it possible in three cases of HPA-1a, one case of HPA-1b, three cases of HPA-2b, four cases of HPA-3b, one case of HPA-5b, and two cases of HPA-6b incompatibility. Thus, incidence of severe confirmed alloimmune thrombocytopenia was one in 1500 live births, and that of all thrombocytopenia one in 900. Data on those infants are presented in Table 2. In five cases, neonatal thrombocytopenia was associated with maternal glycoprotein-specific, platelet-associated or serum-reactive antiplatelet autoantibodies. In all, an immunologic mechanism was detected in ten of 65 (15.4%; 95% CI 6.6, 24.2) infants studied and in four of 15 (26.7%; 95% CI 4.3, 49.1) infants with severe thrombocytopenia.
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). Among infants in whom cord platelet counts were not available, one had a large intracranial hematoma and another hematoma of the adrenal gland. Ultrasonographies were done because of clinical symptoms, and by that time their platelet counts were normal. There were six full-term intrauterine deaths. Autopsies were done on all of them, and none had signs of serious hemorrhage. |
Discussion |
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. In two of the most recent studies, the incidence of neonatal thrombocytopenia, based on neonatal samples, was around 0.5–0.9%.7,8 De Moerloose et al reported the prevalence in cord blood as well (0.9%), which was nearly twice as high as in their neonatal samples (0.5%) collected within 48 hours.7 This was similar to our finding that the frequency of thrombocytopenia was lower in the neonatal samples than cord blood. Of course, cord blood is more susceptible for clotting, but the minimum time for spontaneous resolution of thrombocytopenia in otherwise healthy newborns is not known. In our study, platelet counts were already normal in 45 of 78 control samples collected no later than the following day. Although our study design (repeat testing in only thrombocytopenic infants) limited the conclusions on that issue, rapid spontaneous recovery was seen not only in healthy infants, but in infants who were SGA or had perinatal asphyxia.
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Maternal disorders such as idiopathic thrombocytopenic purpura, other autoimmune disease, or preeclampsia were associated with neonatal thrombocytopenia at birth in eight of 89 infants. In all those, thrombocytopenia was only mild to moderate at birth, which with previous reports9,15,16 convinced us that severe fetal thrombocytopenia is seldom associated with idiopathic thrombocytopenic purpura, gestational thrombocytopenia, or preeclampsia. However, infants born to thrombocytopenic mothers did not have increased risk of neonatal thrombocytopenia.
An immunologic mechanism was involved in 15.4% of all cases, and in 26.7% cases of severe thrombocytopenia. Alloimmune thrombocytopenia was confirmed in five of 65 infants (7.7%; 95% CI 1.2, 14.2). The incidence of severe alloimmune thrombocytopenia was one in 1500 live births, and that of all thrombocytopenia one in 900, consistent with previous reports.6–8,17,18 Incidence in this study might have been underestimated because diagnosis was confirmed only when the specific antibody was detected in the mother of an antigen-incompatible infant. HPA-1a antibodies have been reported to be detectable in less than 80% of clinically suspected cases and even fewer cases when other HPA systems are concerned.6,8 The most frequent alloantigen in this study was HPA-1a, as in other reports.19 Incidence of neonatal thrombocytopenia due to HPA-1a alloimmunization in this study was one in 1200 live births, and with all the possible cases included, one in 600. All clinically important thrombocytopenia, which presented bleeding symptoms and required treatment, were related to HPA-1a alloimmunization.9
Incidence of neonatal thrombocytopenia might be underestimated if results of only neonatal control samples are reported. Although cord blood is susceptible to clotting, the incidence of thrombocytopenia at birth seems to be twice as high as at 1 day old. An immunologic mechanism was involved in 26.7% of cases of severe thrombocytopenia. All clinically important cases of thrombocytopenia, in which infants presented with bleeding symptoms and required treatment, were related to alloimmunization. The most frequent clinical risk factor for thrombocytopenia in this study was LBW, in almost a fourth of infants. However, an immunologic mechanism was also involved in those cases.
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Footnotes |
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Received May 13, 1999. Received in revised form August 4, 1999. Accepted August 19, 1999.
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References |
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2. Castle V, Andrew M, Kelton J, Giron D, Johnston M, Carter C. Frequency and mechanism of neonatal thrombocytopenia. J Pediatr 1986;108:749–55.[Medline]
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7. de Moerloose P, Boehlen F, Exterman P, Hochfeld P. Neonatal thrombocytopenia: Incidence and characterization of maternal antiplatelet antibodies by MAIPA assay. Br J Haematol 1998;100: 735–40.[Medline]
8. Uhrynowska M, Malaska K, Zupanska B. Neonatal thrombocytopenia: Incidence, serological and clinical observations. Am J Perinatol 1998;14:415–8.
9. Burrows R, Kelton J. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med 1993;329:1463–6.
10. Mueller-Eckhardt C, Grubert A, Weisheit M, Mueller-Eckhardt M, Kiefel V, Kroll H, et al. 348 cases of suspected neonatal alloimmune thrombocytopenias. Lancet 1989;i:363–6.
11. Pearson HA, Shulman NR, Marder VJ, Cone TE. Isoimmune neonatal thrombocytopenic purpura: Clinical and therapeutic considerations. Blood 1964;23:154–77.
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14. Joutsi L, Kekomäki R. Comparison of the direct platelet immunoflurescence test (direct PIFT) with a modified direct monoclonal antibody-specific immobilization of platelet antigens (direct MAIPA) in detection of platelet-associated IgG. Br J Haematol 1997;96:204–9.[Medline]
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16. Burrows RF, Andrew M. Neonatal thrombocytopenia in the hypertensive disorders of pregnancy. Obstet Gynecol 1990;76:234–8.
17. Blanchette VS, Chen L, de Friedberg S, Hogan VA, Trudel E, Decary F. Alloimmunization to the P1A1 platelet antigen: Results of a prospective study. Br J Haematol 1990;74:209–15.[Medline]
18. Doughty HA, Murphy MF, Vaters AH. Antenatal screening for fetal alloimmune thrombocytopenia: A result of a pilot study. Br J Haematol 1995;90:321–5.[Medline]
19. Williamson LM, Hackett G, Rennie J, Palmer CR, Maciver C, Hadfield R, et al. The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (P1A1, Zwa) as determined by antenatal screening. Blood 1998;92:2280–7.
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