How I diagnose and treat neonatal thrombocytopenia.

Neonatal thrombocytopenia, defined as the presence of a circulating platelet count <150 × 109/L, is a common abnormality in babies admitted to neonatal intensive care units. Thrombocytopenia that is typically mild and self-limiting often accompanies neonatal stress in scenarios such as premature delivery or intrauterine growth restriction. However, the differential diagnosis of neonatal thrombocytopenia is wide and includes potentially life-threatening disorders, such as bacterial sepsis, viral infection, and necrotizing enterocolitis. Distinguishing these causes of thrombocytopenia from entities such as genetic thrombocytopenia and fetal and neonatal alloimmune thrombocytopenia is critical for the accurate quantitation of significant adverse events, such as intracranial bleeding, and for the selection of treatments, such as platelet transfusion. In this review, we focus on common differential diagnoses of neonatal thrombocytopenia and highlight how the landscape of diagnosis and management is changing with recent advances in genomic technology and the completion of pivotal clinical trials of platelet transfusion practice. Increasing evidence highlights the need for judicious and restrictive use of platelet transfusions in neonates.

New Horizons in Fetal and Neonatal Alloimmune Thrombocytopenia.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a common cause of severe thrombocytopenia in newborns. Intracranial bleeding may lead to severe neurological sequelae and mortality. Current management of pregnancies at risk is suboptimal. Prenatal FNAIT diagnosis commonly requires invasive procedures and therapy is associated with a high treatment burden. The present review explores advances in the field and their potential contribution to modification of the diagnostic and therapeutic landscape. Topics addressed include the role of noninvasive prenatal testing using fetal cell free DNA, insights into novel and prospective therapeutic options achieved through the development of murine models of FNAIT as well as the forecast for the progress in pregnancy risk stratification through advancement in the investigation of biological characteristics of alloantibodies and their association with the risk of fetal bleeding.

Children Newly Diagnosed with Fetal and Neonatal Alloimmune Thrombocytopenia: Neurodevelopmental Outcome at School Age.

OBJECTIVE: To evaluate the neurodevelopmental outcome at school age in children newly diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT). STUDY DESIGN: This observational cohort study included children diagnosed with FNAIT between 2002 and 2014. Children were invited for cognitive and neurological testing. Behavioral questionnaires and school performance results were obtained. A composite outcome of neurodevelopmental impairment (NDI) was used, defined, and subdivided into mild-to-moderate and severe NDI. Primary outcome was severe NDI, defined as IQ <70, cerebral palsy with Gross Motor Functioning Classification System level ≥ III, or severe visual/hearing impairment. Mild-to-moderate NDI was defined as IQ 70-85, minor neurological dysfunction or cerebral palsy with Gross Motor Functioning Classification System level ≤ II, or mild visual/hearing impairment. RESULTS: In total, 44 children were included at a median age of 12 years (range: 6-17 years). Neuroimaging at diagnosis was available in 82% (36/44) of children. High-grade intracranial hemorrhage (ICH) was detected in 14% (5/36). Severe NDI was detected in 7% (3/44); two children had high-grade ICH, and one had low-grade ICH and perinatal asphyxia. Mild-to-moderate NDI was detected in 25% (11/44); one child had high-grade ICH, and eight children were without ICH, yet for two children, neuroimaging was not performed. Adverse outcome (perinatal death or NDI) was 39% (19/49). Four children (9%) attended special needs education, three of whom had severe NDI and one had mild-to-moderate NDI. Total behavioral problems within the clinical range were reported in 12%, which is comparable with 10% in the general Dutch population. CONCLUSION: Children who are newly diagnosed with FNAIT are at increased risk for long-term neurodevelopmental problems, even those without ICH. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (Identifier: NCT04529382).

Research Progress in Neonatal Alloimmune Thrombocytopenia: A Narrative Review.

Background: Neonatal alloimmune thrombocytopenia (NAIT) is an immune disorder characterized by maternal antibodies that destroy fetal platelets, leading to thrombocytopenia. The prevalence of NAIT is approximately 0.05% to 0.15%. Fetal and neonatal severe thrombocytopenia represents the most common form of the disease, primarily occurring in firstborn children. It poses a greater risk and harm to the fetus and newborn. Neonatal intracranial hemorrhage is a severe complication of NAIT, resulting in irreversible damage to cranial nerves and potential neonatal death. Objective: This study aims to assess the current advancements in the pathogenesis, clinical characteristics, laboratory evaluation, and therapeutic interventions for neonatal alloimmune thrombocytopenia. Methods: This narrative review explores neonatal alloimmune thrombocytopenia through a thorough literature review. The study encompasses the pathogenesis, clinical features, laboratory examination, and treatment options associated with this condition. Results: The results of this study highlight that despite the extremely low incidence of NAIT, it carries a high risk. Currently, there is no timely and effective prevention method available. However, using HPA-1a as a screening item for prenatal prevention shows the potential to reduce the mortality rate of NAIT fetuses. Further research is required to evaluate its accuracy and specificity. Conclusions: The findings of this review emphasize the need for further research to develop effective prevention methods. The use of HPA-1a as a screening tool holds promise but requires additional investigation. Enhancing clinical understanding of NAIT will contribute to improved management and outcomes for affected infants.

Anti-human platelet antigen-5b antibodies and fetal and neonatal alloimmune thrombocytopenia; incidental association or cause and effect?

Most cases of fetal and neonatal thrombocytopenia (FNAIT) are caused by maternal anti-human platelet antigen-1a antibodies (anti-HPA-1a). Anti-HPA-5b antibodies are the second most common antibodies in suspected FNAIT cases. Given the high prevalence of anti-HPA-5b antibodies in pregnant women delivering healthy newborns, the association with FNAIT may be coincidental. This review of the literature related to FNAIT using the MEDLINE database was conducted according to PRISMA guidelines. A retrospective analysis of a single-centre cohort of 817 suspected FNAIT cases was conducted. The pooled prevalence of anti-HPA-5b antibodies in unselected pregnant women of European descent was 1.96% (n = 3113), compared with 3.4% (n = 5003) in women with suspected FNAIT. We found weak evidence that a small proportion of pregnant women presenting with anti-HPA-5b antibodies will give birth to a newborn with mild thrombocytopenia. The neonatal platelet counts were not different between suspected FNAIT cases (n = 817) with and without maternal anti-HPA-5b antibodies. The prevalence of maternal anti-HPA-5b antibodies was not different between neonates with intracranial haemorrhage and healthy controls. The current experimental and epidemiological evidence does not support the hypothesis that anti-HPA-5b antibodies cause severe thrombocytopenia or bleeding complications in the fetus or newborn.

Long-term neurodevelopmental outcome in children after antenatal intravenous immune globulin treatment in fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Children with fetal and neonatal alloimmune thrombocytopenia face increased risk of intracranial hemorrhage potentially leading to developmental impairment. To prevent intracranial hemorrhage, pregnant women with alloantibodies against fetal platelets are often treated with intravenous immunoglobulin. Intravenous immunoglobulin seems effective in vastly reducing the risk of fetal or neonatal bleeding complications. However, information on long-term neurodevelopment of these children is lacking. OBJECTIVE: This study aimed to evaluate long-term neurodevelopmental outcome in children with fetal and neonatal alloimmune thrombocytopenia who were treated with intravenous immunoglobulin antenatally. STUDY DESIGN: An observational cohort study was performed, including children of mothers treated with intravenous immunoglobulin during pregnancy because a previous child was diagnosed with fetal and neonatal alloimmune thrombocytopenia. Children were invited for a follow-up assessment including standardized cognitive and neurologic tests. The parents were asked to complete a behavioral questionnaire and school performance reports. The primary outcome was severe neurodevelopmental impairment, defined as severe cognitive impairment (intelligence quotient <70), cerebral palsy with Gross Motor Function Classification System Level ≥3, bilateral blindness, and/or bilateral deafness (requiring amplification). The secondary outcome was mild to moderate neurodevelopmental impairment, defined as either mild to moderate cognitive impairment (intelligence quotient <85), cerebral palsy with Gross Motor Function Classification System Level ≤2, minor neurologic dysfunction, vision loss, and/or hearing loss. RESULTS: Between 2003 and 2017, 51 children were live-born after antenatal intravenous immunoglobulin treatment. One family moved abroad and was therefore not eligible for inclusion. In total, 82% (41/50) of the eligible cases were included for neurodevelopmental assessment at a median age of 9 years and 8 months. Severe neurodevelopmental impairment was not detected. The incidence of mild to moderate neurodevelopmental impairment was 14% (6/41; 95% confidence interval, 6%-29%). The children's mean cognitive score, behavioral scores, and academic achievement were not different from those observed in the Dutch norm groups. Neuroimaging was performed in 90% (37/41) of cases. Severe intracranial hemorrhage was diagnosed in 2 cases (5%), one antenatally before the start of intravenous immunoglobulin and the other case 1 day after birth. Both cases had a normal neurodevelopmental outcome. CONCLUSION: The risk of neurodevelopmental impairment in children whose mothers were treated for fetal and neonatal alloimmune thrombocytopenia with antenatal intravenous immunoglobulin is comparable to that reported in the general population.

Antenatal intravenous immunoglobulins in pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia: comparison of neonatal outcome in treated and nontreated pregnancies.

BACKGROUND: Maternal alloantibodies to human platelet antigen-1a can cause severe intracranial hemorrhage in a fetus or newborn. Although never evaluated in placebo-controlled clinical trials, most Western countries use off-label weekly administration of high-dosage intravenous immunoglobulin in all pregnant women with an obstetrical history of fetal and neonatal alloimmune thrombocytopenia. In Norway, antenatal intravenous immunoglobulin is only recommended in pregnancies wherein a previous child had intracranial hemorrhage (high-risk) and is generally not given in other human platelet antigen-1a alloimmunized pregnancies (low-risk). OBJECTIVE: To compare the frequency of anti-human platelet antigen-1a-induced intracranial hemorrhage in pregnancies at risk treated with intravenous immunoglobulin vs pregnancies not receiving this treatment as a part of a different management program. STUDY DESIGN: This was a retrospective comparative study where the neonatal outcomes of 71 untreated human platelet antigen-1a-alloimmunized pregnancies in Norway during a 20-year period was compared with 403 intravenous-immunoglobulin-treated pregnancies identified through a recent systematic review. We stratified analyses on the basis of whether the mothers belonged to high- or low-risk pregnancies. Therefore, only women who previously had a child with fetal and neonatal alloimmune thrombocytopenia were included. RESULTS: Two neonates with brain bleeds were identified from 313 treated low-risk pregnancies (0.6%; 95% confidence interval, 0.2-2.3). There were no neonates born with intracranial hemorrhage of 64 nontreated, low-risk mothers (0.0%; 95% confidence interval, 0.0-5.7). Thus, no significant difference was observed in the neonatal outcome between immunoglobulin-treated and untreated low-risk pregnancies. Among high-risk mothers, 5 of 90 neonates from treated pregnancies were diagnosed with intracranial hemorrhage (5.6%; 95% confidence interval, 2.4-12.4) compared with 2 of 7 neonates from nontreated pregnancies (29%; 95% confidence interval, 8.2-64.1; P=.08). CONCLUSION: The most reliable data hitherto for the evaluation of intravenous immunoglobulins treatment in low-risk pregnancies is shown herein. We did not find evidence that omitting antenatal intravenous immunoglobulin treatment in low-risk pregnancies increases the risk of neonatal intracranial hemorrhage.

Severe thrombocytopenia and intracranial hemorrhage in a newborn with Noonan syndrome and neonatal alloimmune thrombocytopenia.

Noonan syndrome (NS) is a genetic disorder with distinctive physical features and often multiple organ involvement. Bleeding disorders are reported in over half of patients with NS, including thrombocytopenia and platelet dysfunction. Neonatal alloimmune thrombocytopenia (NAIT) is an alloantigenic thrombocytopenia that can present with severe bleeding. Here, we present a case of intracranial hemorrhage and severe thrombocytopenia in a neonate found to have both NAIT and a de novo heterozygous pathogenic variant in PTPN11, consistent with Noonan syndrome.

New developments in fetal and neonatal alloimmune thrombocytopenia.

Fetal and neonatal alloimmune thrombocytopenia, the platelet equivalent of hemolytic disease of the fetus and newborn, can have devastating effects on both the fetus and neonate. Current management of fetal and neonatal alloimmune thrombocytopenia in a subsequent affected pregnancy involves antenatal administration of intravenous immune globulin and prednisone to the pregnant woman to prevent the development of severe fetal thrombocytopenia and secondary intracranial hemorrhage in utero. That therapy has proven to be highly effective but is associated with maternal side effects and is expensive. This commentary describes 4 advances that could substantially change the current approach to detecting and managing fetal and neonatal alloimmune thrombocytopenia in the near future. The first would be an introduction of a program to screen all antepartum patients in this country for pregnancies at risk of developing fetal and neonatal alloimmune thrombocytopenia. Strategies to implement this complex process have been described. A second advance is testing of cell-free fetal DNA obtained from maternal blood to noninvasively determine the fetal human platelet antigen 1 genotype. A third, in preliminary development, is creation of a prophylactic product that would be the platelet equivalent of Rh immune globulin (RhoGAM). Finally, a fourth major potential advance is the development of neonatal Fc receptor inhibitors to replace the current medical therapy administered to pregnant women with an affected fetus. Neonatal Fc receptor recycles plasma immunoglobulin G to increase its half-life and is the means by which immunoglobulin G crosses the placenta from the maternal to the fetal circulation. Blocking the neonatal Fc receptor is an ideal way to prevent maternal immunoglobulin G antibody from causing fetal and neonatal alloimmune thrombocytopenia in a fetus at risk of developing that disorder. The pertinent pathophysiology and rationale for each of these developments will be presented in addition to our thoughts relating to steps that must be taken and difficulties that each approach would face for them to be successfully implemented.

Neonatal Alloimmune Thrombocytopenia: A Concise Review.

BACKGROUND: Neonatal alloimmune thrombocytopenia (NAIT) is defined as an uncommon platelet disorder caused by maternal alloimmunization to human-specific antigens (HPAs) that are paternally inherited, resulting in low fetal/neonatal platelet levels and debilitating effects on the newborn. The incidence of NAIT is 1 in every 1000 live births within the United States; it is the most common cause of severe thrombocytopenia (<30 × 109/L) and intracranial hemorrhage in term newborns. PURPOSE: The purpose of this article is to discuss the pathophysiology, clinical manifestations, diagnosis, and treatment of NAIT and its implications upon the lifespan of the neonate. METHODS: A literature review was conducted using PubMed, CINAHL, and Google Scholar (2014-2019). Search terms included NAIT, neonatal/fetal alloimmune thrombocytopenia, newborn platelets, and intracranial bleeding and NAIT. RESULTS: NAIT can affect first pregnancies and often goes undiagnosed until delivery. Universal screening tools with a focus on HPA-1a typing via noninvasive testing have been successfully trialed and have yielded promising results indicating a 75% reduction in risks associated with NAIT; however, none have been incorporated into practice and prophylactic treatment remains unavailable. IMPLICATIONS FOR RESEARCH: Adopting a universal screening tool and prophylaxis for NAIT would allow for early diagnosis and treatment in utero. IMPLICATIONS FOR PRACTICE: Many healthcare providers are not familiar with NAIT often focusing on other causes of thrombocytopenia as a potential diagnosis.

A new efficient tool for non-invasive diagnosis of fetomaternal platelet antigen incompatibility.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the consequence of platelet destruction by maternal alloantibodies against fetal human platelet antigens (HPA). This may result in intracranial haemorrhages (ICH) or even fetal death. Currently, fetal HPA genotyping is performed using invasive procedures. Here, we carried out a proof-of-concept study for non-invasive prenatal diagnosis of fetal platelet genotyping in four HPA systems (HPA-1, -3, -5 and-15) by droplet digital polymerase chain reaction (ddPCR) using cell-free DNA extracts from the plasma of 47 pregnant women with suspected, or history of, FNAIT. Results showed that 74% (35/47) of pregnant women presented incompatibility in at least one HPA system, and 38% (18/47) of cases presented HPA-1 incompatibility, including nine women with multiple incompatibilities. ICH occurred in one case of profound fetal thrombocytopenia with HPA-15 incompatibility, confirming the need for non-invasive prenatal genotyping in systems other than HPA-1. Fetal HPA genotypes predicted by ddPCR were confirmed in all FNAIT cases after amniocentesis or delivery. Fetal HPA genotyping on maternal plasma based on ddPCR is a fast, safe and reliable non-invasive method. This technique will be useful for the early identification of pregnancies at high risk of FNAIT requiring antenatal management to minimize the risk of fetal/neonatal haemorrhage.

Congenital thrombocytopenia associated with GNE mutations in twin sisters: a case report and literature review.

BACKGROUND: Neonatal thrombocytopenia is common in preterm and term neonates admitted to neonatal intensive care units. The etiology behind neonatal thrombocytopenia is complex. Inherited thrombocytopenia is rare and usually results from genetic mutations. CASE PRESENTATION: Here we report a case of twins with severe inherited thrombocytopenia presented in the neonatal period who were shown to be compound heterozygotes for 2 UDP-N-acetylglucosamine 2-epimerase (GNE) gene mutations, c.1351C > T and c.1330G > T, of which c.1330G > T is a novel mutation. CONCLUSION: These two GNE mutations may help in the diagnosis and management of thrombocytopenia diagnosed in neonates.

Non-invasive risk-assessment and bleeding prophylaxis with IVIG in pregnant women with a history of fetal and neonatal alloimmune thrombocytopenia: management to minimize adverse events.

INTRODUCTION: In pregnant women with a history of fetal and neonatal alloimmune thrombocytopenia (FNAIT), prenatal intervention in subsequent pregnancies may be required to prevent fetal bleeding. Several invasive and non-invasive protocols have been published: amniocentesis for fetal genotyping, fetal blood sampling for the determination of fetal platelet count, intrauterine platelet transfusions, and weekly maternal i.v. immunoglobulin (IVIG) infusion with or without additional corticosteroid therapy. This is the first retrospective study that report the experience with a non-invasive protocol focused on side effects of maternal IVIG treatment and neonatal outcome. METHODS: Pregnant women with proven FNAIT in history and an antigen positive fetus were treated with IVIG (1 g/kg/bw) every week. To identify potential IVIG-related hemolytic reactions isoagglutinin titer of each IVIG lot and maternal blood count were controlled. IVIG-related side effects were prospectively documented and evaluated. Furthermore, ultrasound examination of the fetus was performed before starting IVIG administration and continued regularly during treatment. Outcome of the index and subsequent pregnancy was compared. Corresponding data of the newborns were analyzed simultaneously. RESULTS: IVIG was started at 20 weeks of gestation (median). Compared to the index pregnancy, platelet counts of the newborns were higher in all cases. No intracranial hemorrhage occurred (Index pregnancies: 1 case). Platelet counts were 187 × 109/l (median, range 22-239, 95% CI) and one newborn had mild bleeding. No severe hemolytic reaction was observed and side effects were moderate. CONCLUSION: Among pregnant women with FNAIT history, the use of non-invasive fetal risk determination and maternal IVIG resulted in favorite outcome of all newborns. Invasive diagnostic or therapeutic procedures in women with a history of FNAIT should be abandoned.

Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may result in severe bleeding, particularly fetal and neonatal intracranial haemorrhage (ICH). As a result, FNAIT requires prompt identification and treatment; subsequent pregnancies need close surveillance and management. An international panel convened to develop evidence-based recommendations for diagnosis and management of FNAIT. A rigorous approach was used to search, review and develop recommendations from published data for: antenatal management, postnatal management, diagnostic testing and universal screening. To confirm FNAIT, fetal human platelet antigen (HPA) typing, using non-invasive methods if quality-assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen. Women with a previous child with an ICH related to FNAIT should be offered intravenous immunoglobulin (IVIG) infusions during subsequent affected pregnancies as early as 12 weeks gestation. Ideally, HPA-selected platelets should be available at delivery for potentially affected infants and used to increase the neonatal platelet count as needed. If HPA-selected platelets are not immediately available, unselected platelets should be transfused. FNAIT studies that optimize antenatal and postnatal management, develop risk stratification algorithms to guide management and standardize laboratory testing to identify high risk pregnancies are needed.

Fast and low-cost direct ELISA for high-throughput serological HPA-1a typing.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal alloantibodies against fetal human platelet antigens (HPAs), mostly caused by anti-HPA-1a. Population-based screening for FNAIT is still a topic of debate. Logistically and financially, the major challenge for implementation is the typing of pregnant women to recognize the 2% HPA-1a-negative women. Therefore, there is need for a high-throughput and low-cost HPA-1a-typing assay. STUDY DESIGN AND METHODS: A sandwich ELISA was developed, using a monoclonal anti-GPIIIa as coating antibody and horseradish-peroxidase-conjugated recombinant anti-HPA-1a, as detecting antibody. The ELISA results were compared to an allelic discrimination PCR-assay. In phase I, samples from unselected consecutive pregnant women were tested with both assays. Phase II was part of a prospective screening study in pregnancy and genotyping was restricted to samples with an arbitrary set, OD < 0.500. RESULTS: The ELISA was optimized to require no additional handling (swirling or spinning) of stored tubes. During phase I, 506 samples were tested. In phase II, another 62,171 consecutive samples were phenotyped, with supportive genotyping in 1,902. In total 1,585 HPA-1a negative and 823 HPA-1a positive women were genotyped. The assay reached 100% sensitivity with a cut-off OD from 0.160, corresponding with a 99.9% specificity and a false-HPA-1a negative rate of 0.03. CONCLUSION: A high-throughput, low-cost, and reliable HPA-1a phenotyping assay was developed which can be used in population-based screening to select samples for testing of presence of anti-HPA-1a. Because plasma from tubes of 3- to 6-days-old samples can be used, this assay is applicable to settings with suboptimal conditions.

Prenatal Management of Pregnancies at Risk of Fetal Neonatal Alloimmune Thrombocytopenia (FNAIT): Scientific Impact Paper No. 61.

WHAT IS IT?: Fetal neonatal alloimmune thrombocytopenia (FNAIT), also known as neonatal alloimmune thrombocytopenia (NAIT) or fetomaternal alloimmune thrombocytopenia (FMAIT), is a rare condition which affects a baby's platelets. This can put them at risk of problems with bleeding, particularly into the brain. One baby per week in the UK may be seriously affected and milder forms can affect one in every 1000 births. HOW IS IT CAUSED?: Platelets are blood cells that are very important in helping blood to clot. All platelets have natural proteins on their surface called human platelet antigens (HPAs). In babies, half of these antigens are inherited from the mother and half from the father. During pregnancy, some of the baby's platelets can cross into the mother's bloodstream. In most cases, this does not cause a problem. But in cases of FNAIT, the mother's immune system does not recognise the baby's HPAs that were inherited from the father and develops antibodies, which can cross the placenta and attack the baby's platelets. These antibodies are called anti-HPAs, and the commonest antibody implicated is anti-HPA-1a, but there are other rarer antibody types. If this happens, the baby's platelets may be destroyed causing their platelet count to fall dangerously low. If the platelet count is very low there is a risk to the baby of bleeding into their brain before they are born. This is very rare but if it happens it can have serious effects on the baby's health. HOW IS IT INHERITED?: A baby inherits half of their HPAs from its mother and half from its father. Consequently, a baby may have different HPAs from its mother. As the condition is very rare, and even if the baby is at risk of the condition we have no way of knowing how severely they will be affected, routine screening is not currently recommended. WHAT CAN BE DONE?: FNAIT is usually diagnosed if a previous baby has had a low platelet count. The parents are offered blood tests and the condition can be confirmed or ruled out. There are many other causes of low platelets in babies, which may also need to be tested for. As the condition is so rare, expertise is limited to specialist centres and normally a haematologist and fetal medicine doctor will perform and interpret the tests together. Fortunately, there is an effective treatment for the vast majority of cases called immunoglobulin, or IVIg. This 'blood product' is given intravenously through a drip every week to women at risk of the condition. It may be started from as early as 16 weeks in the next pregnancy, until birth, which would be offered at around 36-37 weeks. Less common treatments that may be considered depending on individual circumstances include steroid tablets or injections, or giving platelet transfusions to the baby. WHAT DOES THIS PAPER TELL YOU?: This paper considers the latest evidence in relation to treatment options in the management of pregnancies at risk of FNAIT. Specifically, we discuss the role of screening, when IVIg should be started, what dose should be used, and what evidence there is for maternal steroids. We also consider in very rare selected cases, the use of fetal blood sampling and giving platelet transfusions to the baby before birth. Finally, we consider the approaches to blood testing mothers to tell if babies are at risk, which is offered in some countries, and development of new treatments to reduce the risk of FNAIT.

Circulating antiplatelet antibodies in pregnant women with immune thrombocytopenic purpura as predictors of thrombocytopenia in the newborns.

Newborns from mothers with immune thrombocytopenic purpura (ITP) have a risk of thrombocytopenia due to passage of maternal antiplatelet antibodies into fetal/neonatal circulation. We looked for predictors of neonatal thrombocytopenia (nTP) in pregnant women with ITP. One hundred pregnant women with platelet count <100 × 109/l, no non-immune causes of thrombocytopenia and increased platelet associated IgG (PA-IgG) were included in the study. Thirty seven and 63 of them gave birth to babies with and without nTP, respectively (nTP+ and nTP- groups). Platelet count, mean platelet volume, PA-IgG, antiplatelet circulating antibodies (cAB), time of ITP onset (before or during pregnancy), and frequency of corticosteroid treatment were compared in these groups. There were no differences in all test parameters between nTP+ and nTP- groups except cAB. These antibodies were detected in 33 out of 37 in nTP+ group and in 2 out of 63 mothers in nTP- group (p < 0.001). The sensitivity of this test was 89% and its specificity was 97%. A strong reverse correlation (r = -0.749, p < 0.001) was established between maternal cAB titer and neonatal platelet count. Antibodies against glycoproteins IIb-IIIa and/or Ib were identified in antigen specific MAIPA (Monoclonal Antibody Immobilization of Platelet Antigen) assay only in 10 out of 19 (53%) test sera with cAB. Antiplatelet cAB in pregnant women with ITP could serve as reliable predictors of nTP in their babies.

Perinatal Outcome and Long-Term Neurodevelopment after Intracranial Haemorrhage due to Fetal and Neonatal Alloimmune Thrombocytopenia.

OBJECTIVES: To evaluate the perinatal and long-term neurodevelopmental outcome in a cohort of children with intracranial haemorrhage (ICH) due to fetal and neonatal alloimmune thrombocytopenia (FNAIT) and to clearly outline the burden of this disease. SUBJECTS AND METHODS: We performed an observational cohort study and included all consecutive cases of ICH caused by FNAIT from 1993 to 2015 at Leiden University Medical Centre. Neurological, motor, and cognitive development were assessed at a minimum age of 1 year. The primary outcome was adverse outcome, defined as perinatal death or severe neurodevelopmental impairment (NDI). Severe NDI was defined as any of the following: cerebral palsy (Gross Motor Function Classification System [GMFCS] level ≥II), bilateral deafness, blindness, or severe motor and/or cognitive developmental delay (<-2 SD). RESULTS: In total, 21 cases of ICH due to FNAIT were included in the study. The perinatal mortality rate was 10/21 (48%). Long-term outcome was assessed in 10 children (n = 1 lost to follow-up). Severe and moderate NDI were diagnosed in 6/10 (60%) and 1/10 (10%) of the surviving children. The overall adverse outcome, including perinatal mortality or severe NDI, was 16/20 (80%). CONCLUSIONS: The risk of perinatal death or severe NDI in children with ICH due to FNAIT is high. Only screening and effective preventive treatment can avoid this burden.

[FETAL/NEONATAL ALLOIMMUNE THROMBOCYTOPENIA (F/NAIT) - THE PREVALENCE VERSUS AWARENESS OF A LIFE-THREATENING CLINICAL CONDITION].

AIMS: To determine the prevalence and incidence of HPA antigens and antibodies in the Israeli population and to evaluate the degree of awareness to F/NAIT in Israel. BACKGROUND: In fetal/neonatal alloimmune thrombocytopenia (F/NAIT) the fetus suffers from thrombocytopenia mediated by maternal IgG antibodies directed against fetal platelets leading to intracranial hemorrhage (ICH) in about 20% of cases. The antibodies are directed against Human Platelet Antigens (HPA). Diagnosis of F/NAIT is essential because thrombocytopenia may recur and worsen in subsequent pregnancies; hence awareness of F/NAIT is crucial. METHODS: We conducted a retrospective analysis of cases referred to the platelet immunology laboratory between the years 2011-2015 and medical records of newborns born at Rambam Medical Center during 2010-2015. RESULTS: Of the 322 cases studied, 175 (54.35%) had anti-platelet antibodies. The most common antibody was anti-HPA1a (41.85%) followed by anti-HPA5b (28.75%). The prevalence of HPA antigens was similar to that of the Caucasian population. About 80% of the cases were referred due to neonatal thrombocytopenia, found in a random blood count or after bleeding, and 13% of cases were referred due to suspected ICH during pregnancy. In only 22.6% of cases, the diagnosis was made immediately after birth, and 18.7% of the suspected cases were referred only during the subsequent pregnancy. About 84% of infants with severe thrombocytopenia were not referred to F/NAIT diagnosis. CONCLUSIONS: The prevalence of platelet antigens in the Israeli population is similar to that of the Caucasian population. The paucity of referrals points to the need to establish diagnostic guidelines and raise awareness among caregivers.