Upper limb phocomelia: A prenatal case of thrombocytopenia-absent radius (TAR) syndrome illustrating the importance of chromosomal microarray in limb reduction defects.

OBJECTIVE: To describe the ultrasonographic, pathologic and molecular findings in a fetus with TAR syndrome, and to illustrate the contribution of chromosomal microarray analysis (CMA) to the etiological investigation of fetal upper limb reduction defects. CASE REPORT: A 35-year-old woman was referred for Genetic Counseling after pregnancy termination for severe upper limb bilateral phocomelia detected in the second trimester. Fetal autopsy showed severe shortening of the arms and forearms. The fetal skeletal survey confirmed the absence of the radii, ulnae and humeri. CMA revealed an interstitial deletion in 1q21 including the RBM8A gene. Subsequent Sanger sequencing of this gene identified a hypomorphic mutant allele, c.-21G > A, confirming the diagnosis of TAR syndrome. CONCLUSION: The differential diagnosis of upper limb defects is broad. Identification of their cause is essential for adequate genetic counseling including prognosis and recurrence risk estimation. CMA should be considered in fetuses with upper limb reduction defects, especially when the thumbs are present.

Management and outcome of pregnancies with parvovirus B19 infection over seven years in a tertiary fetal medicine unit.

OBJECTIVES: To determine rates of fetal anaemia and pregnancy outcome in susceptible pregnant women infected with human parvovirus B19 infection in a tertiary fetal medicine department over a 7-year period. Additional features enabling identification of fetuses that progress to severe anaemia were also investigated. METHODS: Forty-seven susceptible, pregnant women with confirmed parvovirus infection referred to a regional fetal medicine unit, over a 7-year period (1999-2006), were identified. Where possible maternal serum AFP measurements were obtained from second-trimester serum screening and the presence or absence of echogenic bowel noted. RESULTS: Of the 47 cases, one was excluded. Of the remaining 46 cases, 34 (74%) showed no signs of fetal anaemia and delivered at term. The remaining 12 (26%) showed signs of fetal anaemia. Eight of the 12 developed hydrops and underwent fetal blood sampling and transfusion (median pretransfusion Hb 3.6 g/dl). Seven of the 8 transfused fetuses were thrombocytopenic with a platelet count <150 x 10(9)/l, with 2 fetuses having platelet counts <50 x 10(9)/l. The median gestation age at transfusion was 22 weeks (range 18-27 weeks). The median number of weeks between seroconversion and transfusion was 6 (range 3-12). The signs of anaemia resolved after one transfusion in 5 of the 8 transfused fetuses and they subsequently delivered at term. There were 2 fetal deaths during or shortly after transfusion and one neonatal death following delivery at 28 weeks gestation due to severe pre-eclampsia, 5 days after successful transfusion. CONCLUSIONS: Following parvovirus seroconversion, the incidence of significant fetal anaemia requiring transfusion was 17%. Seroconversion after 21 weeks did not result in severe fetal anaemia. Significant anaemia requiring intervention did not occur 12 weeks after maternal seroconversion. We did not demonstrate a correlation with either maternal serum AFP or the presence of fetal echogenic bowel and the development of severe fetal anaemia. Because of the association between fetal anaemia and severe thrombocytopenia, it may be prudent to have compatible platelets available at the time of fetal blood sampling.

Noninvasive antenatal management of fetal and neonatal alloimmune thrombocytopenia: safe and effective.

OBJECTIVE: To describe the outcome of pregnancies with fetal and neonatal alloimmune thrombocytopenia (FNAIT) in relation to the invasiveness of the management protocol. DESIGN: Retrospective analysis of prospectively collected data from a national cohort. SETTING: Leiden University Medical Centre, the national centre for management of severe red cell and platelet alloimmunisation in pregnancy. POPULATION: Ninety-eight pregnancies in 85 women with FNAIT having a previous child with thrombocytopenia with (n= 16) or without (n= 82) an intracranial haemorrhage (ICH). METHODS: Our management protocol evolved over time from (1) serial fetal blood samplings (FBS) and platelet transfusion (n= 13) via (2) combined FBS with maternal intravenous immunoglobulins (n= 33) to (3) completely noninvasive treatment with immunoglobulins only (n= 52 pregnancies, resulting in 53 neonates). Perinatal outcome was assessed according to the three types of management. MAIN OUTCOME MEASURES: Occurrence of ICH, perinatal survival, gestational age at birth and complications of FBS. RESULTS: All but one of 98 pregnancies ended in a live birth; none of the neonates had an ICH. The median gestational age at birth was 37 weeks (range 32-40). In groups 1 and 2, three emergency caesarean sections were performed after complicated FBS, resulting in two healthy babies and one neonatal death. CONCLUSION: Noninvasive antenatal management of pregnancies complicated by FNAIT appears to be both effective and safe.

[Fetal/neonatal allo-immune thrombocytopenias: the unsolved questions]. / Les thrombopénies foetales et néonatales allo-immunes: problèmes en suspens.

The allo-immune thrombocytopenias are the major cause of severe thrombocytopenia in the fetus and the neonate. The frequency of this affection has been evaluated to be 1 out of 800 to 1000 live births. The deleterious consequences of severe thrombocytopenia are intracranial hemorrhages leading to death or neurological sequelae. Progress in platelet immunology and antenatal medicine has allowed a better diagnosis of this affection and development of the antenatal management of high-risk pregnancies. Nevertheless there are unsolved questions, particularly concerning the mechanism of the maternal immunization, the laboratory difficulties for the identification of the alloantibodies, the absence of antenatal management standardization.

[Three special cases of pregnancy outcome to reflect about]. / Tre spesielle graviditetsforløp til ettertanke.

BACKGROUND: Neonatal alloimmune thrombocytopenia (NAITP) may be a serious condition with prenatal intracranial haemorrhages. Our three cases of serious NAITP raise the question of whether pregnant women should be screened for thrombocyte type and then for HPA-1a antibodies if they are HPA-1bb positive. CASE REPORTS: We present three cases of severe NAITP in which screening and follow up of HPA-1a antibodies prevented serious sequelae in two of the siblings. The first child was a stillbirth with congenital hydrocephalus caused by an intraventricular haemorrhage. In the second pregnancy, the mother was found to be platelet type HPA-1bb with platelet antibodies against HPA-1a. The antibody level was extremely high and an elective caesarean section was performed four weeks before term. The platelet count at birth was 3 and 5 x 10(9)/L and a transfusion of matched platelets was immediately performed followed by infusion of intravenous immunoglobulin. In the third pregnancy, an intracerebral haemorrhage was detected by ultrasound at 27 weeks of gestation. The mother was given steroids to induce foetal lung maturation followed by a caesarean section in week 28. The platelet count was 6 x 10(9)/L. The child was transfused with compatible platelets and given an infusion of intravenous immunoglobulin. OUTCOME: None of the two children have developed any psychomotor sequelae by the age of five and three years, respectively. The importance of screening for platelet type and anti-platelet antibodies and mode of delivery is discussed.

Alloimmune thrombocytopenia in the fetus: current management theories.

Fetal alloimmune thrombocytopenia (AIT) affects only a small number of fetuses but the consequences may be devastating. Outcomes range from mild thrombocytopenia without signs or symptoms to intracranial hemorrhage (ICH) and fetal or neonatal death. Antenatal screening is available but not used routinely in the United States. The most frequent method of AIT identification is its diagnosis in the neonatal period (index neonate). AIT may be diagnosed antenatally if an ICH is noted on routine obstetric ultrasound. There are accurate predictors of AIT, as well as antenatal therapies, to prevent the occurrence of severe disease and ICH.

Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit.

UNLABELLED: Phlebotomy-induced anaemia excepted, thrombocytopenia is the most common haematological abnormality in neonatal intensive care unit (NICU) patients. Roughly one-quarter of all NICU patients and half of all sick preterm neonates develop thrombocytopenia. Whereas a large number of varied precipitating conditions has been identified, early-onset thrombocytopenia (<72 h) is most commonly associated with fetomaternal conditions complicated by placental insufficiency and/or fetal hypoxia, e.g. maternal pre-eclampsia and fetal intrauterine growth restriction. The resulting neonatal thrombocytopenia is usually mild to moderate, resolves spontaneously and requires no specific therapy. Deviation from this pattern of thrombocytopenia suggests the presence of more significant precipitating conditions. The most important of these are the immune thrombocytopenias, and every NICU should develop investigation and treatment protocols to manage these cases promptly and avoid unnecessary risk of haemorrhage. In contrast, late-onset thrombocytopenia (>72 h) is almost always associated with sepsis or necrotizing enterocolitis and the associated thrombocytopenia is severe, prolonged and often requires treatment by platelet transfusion. Unfortunately, evidence-based guidelines for platelet transfusion therapy in NICU patients are currently unavailable, making it difficult to define widely accepted thresholds for transfusion and leading to a significant variation in transfusion practice between centres. CONCLUSION: While improving this situation remains a pressing need, the growing evidence that impaired megakaryocytopoiesis and platelet production are major contributors to many neonatal thrombocytopenias suggests that recombinant haemopoietic growth factors, including thrombopoietin and interleukin-11, may be useful future therapies to ameliorate neonatal thrombocytopenia.

Mechanisms underlying thrombocytopenia in the neonatal intensive care unit.

UNLABELLED: Thrombocytopenia is one of the most common hematological problems among neonates in the neonatal intensive care unit (NICU), but in the majority of cases the kinetic mechanism responsible is unclear. This review focuses on both traditional and innovative methods used to evaluate the mechanisms responsible for thrombocytopenia in neonates, and analyzes the data generated from those methods. CONCLUSION: Results of studies using new methods for evaluating thrombocytopenia, coupled with recent descriptions of marrow megakaryocyte mass, suggest that decreased platelet production complicates most cases of thrombocytopenia among neonates in the NICU.

Alloimmune thrombocytopenia of the fetus and the newborn.

Fetal/neonatal alloimmune thrombocytopenia results from a maternal alloimmunization against fetal platelet antigens. Care must be taken in making a correct diagnosis that eliminates other causes of thrombocytopenia that may occur during pregnancy. Biological diagnosis is normally made by platelet genotyping and search for the maternal alloantibody using monoclonal antibodies in an antigen capture assay. Fetal alloimmune thrombocytopenia, when severe, may result in intracerebral hemorrhage leading to hydrocephalus and death of the fetus. Neonatal alloimmune thrombocytopenia may be present in an otherwise healthy infant. While screening procedures are not in place to detect fetal/neonatal alloimmune thrombocytopenia, it is true that fetal hydrocephalus, unexplained fetal thrombocytopenia with or without anemia, or recurrent miscarriages should be adequate indicators for suspecting fetomaternal alloimmune thrombocytopenia. Multiparous women with a history of giving birth to at least one alloimmune thrombocytopenic infant should be carefully monitored in subsequent pregnancies. Postnatal management of neonatal alloimmune thrombocytopenia involves compatible platelet transfusion in the neonate. Antenatal management of fetal alloimmune thrombocytopenia is controversial and includes a combination of maternal intravenous gamma globulin (i.v.IgG) administration, intrauterine platelet transfusions, and corticosteroid therapy, while monitoring fetal platelet counts closely throughout the course of pregnancy. Screening of pregnant women may become a public health issue only after antenatal therapy is more standardized.

Immune thrombocytopenia in the foetus and the newborn: diagnosis and therapy.

Thrombocytopenia is a common condition in intensive care units. However the frequency of neonatal thrombocytopenia in all newborns (< 150 x 10(9)/L) has been estimated at 1-4%. 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 mother's disease status. Foetal thrombocytopenia can occur as early as 20 weeks of gestation. The frequency of ICH has been estimated to be 1-3% 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 800-1000 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.

Provision of platelet support for fetuses and neonates affected by severe fetomaternal alloimmune thrombocytopenia.

Severe fetomaternal alloimmune thrombocytopenia requires urgent treatment with compatible platelet concentrates. As prompt treatment is sometimes delayed owing to the unavailability of compatible platelets, we established an accredited platelet donor panel to provide effective and timely transfusion support for fetal and neonatal therapy. After a mass screening programme of over 60,000 blood donations, 45 HPA-1a-negative donors with no antibodies to HPA, HLA, red cell antigens and granulocytes/lymphocytes, and with low titre anti-A and/or -B were accredited. All accredited donors were fully genotyped for HPA-1, -2, -3 and -5 by PCR-SSP. Ninety-one per cent of the accredited donors were also negative for HPA-5b.

Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia.

In pregnant women with antecedents of autoimmune thrombocytopenia (AITP), no predictive factor for severe fetal thrombocytopenia has been identified. We evaluated the relationships between the course of the maternal disease before and during pregnancy and the risk of severe fetal thrombocytopenia, in 64 pregnant women with known chronic AITP antecedents, over a 12-year period. 28 pregnant women had undergone splenectomy before pregnancy and 17 experienced severe thrombocytopenia (< 50 x 10(9)/l) during pregnancy (monthly determination). Eight infants presented with severe thrombocytopenia at birth (12.5%), and four in the following days (6.25%). No severe haemorrhage was observed. Severe thrombocytopenia at birth was present in 57% (CI 95% 18-90%) of the infants born to mothers with severe pregnancy-associated thrombocytopenia and splenectomy antecedents, and in 0% (CI 95% 0-15%) of the infants born to mothers who presented none of these antecedents (P=0.001). In thrombocytopenic mothers the infant platelet counts at birth were positively correlated to the nadir maternal platelet count during the index pregnancy (r=0.42, P=0.0075). These results suggest that severe autoimmune disease is a risk factor for severe fetal thrombocytopenia, and that pregnant women with no antecedent of splenectomy nor severe thrombocytopenia during pregnancy have a very low risk of severe fetal thrombocytopenia.

Fetal alloimmune thrombocytopenia: consensus and controversy.

Fetal and neonatal alloimmune thrombocytopenia (AIT) is a serious disease that can affect subsequent siblings to an even greater degree than a first affected child. The devastating outcome of antenatal intracranial hemorrhage (ICH) is not uncommon. Great strides have been made in the antenatal diagnosis and treatment of this disease. This article reviews our knowledge of the laboratory diagnosis of AIT during pregnancy, the pitfalls in this diagnosis, the natural history of AIT during pregnancy, and the collected series of the management of fetal AIT in both Europe and the United States. Discrepancies in outcome between European and American studies exist. Reasons for these discrepancies are highlighted, including differences in populations studied, differences in management, and differences in the definition of response to treatment. Intravenous immune globulin appears to be efficacious in increasing the fetal platelet count and decreasing the occurrence of ICH.

Devastating sequelae of alloimmune thrombocytopenia: an entity that deserves more attention.

UNLABELLED: In alloimmune thrombocytopenia, maternal sensitization to a fetal platelet alloantigen results in fetal thrombocytopenia. Even in primipara, 20% of offspring can suffer intracranial hemorrhage, half of which occur in utero. Ninety percent of subsequent pregnancies will be equally or more severely affected. We describe two patients whose previous pregnancies were complicated by neonatal alloimmune thrombocytopenia (NAIT). As expected, NAIT recurred, with devastating sequelae in both cases. One case presented with hydrops fetalis, a previously unreported association; the other fetus developed extensive intracranial hemorrhages in utero. Because both previous obstetrical histories had gone unrecognized, no preventative strategies had been undertaken. CONCLUSION: Better recognition of this disease through a positive obstetrical history is needed in order to properly counsel patients and institute appropriate prenatal treatment regimens.

Fetal thrombocytopenia: a retrospective survey of 5,194 fetal blood samplings.

Fetal platelet counts were retrospectively studied in a series of 5,194 consecutive fetal blood samplings (FBS). The mean value was 245 +/- 65 x 10(9)/L, without significant variation between 17 and 41 weeks' gestation. After exclusion of false thrombocytopenia due to contamination with amniotic fluid, 247 fetuses had platelet counts less than 150 x 10(9)/L. In 70 cases, thrombocytopenia was due to congenital infectious diseases (toxoplasmosis, rubella, and cytomegalovirus). It was related to immune causes in 45 cases: anti-HPA-1a (n = 23), anti-HPA-5b (n = 2) or possible anti-HLA (n = 2) alloimmunizations, and immune thrombocytopenic purpura (n = 18). Chromosomal abnormality was the etiology in 43 cases (trisomy 13, 18, and 21, Turner's syndrome, triploidy), and other disorders (multiple birth defects, intrauterine growth retardation, rhesus disease, and gestational thrombocytopenia) in 62 cases. No specific cause for the low platelet count could be established in 27 fetuses (range, 115 to 149 x 10(9)/L). Severe thrombocytopenia (< or = 50 x 10(9)/L) occurred mainly in immune cases (16%), congenital infectious diseases (7%), and chromosomal abnormalities (1%). Diagnosis, prognosis, and management of fetal thrombocytopenia are presented in the different clinical situations. In this series, FBS was never associated with serious bleeding, and no fetal exsanguination was observed.

Successful treatment of fetal cardiac arrest by left ventricular exchange transfusion.

A 36-year-old pregnant woman with anti-HPA1a antibodies underwent six fetal platelet concentrate transfusions. During the second, at 28 weeks' gestation, fetal asystole occurred in association with a post-transfusion platelet count of 813 x 10(9)/l. Asystole was reversed by an intracardiac partial exchange transfusion of normal saline for fetal blood, simultaneously reducing fetal plasma viscosity and enabling re-commencement of the fetal circulation.