Heidi Tiller

Fetal intracranial haemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry

Objective To characterise pregnancies where the fetus or neonate was diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT) and suffered from intracranial haemorrhage (ICH), with special focus on time of bleeding onset. Design Observational cohort study of all recorded cases of ICH caused by FNAIT from the international No IntraCranial Haemorrhage (NOICH) registry during the period 2001–2010. Setting 13 tertiary referral centres from nine countries across the world. Participants 37 mothers and 43 children of FNAIT pregnancies complicated by fetal or neonatal ICH identified from the NOICH registry was included if FNAIT diagnosis and ICH was confirmed. Primary and secondary outcome measures Gestational age at onset of ICH, type of ICH and clinical outcome of ICH were the primary outcome measures. General maternal and neonatal characteristics of pregnancies complicated by fetal/neonatal ICH were secondary outcome measures. Results From a total of 592 FNAIT cases in the registry, 43 confirmed cases of ICH due to FNAIT were included in the study. The majority of bleedings (23/43, 54%) occurred before 28 gestational weeks and often affected the first born child (27/43, 63%). One-third (35%) of the children died within 4 days after delivery. 23 (53%) children survived with severe neurological disabilities and only 5 (12%) were alive and well at time of discharge. Antenatal treatment was not given in most (91%) cases of fetal/neonatal ICH. Conclusions ICH caused by FNAIT often occurs during second trimester and the clinical outcome is poor. In order to prevent ICH caused by FNAIT, at-risk pregnancies must be identified and prevention and/or interventions should start early in the second trimester.

Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against β3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-β3 integrin-mediated, but not anti-GPIbα-mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti-β3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti-β3 integrin, but not anti-GPIbα antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti-β3 integrin antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.

Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody‐mediated immune suppression and prevention of severe clinical complications in a murine model

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody–mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA‐1a might therefore be preventable by a prophylactic regimen of inducing antibody‐mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof‐of‐concept study investigated whether passive administration of anti‐β3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT.

Neonatal alloimmune thrombocytopenia in Norway: poor detection rate with nonscreening versus a general screening programme

The implementation of an antenatal screening programme for neonatal alloimmune thrombocytopenia (NAIT) is currently under debate. We evaluated the detection rate for NAIT in a nonscreened population of 661 200 births where NAIT was diagnosed on clinical indication. We did a cross‐sectional comparison with a population of 100 448 human platelet antigen 1a (HPA1a)‐screened pregnancies from three of the five health regions in Norway. In a nonscreening situation, 7.5 cases of NAIT were detected per year compared with 53 cases when screening was applied. The detection rate of NAIT in Norway was therefore 14% of the expected rate.

Reconsidering fetal and neonatal alloimmune thrombocytopenia with a focus on screening and prevention

Uncertainty regarding the pathophysiology of fetal and neonatal alloimmune thrombocytopenia (FNAIT) has hampered the decision regarding how to identify, follow-up and treat the women and children with this potentially serious condition. Since knowledge of the condition is derived mainly from retrospective studies, understanding of the natural history of this condition remains incomplete. General screening programs for FNAIT have still not been introduced, mainly because of a lack of reliable risk factors and effective treatment. Now, several prospective screening studies involving up to 100,000 pregnant women have been published and the results have changed the understanding of the pathophysiology of FNAIT and, thereby, the approach toward diagnostics, prevention and treatment in a more appropriate way.

Platelet antibodies and fetal growth: maternal antibodies against fetal platelet antigen 1a are strongly associated with reduced birthweight in boys

Objective. To assess whether maternal HPA 1a alloimmunization is associated with birthweight. Design. A retrospective observational cohort study. Setting. The national reference laboratory for clinical platelet immunology at a university hospital. Population. 165 HPA 1a incompatible pregnancies identified from a recent screening study of 100 448 women (124 pregnancies) and the national reference laboratory for clinical platelet immunology (41 pregnancies). Methods. A linear mixed model analysis was used to assess whether maternal anti‐HPA 1a antibodies were associated with birthweight. A generalized linear model was used to assess maternal anti‐HPA 1a antibodies as risk factor for small‐for‐gestational age neonates. Both models were adjusted for gestational age at time of delivery, maternal age, parity, smoking habits during pregnancy, preeclampsia, diabetes mellitus and fetal sex. Main outcome measures. Maternal anti‐HPA 1a antibody as risk factor of reduced birthweight and small‐for‐gestational age neonates. Results. The level of maternal anti‐HPA 1a antibodies was significantly associated with birthweight and risk of small‐for‐gestational age neonates after correcting for confounding variables (p<0.001). However, this association was only significant for boys. When the mother had high levels of anti‐HPA 1a antibodies during pregnancy, the adjusted mean birthweight in boys was 530g lower compared with anti‐HPA 1a antibody negative pregnancies (p<0.001). Conclusions. A linear relation between maternal anti‐HPA 1a antibody levels and reduced birthweight in boys was demonstrated. Reduced birthweight should be considered a possible complication of fetal and neonatal alloimmune thrombocytopenia.

True risk of fetal/neonatal alloimmune thrombocytopenia in subsequent pregnancies: a prospective observational follow-up study

To assess neonatal platelet counts by comparing alloimmunised pregnancies from a Norwegian screening and intervention study with subsequent pregnancies from the same women.

Foetal and neonatal alloimmune thrombocytopenia (FNAIT)

Thrombocytopenia is detected in around one percent of newborns. In otherwise healthy term newborns, thrombocytopenia is most often caused by alloantibodies transferred from the mother to the foetus. In the Caucasian populations human platelet antigen (HPA)‐1a is the most immunogenic HPA. In Japan and China antibodies in the HPA‐4 system are the most frequent cause of FNAIT. The immune response against the HPA must be understood in order to avoid immunization or prevent induction of FNAIT where mothers are already immunized.

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Human platelet Ag (HPA)-1a, located on integrin β3, is the main target for alloantibodies responsible for fetal and neonatal alloimmune thrombocytopenia (FNAIT) in the white population. There are ongoing efforts to develop an Ab prophylaxis and therapy to prevent or treat FNAIT. In this study, an mAb specific for HPA-1a, named 26.4, was derived from an immortalized B cell from an alloimmunized woman who had an infant affected by FNAIT. It is the only HPA-1a–specific human mAb with naturally paired H and L chains. Specific binding of mAb 26.4, both native and recombinant forms, to platelets and to purified integrins αIIbβ3 (from platelets) and αVβ3 (from trophoblasts) from HPA-1a+ donors was demonstrated by flow cytometry and surface plasmon resonance technology, respectively. No binding to HPA-1a− platelets or integrins was detected. Moreover, the Ab binds with higher affinity to integrin αVβ3 compared with a second HPA-1a–specific human mAb, B2G1. Further in vitro experimentation demonstrated that mAb 26.4 can opsonize HPA-1a+ platelets for enhanced phagocytosis by monocytes, inhibit binding of maternal polyclonal anti–HPA-1a Abs, and weakly inhibit aggregation of HPA-1a–heterozygous platelets, the latter with no predicted clinical relevance. Thus, mAb 26.4 is highly specific for HPA-1a and could potentially be explored for use as a prophylactic or therapeutic reagent for FNAIT intervention and as a phenotyping reagent to identify women at risk for immunization.

Fetal and Neonatal Alloimmune Thrombocytopenia: Management and Outcome of a Large International Retrospective Cohort.

Objective: To evaluate the management and outcome of a large international cohort of cases of pregnancies complicated by fetal and neonatal alloimmune thrombocytopenia (FNAIT). Methods: This was an observational prospective and retrospective cohort study of all cases of FNAIT entered into the international multicentre No IntraCranial Haemorrhage (NOICH) registry during the period of 2001-2010. We evaluated human platelet antigen (HPA) specificity, the antenatal and postnatal interventions performed, and clinical outcome. Results: A total of 615 pregnancies complicated by FNAIT from 10 countries were included. Anti-HPA-1a was the most commonly implicated antibody. Antenatal treatment was administered in 273 pregnancies (44%), varying from intrauterine platelet transfusion to maternal administration of immunoglobulins, steroids, or a combination of those. Intracranial haemorrhage was diagnosed in 23 fetuses or neonates (3.7%). Overall perinatal mortality was 1.14% (n = 7). Conclusion: This study presents the largest cohort of cases of FNAIT published. Our data show that antenatal treatment for FNAIT results in favourable perinatal outcome. Over time, in most centres, treatment for FNAIT changed from an invasive to a complete non-invasive procedure.