Clinical management in FNAIT - navigating a complicated landscape.

Fetal and neonatal alloimmune thrombocytopenia in 2022: a response

Fetal and Neonatal Alloimmune Thrombocytopenia: Lessons Learned from Animal Models

New elegant methods for maternal and fetal HPA-1a typing.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) represents the most frequent cause of severe fetal or neonatal severe thrombocytopenia and intracranial haemorrhage in full-term infants. It should be suspected with isolated thrombocytopenia or with a personal or family history of alloimmune thrombocytopenia, especially if the fetus experienced intracranial haemorrhage. FNAIT results from maternal alloimmunization during pregnancy against specific fetal platelet antigens (HPA) inherited from the father and absent in the mother. These maternal IgG alloantibodies bind to the fetal platelets, leadind to their distruction. Although rare, FNAIT has a poor outcome, due to possible severe complications and long-term disabilities. The immediate antenatal maternal treatment, using high dose i.v. IG and corticosteroids has shown that both the degree of thrombocytopenia in the fetus and the risk of intracranial haemorrhage can be reduced. The aim of this paper is to put an exclamation point on the importance of adequate diagnosis and treatment on reducing both associated morbidity and mortality. We worked on a meta-analysis of numerous studies, drawing conclusions on pathogenesis, genetic testing, diagnosis and screening principles, as well as on treatment recommendations based on antenatal risk stratification algorithms. We present in detail the severity-based approach for treatment of pregnancies at undetermined risk, standard, high and extremely high risk, so this paper could be even used as a guide to FNAIT management. An important chapter is the management of subsequent pregnancies, where we presented the latest protocols of recommendation for parental and fetal genotyping and methods for estimating the severity of FNAIT.

Fetal and Neonatal Alloimmune Thrombocytopenia: Risk of ICH in Second Pregnancy and Treatments to Maintain an Adequate Platelet Count

ObjectiveTo 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...

To evaluate the rate and consequences of a late or missed diagnosis of fetal and neonatal alloimmune thrombocytopenia (FNAIT). Retrospective analysis of prospectively collected data of a national cohort. National referral centre for fetal therapy in the Netherlands. Twenty-six women with pregnancies complicated by FNAIT and at least one previous pregnancy with a thrombocytopenic child. Retrospective analysis of data from our electronic FNAIT database. In a consecutive cohort managed between July 2008 and July 2010, timing of first diagnosis of FNAIT was correlated to severity and outcome in the subsequent pregnancies. Occurrence of delayed diagnosis of FNAIT, and possibly associated intracranial haemorrhage (ICH). In four of 26 pregnancies, timely diagnostic testing for FNAIT was not performed despite fetal or neonatal thrombocytopenia or ICH. Down syndrome, dysmaturity and birth trauma were perceived to be the cause of the thrombocytopenia/ICH. In two of these four subsequent, untreated pregnancies, severe fetal ICH occurred. The other 22 women were treated for FNAIT using intravenous immunoglobulin, all children are alive and well. All neonates with thrombocytopenia at birth should be evaluated for FNAIT. Missing this diagnosis can have severe consequences for subsequent pregnancies.

Are HPA-5b antibodies a significant cause of FNAIT and associated bleeding or merely an incidental finding?

Children affected by fetal and neonatal alloimmune thrombocytopenia (FNAIT) are at risk of severe intracranial haemorrhage. Management in the postnatal period is based on sparse evidence. We aimed to describe the contemporary management and outcomes of patients with FNAIT in high-income countries. In this multicentre, retrospective, cohort study, we set up a web-based registry for the collection of deidentified data on the management and course of neonates with FNAIT. Eight centres from seven countries (Australia, Norway, Slovenia, Spain, Sweden, the Netherlands, and the USA) participated. Eligibility criteria comprised neonates with FNAIT being liveborn between Jan 1, 2010, and Jan 1, 2020; anti-human platelet antigen (HPA) alloantibodies in maternal serum; confirmed maternal and fetal HPA incompatibility; and bleeding detected at antenatal ultrasound, neonatal thrombocytopenia (<150 × 109 platelets per L), or both in the current or previous pregnancy. Clinical data were retrieved from local medical records of the first neonatal admission and entered in the registry. The key outcome was the type of postnatal treatment given to neonates with FNAIT. Other outcomes were daily median platelet counts in the first week of life, median platelet count increment after first unmatched versus first matched transfusions, and the proportion of neonates with mild or severe bleeding. 408 liveborn neonates with FNAIT were entered into the FNAIT registry, of whom 389 from Australia (n=74), Norway (n=56), Slovenia (n=19), Spain (n=55), Sweden (n=31), the Netherlands (n=138), and the USA (n=16) were included in our analyses. The median follow-up was 5 days (IQR 2-9). More neonates were male (241 [64%] of 379) than female (138 [36%]). Severe thrombocytopenia (platelet count <50 × 109 platelets per L) was reported in 283 (74%) of 380 neonates, and extreme thrombocytopenia (<10 × 109 platelets per L) was reported in 92 (24%) neonates. Postnatal platelet count nadir was higher in the no-treatment group than in all other groups. 163 (42%) of 389 neonates with FNAIT received no postnatal treatment. 207 (53%) neonates received platelet transfusions, which were either HPA-unmatched (88 [43%] of 207), HPA-matched (84 [41%]), or a combination of both (35 [17%]). The proportion of neonates who received HPA-matched platelet transfusions varied between countries, ranging from 0% (Slovenia) to 63% (35 of 56 neonates; Norway). Postnatal intravenous immunoglobulin treatment was given to 110 (28%) of 389 neonates (alone [n=19] or in combination with platelet transfusions [n=91]), with the proportion receiving it ranging from 12% (17 of 138 neonates; the Netherlands) to 63% (ten of 16 neonates; the USA) across countries. The median platelet increment was 59 × 109 platelets per L (IQR 35-94) after HPA-unmatched platelet transfusions and 98 × 109 platelets per L (67-134) after HPA-matched platelet transfusions (p<0·0001). Severe bleeding was diagnosed in 23 (6%) of 389 liveborn neonates, with one having a severe pulmonary haemorrhage and 22 having severe intracranial haemorrhages. Mild bleeding was diagnosed in 186 (48%) neonates. Postnatal management of FNAIT varies greatly between international centres, highlighting the absence of consensus on optimal treatments. Our data suggest that HPA-matched transfusions lead to a larger median platelet count increment than HPA-unmatched transfusions, but whether HPA matching is also associated with a reduced risk of bleeding remains unknown. Sanquin.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, which may lead to intracranial haemorrhage (ICH), with neurological damage as a consequence. In the absence of screening, FNAIT is only diagnosed after bleeding symptoms, with preventive options limited to a next pregnancy. To estimate the population incidence of FNAIT and its consequences to prepare for study design of a screening programme. An electronic literature search using MEDLINE, EMBASE and Cochrane database, and references of retrieved articles. No language restrictions were applied. Prospective studies on screening for human platelet antigen 1a (HPA-1a) alloimmunisation in low-risk pregnant women. Two reviewers independently assessed studies for inclusion and extracted data. Main outcome data were prevalence of HPA-1a negativity, HPA-1a immunisation, platelet count at birth and perinatal ICH. We aimed to compare outcome with and without intervention. HPA-1a alloimmunisation occurred in 294/3028 (9.7%) pregnancies at risk. Severe FNAIT occurred in 71/227 (31%) immunised pregnancies, with perinatal ICH in 7/71 (10%). True natural history data were not found because interventions were performed in most screen-positive women. Screening for HPA-1a alloimmunisation detects about two cases in 1000 pregnancies. The calculated risk for perinatal ICH of 10% in pregnancies with severe FNAIT is an underestimation because studies without interventions were lacking. Screening of all pregnancies together with effective antenatal treatment such as intravenous immunoglobulin may reduce the mortality and morbidity associated with FNAIT.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of intracranial hemorrhage (ICH) in thrombocytopenic term infants. We investigated clinical and laboratory predictors of severe FNAIT in a tertiary care referral center. Retrospective cohort study over a 30-year period. We defined FNAIT as recurrence of neonatal thrombocytopenia in a subsequent pregnancy; and severe outcomes as any of: (1) a birth platelet count below 20 × 109 /L; (2) ICH or (3) fetal death. We used a generalized estimating equations analysis and classification tree analysis to identify risk factors for severe FNAIT in a subsequent pregnancy. During index pregnancies (n=135 in 131 mothers), 71 infants (52.6%) had severe outcomes including a platelet count <20 × 109 /L (n=45), fetal or neonatal ICH (n=32), or fetal death (n=4). During subsequent pregnancies (n=72), 15 infants (20.8%) had severe outcomes including birth platelets <20 × 109 /L (n=10), ICH (n=2), or death (n=3). Forty-two women (58.3%) received antenatal intravenous immune globulin (IVIG) during subsequent pregnancies. Eight mothers (n=9 infants) had severe FNAIT outcomes despite receiving antenatal IVIG. Maternal antibodies to human platelet antigens (HPA) was the only independent predictor of severe FNAIT in a subsequent pregnancy (OR=25.3, p=.004). Nevertheless, one of 43 infants from antibody-negative mothers had a severe outcome. The presence of anti-HPA is highly indicative of the diagnosis of severe FNAIT; however, we observed one infant who had severe FNAIT recurrence, defined using strict clinical criteria, without a maternal antibody. Improved diagnostic and therapeutic strategies are needed to prevent severe FNAIT in high-risk mothers.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, seen in one in 800 to 1000 neonates. FNAIT is the most common cause of early-onset isolated severe neonatal thrombocytopenia in maternity wards. The complication of this disorder most to be feared is intracranial hemorrhage, leading to death or to neurologic sequels. As there is no systematic screening of at-risk pregnancies, FNAIT is often discovered when signs of bleeding are observed during pregnancy or at delivery. Platelet transfusion is required in case of bleeding or severe thrombocytopenia (<30 × 10(9) /L) during the 48-hour-postdelivery period. Diagnosis of alloimmunization is important for management of the index case and for subsequent pregnancies, due to the increasing severity of this syndrome as it recurs. Noninvasive antenatal therapy is based on maternal perfusion of intravenous immunoglobulins and risk stratification. In our experience, the addition of corticoids during the last trimester significantly improves the efficiency of treatment. Follow-up of antibody concentration during pregnancy may constitute a useful variable for therapy effectiveness.

Management of neonatal thrombocytopenia in a context of maternal antiplatelet alloimmunization: Expert opinion of the French-speaking working group

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 12weeks 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.

Rising to the challenge: an international Delphi consensus study on fetal and neonatal alloimmune thrombocytopenia.