How I manage pregnant patients who are alloimmunized to RBC antigens.

Hemolytic disease of the fetus and newborn (HDFN) remains an important cause of perinatal morbidity and mortality. HDFN is caused by maternal alloimmunization to red blood cell (RBC) antigens. This article describes and highlights issues in the care of pregnant women with red blood cell (RBC) alloimmunization. This includes monitoring for, and management of fetal anemia caused by maternal red cell alloantibodies, but also considerations for transfusion support for the woman in the event of major bleeding. Many aspects of care for women with RBC alloantibodies are not covered within specific guidelines, particularly with respect to best practice for antenatal management of women with prior significant obstetric morbidity or mortality due to HDFN, and we will outline our approach in these cases. The use of non-invasive monitoring for fetal anemia through measurement of the middle cerebral artery peak systolic velocity has led to a paradigm shift in antenatal care for women with high-risk antibodies, and medical therapies hold promise for women with the most severe disease.

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.

Maternal HPA-1a antibody level and its role in predicting the severity of Fetal/Neonatal Alloimmune Thrombocytopenia: a systematic review.

BACKGROUND AND OBJECTIVES: In Caucasians, fetal/neonatal alloimmune thrombocytopenia (FNAIT) is most commonly due to maternal HPA-1a antibodies. HPA-1a typing followed by screening for anti-HPA-1a antibodies in HPA-1bb women may identify first pregnancies at risk. Our goal was to review results from previous published studies to examine whether the maternal antibody level to HPA-1a could be used to identify high-risk pregnancies. MATERIALS AND METHODS: The studies included were categorized by recruitment strategies: screening of unselected pregnancies or samples analyzed from known or suspected FNAIT patients. RESULTS: Three prospective studies reported results from screening programmes, and 10 retrospective studies focused on suspected cases of FNAIT. In 8 studies samples for antibody measurement, performed by the monoclonal antibody immobilization of platelet antigen (MAIPA) assay, and samples for determining fetal/neonatal platelet count were collected simultaneously. In these 8 studies, the maternal antibody level correlated with the risk of severe thrombocytopenia. The prospective studies reported high negative predictive values (88-95%), which would allow for the use of maternal anti-HPA-1a antibody level as a predictive tool in a screening setting, in order to identify cases at low risk for FNAIT. However, due to low positive predictive values reported in prospective as well as retrospective studies (54-97%), the maternal antibody level is less suited for the final diagnosis and for guiding antenatal treatment. CONCLUSION: HPA-1a antibody level has the potential to predict the severity of FNAIT.

How clinically important are non-D Rh antibodies?

INTRODUCTION: The advent of RhD immunoglobulin prophylaxis to prevent maternal RhD alloimmunization has reduced the incidence of this condition and its associated poor outcomes. Consequently, non-D Rh antibodies now account for a greater proportion of alloimmunized pregnancies. These antibodies have been the subject of comparatively little research. This study investigated the incidence and clinical outcome of pregnancies affected by non-D Rh alloimmunization at an Australian tertiary maternity service. MATERIAL AND METHODS: This was a retrospective study of all pregnancies with non-D Rh antibodies (namely anti-C, -E, -c, -e, -Cw as well as the compound antibodies anti-CD, -cE and -ce) managed at the Royal Women's Hospital, Victoria, Australia, from 2009 to 2013 inclusive. Information collected included maternal demographics, details of the antibodies, course of the pregnancy and neonatal outcomes. RESULTS: During the study period, 115 non-D Rh alloimmunized pregnancies were identified in 102 mothers. Forty-nine pregnancies reached the critical titer (> 16) from non-D Rh alone and 11 fetuses received intrauterine red blood cell transfusion. Labor was induced or cesarean section performed in 38 cases. Forty-three neonates were admitted to the special care nursery and 59 received phototherapy. Nine received treatment for anemia and 10 neonates received intravenous immunoglobulin. CONCLUSIONS: Non-D Rh alloimmunization is a relatively uncommon complication of pregnancy, occurring in only .33% of pregnancies in the study period. It can lead to significant fetal/neonatal morbidity (and may lead to mortality). The most severe outcomes (including perinatal deaths) were mostly associated with the compound antibodies anti-CD and anti-cE, or a non-D Rh antibody in conjunction with anti-D.

Misinterpretation of blood group and antibody screen leading to serious errors in RhD immunoglobulin administration: A report on first two years of data from Serious Transfusion Incident Reporting program.

The Serious Transfusion Incident Reporting program (STIR) commenced haemovigilance in relation to RhD immunoglobulin (Ig) administration in 2015. During two years of reporting, 21 reports relating to RhD Ig administration were received. Thirty-three percent (7/21) were related to omission of RhD Ig, putting women at risk of RhD alloimmunisation and adverse consequences in future pregnancies. A recent case reported to STIR highlights poor communication and misinterpretation of pathology results leading to significant morbidity from haemolysis in the fetus. STIR makes recommendations related to education of staff and communication between clinical and laboratory staff to improve the safety of patient care.

Blood Group Antigen Matching Influence on Gestational Outcomes (AMIGO) study.

BACKGROUND: Red blood cell (RBC) antigen matching policies to prevent alloimmunization in females of childbearing potential (FCP) vary between centers. To inform transfusion centers responsible for making decisions about matching policies for FCPs, the causal stimulus of the antibodies implicated in severe hemolytic disease of the fetus and newborn (HDFN) must be determined. STUDY DESIGN AND METHODS: We conducted a multinational retrospective study of women with offspring affected by severe HDFN requiring neonatal exchange transfusion and/or intrauterine transfusion. Mothers treated at centers that provide extended antigen-negative RBCs (MATCH, five centers) and those that do not (NoMATCH, nine centers) were compared. RESULTS: A total of 293 mothers had at least one affected pregnancy: 179 at MATCH centers and 114 at NoMATCH centers. Most alloimmunization (83%) was attributed to previous pregnancy: 3% to transfusion (two cases at MATCH, six at NoMATCH centers) and 14% undetermined (both antecedent transfusion and pregnancy). Only 50 mothers had received transfusions; 13 had HDFN due to anti-K at MATCH and four at NoMATCH centers. Most (12/13, 92%) of the anti-K HDFN cases at MATCH centers had K+ paternal antigen status. Mothers at the MATCH centers do not appear to be protected from HDFN due to K, C, c, and E antibodies, although the low number of FCPs who received transfusions precluded drawing firm conclusions. CONCLUSION: The causal stimulus of antibodies that cause HDFN is predominantly from previous pregnancy. Although extended RBC matching for FCPs may impart some protection from allosensitization, we were unable to show a positive effect, possibly because matching policies are not uniform and there was a small number of mothers who previously received transfusions.

Safety and Efficacy Outcomes of Home and Hospital Warfarin Management Within a Pediatric Anticoagulation Clinic.

The complexity of managing children with chronic disease has led to an increase in the use of long-term warfarin therapy. Time in therapeutic range (TTR) is the preferred method for determining efficacy and stability of warfarin management. This study aimed to determine the TTR achievement and incidence of adverse events among pediatric warfarin patients managed by an anticoagulation clinic over 12 months and to compare TTR achievement between patients self-testing (PST) at home and those monitored using routine methods. International normalized ratio (INR) results reported for 2012 for children currently having their warfarin therapy managed by a dedicated pediatric anticoagulation clinic were analyzed. Warfarin-related adverse events were recorded. A total of 164 patients were included. In total, 93 children performed PST and 71 children tested their INR at a hospital or pathology service. TTR achievement for the cohort was 67.1% (95% confidence interval, 64.4-69.7). A total of 69.2% of INR tests conducted at home were within the TTR compared with 64.3% of INR tests conducted at a hospital or pathology service (P=0.07). One major bleeding event occurred and there was 1 thrombotic episode. PST demonstrated noninferior warfarin stability compared with routine methods. Routine outcome evaluation of pediatric anticoagulation management within single institutions is necessary to confirm the success of such programs.

Fulminant liver failure in a neonate.

Neonatal acute liver disease is relatively rare, with multiple different aetiologies including congenital infections, metabolic disorders, gestational alloimmune liver disease, haemophagocytic lymphohistiocytosis, and ischaemic injury. We report a case of neonatal liver failure in a preterm, growth-restricted infant, who underwent extensive investigation and was clinically diagnosed with gestational alloimmune liver disease, which was confirmed on post-mortem examination. We then discuss management of neonatal liver failure and gestational alloimmune liver disease, including maternal management in future pregnancies.

Caring for pregnant women for whom transfusion is not an option. A national review to assist in patient care.

Postpartum haemorrhage (PPH) is the leading cause of maternal mortality and morbidity globally. Obstetric bleeding can be catastrophic and management is challenging, involving a coordinated multidisciplinary approach, which may include blood products. In settings where blood transfusion is not an option, either because of patient refusal (most commonly in Jehovah Witnesses) or because of unavailability of blood, management becomes even more challenging. Observational studies have demonstrated an association between refusal of blood products in major obstetric haemorrhage and increased morbidity and mortality. This review draws upon evidence in the literature, physiological principles and expert opinion for strategies and guidance to optimise the outcomes of pregnant women in whom blood transfusion is either refused or impossible. The importance of a multidisciplinary antenatal and perinatal management plan, including optimisation of haemoglobin and iron stores pre-delivery, blood loss minimisation, early haemorrhage control and postpartum anaemia treatment, is discussed.

Continuous reference intervals for holotranscobalamin, homocysteine and folate in a healthy paediatric cohort.

BACKGROUND: The detection of deficiencies in B12 and folate children is important. However, despite the availability of various markers to assess B12 and folate metabolism, there are limited studies describing the reference intervals (RIs) and changes during growth and development for these markers in healthy children. METHODS: Using samples collected from 378 children aged 30 days-< 18 years, we derived continuous RIs for holotranscobalamin, homocysteine and red cell folate. RESULTS: The lower RI for holotranscobalamin was lowest at birth, rising during early childhood and then declining following ages 4-6 years whereas red cell folate was highest early in life and then declined steadily towards adulthood. Total homocysteine, reflective of both B12 and folate status was elevated early in life, reaching a nadir at age 2 and then increasing towards adulthood. CONCLUSIONS: Continuous central 95th percentile RI for holotranscobalamin, homocysteine and red cell folate for children ages 30 days to <18 years were established. Each marker shows dynamic changes throughout childhood and adolescence which will assist clinicians in more appropriately assessing B12 and folate status in this population.

Antenatal immunoglobulin for fetal red blood cell alloimmunization.

BACKGROUND: Red blood cell alloimmunization in pregnancy can lead to fetal anaemia with potentially disastrous consequences. Traditional management involves the use of intrauterine transfusion, which is associated with significant procedure-related risks. An alternative treatment that has been trialled is the use of immunoglobulin administered intravenously to the mother. OBJECTIVES: The objective of this review was to assess the efficacy and safety of the use of intravenous immunoglobulin antenatally to women with severe fetal red blood cell alloimmunization. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group trials register (19 December 2012), and reference lists of articles. SELECTION CRITERIA: Randomized trials assessing the antenatal use of intravenous immunoglobulin administered at any dose, frequency or duration with a control group (using any other, or no treatment) in the management of fetal red blood cell alloimmunization. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the available evidence. MAIN RESULTS: There are no included studies. AUTHORS' CONCLUSIONS: No information is available from randomized trials to indicate whether the antenatal use of intravenous immunoglobulin is effective in the management of fetal red blood cell alloimmunization. Several case series suggest a beneficial role in delaying the onset of fetal anaemia requiring invasive intrauterine transfusion.

Hospitalisations for sickle-cell disease in an Australian paediatric population.

AIM: Sickle-cell disease (SCD) is more prevalent in Australia due to increased migration; however, the Australian paediatric SCD population has not been previously described. This study aimed to identify the demographic features of and quantify the hospital resource utilisation in the SCD population at The Royal Children's Hospital in Victoria. METHODS: This was a retrospective chart review of SCD patients who presented to the Royal Children's Hospital over a 10.5-year period. Descriptive analyses were conducted. RESULTS: Thirty-seven SCD patients aged from 0.2 to 18.0 years (mean: 8.5 ± 4.8 years) had 535 admissions over the 10.5-year period. The population was made up of 28 homozygous sickle-cell disease, 1 sickle C disease and 8 sickle-cell beta patients from a variety of ethnic backgrounds. Admissions included 264 unplanned admissions, that is 258 admissions via the emergency department and 6 admissions via outpatients, and 271 planned admissions. Mean length of stay for unplanned admissions was 3.2 ± 2.6 days. Common diagnoses for unplanned admissions were 187 vaso-occlusive crisis (70.8%), 32 infections (12.1%) and 26 anaemic episodes (9.8%). Transfusion therapy (91.9%) accounted for the majority of planned admissions. CONCLUSIONS: Children with sickle-cell disease in an Australian setting require hospitalisation for various reasons related to disease, either unexpected complications or elective procedures. Factors affecting the provision of optimal healthcare to be explored include the multicultural demographics of the SCD population, the timely management of vaso-occlusive crises and the availability of SCD-related protocols.

Neonatal exchange transfusions in the 21st century: a single hospital study.

AIM: In the 21st century, neonatal exchange transfusions (ETs) are uncommon procedures usually performed in tertiary neonatal units. As junior clinical staff now lack familiarity with the procedure, it is important to maintain awareness of its complications in order to manage clinical risks and counsel parents appropriately. The study aims to analyse the ET rate, its indications and its associated complications, in a single tertiary centre in the 21st century. METHODS: This is a retrospective cohort study of all infants receiving ET from 1 January 2001 to 31 December 2010 at the Royal Women's Hospital, Melbourne. RESULTS: Sixty-four ETs were performed in 51 infants, an average of 6.4 ETs per year. Forty-nine (96%) infants were exchanged for hyperbilirubinaemia and two (4%) for anaemia. Thirty-six (71%) infants had Rhesus haemolytic disease of the newborn and six (12%) had ABO incompatibility. Six infants were intubated and mechanically ventilated after ET; these infants were significantly more acidotic during the ET than those who were never on respiratory support (mean pH 7.153 and 7.309 respectively, mean difference -0.156, 95% CI -0.196 to -0.116, t = 7.85, P < 0.001). Overall mortality was 8% (n = 4). CONCLUSIONS: Our current ET rate is very low compared with historical data. It is difficult to ascribe mortality and morbidity directly to ET as the procedure is now often performed on smaller, sicker or more premature infants whose risks of mortality and morbidity are high regardless of ET. Prospective multi-centre studies are needed to provide adequate data to analyse complications in greater detail.

A review of pathophysiology and current treatment for neonatal alloimmune thrombocytopenia (NAIT) and introducing the Australian NAIT registry.

Fetomaternal or neonatal alloimmune thrombocytopenia (NAIT) is a rare but serious condition associated with significant fetal and neonatal morbidity and mortality. The most useful predictor of severe disease is a history of a sibling with an antenatal intracranial haemorrhage. However, NAIT can occur during the first pregnancy and may not be diagnosed until the neonatal period. Antenatal treatment options include maternal intravenous immunoglobulin (IVIG) and corticosteroid treatment, fetal blood sampling (FBS) and intrauterine platelet transfusion (IUT) and early delivery. FBS (with or without IUT) can be used to direct and monitor response to therapy, and to inform mode and timing of delivery. However, this procedure is associated with significant risks, including fetal death, and is generally now reserved for high-risk pregnancies. This review highlights the current understanding of the epidemiology and pathophysiology of NAIT and summarises current approaches to investigation and management. It also introduces the newly established Australian NAIT registry. Owing to the relative rarity of NAIT, accruing sufficient patient numbers for studies and clinical trials at an institutional level is difficult. This national registry will provide an opportunity to collect valuable information and inform future research on this condition.

Changes in emergency department blood product use for major paediatric trauma following the implementation of a major haemorrhage protocol.

OBJECTIVE: Fixed ratio blood product administration may improve outcomes in trauma patients with massive blood loss. The present study aimed to describe the impact of a major haemorrhage protocol (MHP) on the ratio of blood products administered for paediatric major trauma. METHODS: Retrospective observational study in a state-designated paediatric major trauma centre in Melbourne, Australia. Children with major trauma who received blood products in the ED were identified from a hospital trauma registry. Blood product ratios before, during and after implementation of a hospital MHP were compared in consecutive 2 year blocks. RESULTS: Over a 6 year period, 767 major trauma patients were identified, of whom 47 received blood products in the ED and were included in the analysis; 14 pre-MHP implementation, 24 during-MHP implementation and nine post-MHP implementation. No patients received blood products at a ratio of 1:1:1 for red blood cells:fresh frozen plasma:platelets, respectively, during any time period. In this cohort of predominantly blunt trauma, blood products were infrequently administered in the ED because of the low prevalence of massive blood loss. Coagulopathy and hypofibrinogenaemia were commonly observed, nearly half of included patients were managed operatively and one quarter did not survive their injuries. CONCLUSION: The implementation of a MHP did not change the ratio of blood product administration in this cohort of patients because of the infrequency of massive blood loss. Future studies may focus on the impact of treating coagulopathy and hypofibrinogenaemia on patient-centred outcomes.

Fetal/neonatal alloimmune thrombocytopenia: a systematic review of impact of HLA-DRB3*01:01 on fetal/neonatal outcome.

The most common, severe cases of fetal and neonatal alloimmune thrombocytopenia among whites are caused by antibodies against human platelet antigen 1a (HPA-1a). The aims of this systematic review and meta-analysis are to determine the association between maternal HLA-DRB3*01:01 and: (1) HPA-1a-alloimmunization and (2) neonatal outcome in children born of HPA-1a-immunized women. A systematic literature search identified 4 prospective and 8 retrospective studies. Data were combined across studies to estimate pooled odds ratios (ORs) and the associated 95% confidence intervals (CIs). The population represented by the prospective studies was more than 150 000. In the prospective studies, there were 64 severely thrombocytopenic newborns (platelet count <50 × 109/L) of whom 3 had intracranial hemorrhage. The mothers of all 64 children were HLA-DRB3*01:01+. The number of severely thrombocytopenic children born of HPA-1a-alloimmunized women in the retrospective studies was 214; 205 of whom were born of HLA-DRB3*01:01+ women. For HLA-DRB3*01:01- women, the OR (95% CI) for alloimmunization was 0.05 (0.00-0.60), and for severe neonatal thrombocytopenia 0.08 (0.02-0.37). This meta-analysis demonstrates that the risk of alloimmunization and of having a child with severe thrombocytopenia are both very low for HPA-1a- women who are HLA-DRB3*01:01-.

An audit of transfusion of red blood cell units in pediatric anesthesia.

BACKGROUND: Patients undergoing surgery are an important user of red blood cells (RBC). Increasingly, medical staff and patients wish to know the likelihood of RBC transfusion for appropriate resource allocation and to inform preoperative discussions regarding risk. Although some adult data are available, little is known about RBC use in children. AIM: The aim of this study was to describe RBC use in the perioperative period in a large pediatric hospital. METHODS: Over a 2-year period the hospital operating theatre database and trauma registry was merged with the blood bank database to identify episodes where RBC units were transfused in association with anesthesia. Incidence of transfusion of RBC units associated with particular procedures was then calculated. RESULTS: A total of 21 441 patients underwent 32 511 anesthetics from January 1, 2006 to December 31, 2007, and 9838 units of RBC were released from the hospital blood bank of which 4070 (41%) were transfused in the perioperative period. Cardiac surgery was the greatest user of RBC units (2359 units). Acute major trauma accounted for only 159 units. Overall 6.3% of anesthetics were associated with a RBC transfusion. The procedures with the greatest frequency of RBC transfusion were cardiac surgery on bypass (79%), cardiac off bypass (55%), liver transplant (87%) and cranioplasty (61%). CONCLUSION: In a tertiary pediatric hospital surgery accounts for a substantial proportion of total RBC use, with particular procedures accounting for the majority of transfusions.

Postnatal intervention for the treatment of FNAIT: a systematic review.

OBJECTIVE: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is associated with life-threatening bleeding. This systematic review of postnatal management of FNAIT examined transfusion of human platelet antigen (HPA) selected or unselected platelets, and/or IVIg on platelet increments, hemorrhage and mortality. STUDY DESIGN: MEDLINE, EMBASE and Cochrane searches were conducted until 11 May 2018. RESULT: Of 754 neonates, 382 received platelet transfusions (51%). HPA-selected platelets resulted in higher platelet increments and longer response times than HPA-unselected platelets. However, unselected platelets generally led to sufficient platelet increments to 30 × 109/L, a level above which intracranial hemorrhage or other life-threatening bleeding rarely occurred. Platelet increments were not improved with the addition of IVIg to platelet transfusion. CONCLUSION: Overall, HPA-selected platelet transfusions were more effective than HPA-unselected platelets but unselected platelets were often effective enough to achieve clinical goals. Available studies do not clearly demonstrate a benefit for addition of IVIg to platelet transfusion.