Neonatal Transfusion Research Articles

Warming blood products for transfusion to neonates: In vitro assessments

Blood products may be transfused into neonates at temperatures at or below room temperature. The benefits and risks of warming blood to 37°C are not defined in this population or with the equipment used in neonates. Physiologic warming might enhance product effectiveness or decrease transfusion-associated hypothermia. We utilized an in vitro model of neonatal transfusions, with a syringe pump, blood tubing, and 24-gauge catheter and compared current practice (cold products) vs an inline blood warmer. Transfusions were performed rapidly (30 minutes) and slower (120 minutes) to model emergent vs routine situations. We tested red blood cells, fresh-frozen plasma, apheresis platelets (PLTs), and cold-stored low-titer group O whole blood. We used infrared detectors and inline probes to measure temperatures at the origin and at the simulated patient. We assessed warmer-induced damage by measuring plasma hemoglobin and hematocrit (seeking hemolysis), fibrinogen (seeking activation of coagulation), and PLT count and TEG-MA (seeking PLT destruction or dysfunction). The cold-stored products were 4.2 ± 1.0°C (mean ± SD) at the origin and 21.5 ± 0.1°C at the patient. With the inline warmer, products were 37.8 ± 0.6°C at the warmer and 32.6 ± 1.7°C at the patient during a 30-minute infusion, but were 34.5 ± 2.1 with a foil sheath covering the terminal tubing. We found no warmer-induced damage using any metric. In simulated neonatal intensive care unit (NICU) transfusions, an inline blood warmer can deliver blood products at near-physiologic temperatures with no detected damage. We suggest in vivo testing of warmed NICU transfusions, assessing product effectiveness and hypothermia risk reduction.

Molecular heterogeneity of pyruvate kinase deficiency.

Red cell pyruvate kinase (PK) deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an autosomal recessive trait, is caused by mutations in the PKLR gene and is characterized by molecular and clinical heterogeneity; anemia ranges from mild or fully compensated hemolysis to life-threatening forms necessitating neonatal exchange transfusions and/or subsequent regular transfusion support; complications include gallstones, pulmonary hypertension, extramedullary hematopoiesis and iron overload. Since identification of the first pathogenic variants responsible for PK deficiency in 1991, more than 300 different variants have been reported, and the study of molecular mechanisms and the existence of genotype-phenotype correlations have been investigated in-depth. In recent years, during which progress in genetic analysis, next-generation sequencing technologies and personalized medicine have opened up important landscapes for diagnosis and study of molecular mechanisms of congenital hemolytic anemias, genotyping has become a prerequisite for accessing new treatments and for evaluating disease state and progression. This review examines the extensive molecular heterogeneity of PK deficiency, focusing on the diagnostic impact of genotypes and new acquisitions on pathogenic non-canonical variants. The recent progress and the weakness in understanding the genotype-phenotype correlation, and its practical usefulness in light of new therapeutic opportunities for PK deficiency are also discussed.

Intrauterine transfusions for maternofetal red‐blood‐cell incompatibility in monochorionic diamniotic twin pregnancy

Maternal alloimmunization to fetal red-blood-cell (RBC) antigens may cause hemolytic disease in the fetus with severe anemia. Intrauterine transfusions (IUTs) in twin pregnancy represent 1.5% of all fetal transfusions for RBC alloimmunization1, 2. Here, we present a case of a monochorionic diamniotic twin pregnancy complicated by severe anti-D maternofetal incompatibility, monitored by fetal middle cerebral artery (MCA) peak systolic velocity (PSV) and treated successfully by repeat IUTs of a single cotwin. The patient was referred to our center at 24 weeks' gestation for suspected fetal anemia. Fetal middle cerebral artery (MCA) peak systolic velocity (PSV) reached 1.64 multiples of the median (MoM) in Twin A and 2.02 MoM in Twin B. Both fetuses presented with ascites. Twin A was transfused with 30 mL of packed RBC. Pretransfusion hemoglobin (Hb) was 3.0 g/dL, with a Kleihauer–Betke test (KBT) result of 100% in fetal blood3, 4. Post-transfusion Hb increased to 8.8 g/dL and KBT decreased to 18%. MCA-PSV decreased from 1.64 to 1.19 MoM in Twin A and from 2.02 to 1.64 MoM in Twin B. Thirty minutes later, as MCA-PSV remained above 1.5 MoM in Twin B, an IUT of 15 mL was administered to Twin B, which enabled Hb level in Twin B to increase from 8.1 to 11.4 g/dL, and KBT in fetal blood decreased from 17% to 10%. The direct antiglobulin test showed a result of 3+ (high intensity) and cord bilirubin was over 70 µmol/L. These findings were suggestive of ongoing hemolytic disease. For subsequent IUTs at 25 + 4, 27 + 3 and 30 + 3 weeks' gestation, only Twin A was transfused. This strategy allowed for the normalization of MCA-PSV in both fetuses (Figure 1, Table 1). Cesarean section was performed at 31 weeks' gestation for non-reassuring fetal-heart tracing. The first delivered male neonate had birth weight of 1330 g, arterial cord blood pH of 7.37, Hb of 11.3 g/dL and bilirubin of 90 µmol/L. The second neonate had birth weight of 1310 g, arterial cord blood pH of 7.43, Hb of 11.5 g/dL and bilirubin of 88 µmol/L. Placental colored dye injection showed several arterioarterial anastomoses. The twins had respiratory distress syndrome which was treated by non-invasive ventilatory support. Severe jaundice worsened despite intensive phototherapy and albumin infusion, requiring exchange transfusion in both neonates. Two transfusions at 15 and 45 days were also needed. The neonates were discharged at 66 days postpartum. In this case, during the first IUT, transplacental intertwin anastomoses were demonstrated by (1) MCA-PSV values in Twin B decreasing after IUT of Twin A, (2) KBT in fetal blood already being reduced in Twin B after IUT of Twin A but before IUT of Twin B, and (3) Hb in Twin B being similar to that observed in Twin A after IUT of Twin A but before IUT of Twin B. To our knowledge, this is the first reported case demonstrating the contribution of MCA-PSV to monitoring monochorionic twin pregnancy complicated by RBC alloimmunization, treated by repeat IUTs of a single cotwin. One case of a monochorionic twin pregnancy in which IUTs performed in turn in each cotwin has been reported, without using MCA-PSV monitoring2. In cases of fetal anemia caused by Rh alloimmunization in monochorionic twin gestations, it appears sufficient to transfuse only one of the fetuses at 2–3 week intervals.

Transfusion rates and disease spectrum in neonates treated with blood transfusion in China.

This study aimed to investigate blood transfusion rates and spectrum of diseases in hospitalized neonates treated with blood transfusion in China to provide supporting data for future studies on neonatal blood transfusion.Data on hospitalized neonates were obtained from more than 100 experts from the Department of Neonatology of 55 hospitals in China between January 1, 2012 and December 31, 2016, using a standardized survey. A statistical analysis was conducted to evaluate the data collected, including the blood transfusion rates, blood component transfused, spectrum of diseases, and spectrum of major diseases.Between 2012 and 2016, 541,128 neonates were hospitalized in the 55 hospitals surveyed. There were 70,433 neonates who received blood transfusion, with an average transfusion rate of 13.02%. The rates of red blood cell transfusion, platelet transfusion, and plasma transfusion were 9.44%, 0.66%, and 4.77%, respectively. The neonatal blood transfusion rate was 17.99% in Northeast China, 9.74% in Northwest China, and between 10.60% and 16.22% in other regions. The neonatal blood transfusion rate was 12.3% in general hospitals and 13.8% in women and children's hospitals. The top 10 diseases identified in hospitalized neonates treated by blood transfusion were, in rank order, as follows:prematurity,pneumonia, hyperbilirubinemia, bacterial sepsis, respiratory distress syndrome, anemia, hemolytic disease, asphyxia, hemorrhage, and necrotizing enterocolitis.The neonatal blood transfusion rate in China is 13.03%.The rank order in the disease spectrum of the hospitalized neonates and that in hospitalized neonates treated with blood transfusion are different.

Intrauterine transfusion: an international review of practice and policy

BackgroundIntrauterine transfusion (IUT) is a treatment for fetal anemia. This technique involves ultrasound guided needle placement followed by transfusion of a specially prepared blood component. The most common indications include hemolytic disease of the fetus and newborn (HDFN) and prenatal infection.MethodsThe literature was reviewed, and blood component characteristics and preparatory techniques identified. An international survey of IUT was conducted.ResultsComponent preparation for IUT differs from preparation for other transfusions. Differences relate to unique characteristics of the fetus including a small blood volume, invasive access for transfusion and immune deficiency. The techniques for preparation of red blood cells (RBC) are variable with limited evidence. Most use fresh concentrated RBC. Irradiation is uniformly recommended. RBC that are antigen negative for the maternal alloantibody are provided, and the product is selected or modified to minimize risk for cytomegalovirus transmission. Selection of ABO group and the degree of additional prophylactic phenotype matching are variable. While maternal RBC transfusion may be used, compatible allogeneic RBC are more common. For maternal antibodies to high prevalence antigens rare phenotype deglycerolized RBC may be used. There are challenges in providing RBC for IUT. Pre and post transfusion blood samples must be correctly managed in the medical record. Hemovigilance requires that both the fetus and the mother be documented as recipients. Preparation may be urgent, and sterile technique is required. Records of IUT must be conveyed to neonatal care providers as the transfused blood may mask the true blood group for weeks to months post transfusion, and component modifications may be required for any postnatal transfusion in neonates who were treated with IUT.

Are there gender-specific differences in pregnancy outcome and placental abnormalities of pregnancies complicated with small for gestational age?

Adaptations to pathological intrauterine environment might differ in relation to fetal gender. We aimed to study sex-specific differences in placental pathology of pregnancies complicated by small for gestational age (SGA). The medical records and placental histology reports of all neonates with a birth-weight ≤ 10th percentile, born between 24 and 42weeks of gestation, during 2010-2018, were reviewed. Composite neonatal outcome was defined as one or more of early following complications: neonatal sepsis, blood transfusion, phototherapy, respiratory morbidity, cerebral morbidity, necrotizing enterocolitis, or death. Results were compared between the male and female groups of neonates. Placental lesions were classified into maternal and fetal vascular malperfusion (MVM and FVM) lesions, maternal and fetal inflammatory responses (MIR and FIR), and villitis of unknown etiology (VUE). The male SGA group (n = 380) and the female SGA group (n = 363) did not differ in regard to maternal age, BMI, smoking, associated pregnancy complications, gestational age, and mode of delivery. Neonates in the SGA male group had increased birth-weight and increased respiratory morbidity as compared to the female SGA group (p = 0.007, p = 0.005, respectively). There was no between-group differences in the rate of placental lesions. By multivariate logistic regression analysis, male gender (aOR 1.55, 95% CI 1.05-2.30, p = 0.025), FIR (aOR 4.83, 95% CI 1.07-13.66, p = 0.003), and VUE (aOR 1.89, 95% CI 1.03-3.47, p = 0.04), were found to be independently associated with adverse composite neonatal outcome. Male gender as well as placental FIR and VUE are independently associated with adverse neonatal outcome in SGA neonates.

Determinants and effects of fluid status changes in caesarean delivered neonates

Evidence suggests that caesarean section is associated with a reduced placental transfusion and poor iron-related haematological indices, both in cord and peripheral blood, compared with vaginal delivery. We assessed determinants and effects of fluid status changes on placental transfusion in neonates delivered by elective (ElCD) and emergency (EmCD) caesarean section. Placental transfusion was estimated by ∆ haematocrit (Hct) increase from birth to 48hours of life, accounting for contemporaneous ∆ body weight decrease, in 143 women/infant pairs, 62 who underwent ElCD and 81 EmCD, respectively. Cord blood Hct levels at birth of ElCS neonates were significantly lower than those of EmCD neonates (44.58+4.87vs 49.93+4.29, P=.01). At 48hours of life, capillary heel Hct levels of ElCD and of EmCD neonates were comparable. ElCD had a higher ∆ body weight decrease (ElCD -7.25±1.74% vs EmCD -6.31±2.34% [P: .011]) and ∆ Hct increase ([ElCD+5.93±4.92 vs EmCD+3.59±5.29, [P: .011]). In a linear regression model analysis, gestational age in ElCD neonates had a significant effect on the differences in arterial cord blood Hct, body weight at birth and body weight decrease at 48hours after birth. Early-term surgical delivery is a determinant of transient dilutional anaemia in ElCD neonates, lacking neuroendocrine response of labour and delivery.

Red blood cell transfusion in preterm neonates: a huge debate on tiny patients

Preterm infants are more liable to suffer from anemia, as 90% of extremely low birth weight infants receive red blood cell transfusion. When to receive red blood cell transfusion is not well defined until now, even the complications and hazards resulting from the transfusion of adult red blood cell into the premature circulation is still a matter of debate. In this review, fetal erythropoiesis and the unique pathophysiology of anemia of prematurity is discussed, different meta-analysis studies are presented regarding liberal (high hemoglobin threshold) or restrictive (low hemoglobin threshold) transfusion protocols, early or late transfusion preferences. To clarify the picture of this, everyday decision neonatologists need to take, whether or not to give this premature infant a red packed cell transfusion, which may affect the life of this infant indefinitely. Until now, no fixed guidelines are present regarding when to transfuse anemia and still dependent on expert opinion and center experience.

Neonatal red blood cell transfusion practices in Switzerland: national survey and review of international recommendations.

The aim of the study was to analyse Swiss practices in blood transfusion services and neonatal units for the preparation and administration of red blood cells in newborns. Two questionnaires were developed and their results analysed. A first questionnaire was developed for the Swiss blood transfusion services and local hospital haematology laboratories, and a second for the neonatal units in Switzerland. 18/25 (72%) of laboratories and 26/29 (90%) of neonatal units performing red blood cell transfusions participated. Responses revealed a lack of consensus for the majority of questions. Differences were found in all steps of the process, from preparation (testing, irradiation, splitting, shelf life and storage of blood bags) to indication and administration (volume, speed, vascular access, patient monitoring) of red blood cells. Forty-six percent of neonatal units stated that they apply internal guidelines. Nevertheless, all but two would welcome the establishment of national recommendations. This study confirmed the large variety in neonatal red blood cell transfusion practices in Switzerland. In the absence of clear evidence, national guidelines – as applied in other countries – would foster a common policy among Swiss neonatologists and facilitate the implementation of a national database for future research and comparison with international literature.

Neonatal exchange transfusion: Experience in Korea

BackgroundExchange transfusion (ET) is an established, efficacious, and reliable practice for severe neonatal hyperbilirubinemia, hemolytic disease of the newborn, and neonatal sepsis. This study assessed the indications and clinical outcomes of ET performed in a tertiary hospital in Korea. Materials and methodsWe studied 64 ET sessions performed on 23 neonates between March 1999 and March 2018. ET was performed based on estimated double volume exchange transfusion using fresh red blood cells and fresh frozen plasma. Patients’ clinical information, including demographic data and ET indication, and laboratory data were collected pre- and post-ET. ResultsThe most common ET indication was hyperbilirubinemia with hemolytic anemia due to non-ABO maternal blood group discrepancies. In three preterm babies, ETs were performed for severe anemia, leukocytosis, and hyperkalemia cases. Before ET, the patients showed slightly high WBC counts, low hemoglobin levels, and low platelet counts. After ET, blood examination revealed normal WBC counts, increased hemoglobin levels, and decreased platelet counts (all P < 0.001). Bilirubin levels decreased immediately after ET (P < 0.001). Electrolyte and C-reactive protein levels showed no significant changes after ETs. Adverse events occurred in 11 (47.8 %) patients; the most common were hypoxemia and hypotension. One infant experienced cardiorespiratory arrest due to hypercalcemia and was successfully resuscitated. No one died within 24 h of ET. However, five infants showed hyperbilirubinemia aggravation. ConclusionsET is an effective treatment modality for leukocytosis and hyperbilirubinemia with low mortality but involves common adverse events post-ET. This report provides an overview of current ET practices in Korea.

Red blood cell transfusion in preterm neonates: a huge debate on tiny patients

Preterm infants are more liable to suffer from anemia, as 90% of extremely low birth weight infants receive red blood cell transfusion. When to receive red blood cell transfusion is not well defined until now, even the complications and hazards resulting from the transfusion of adult red blood cell into the premature circulation is still a matter of debate. In this review, fetal erythropoiesis and the unique pathophysiology of anemia of prematurity is discussed, different meta-analysis studies are presented regarding liberal (high hemoglobin threshold) or restrictive (low hemoglobin threshold) transfusion protocols, early or late transfusion preferences. To clarify the picture of this, everyday decision neonatologists need to take, whether or not to give this premature infant a red packed cell transfusion, which may affect the life of this infant indefinitely. Until now, no fixed guidelines are present regarding when to transfuse anemia and still dependent on expert opinion and center experience. In conclusion the decision of RBCT is a multifactorial expert needing opinion but may be the only treatment option when the preterm neonate reaches a critical oxygen point beyond their ability to cope. So, a judicious use of blood transfusions is recommended, by unit specific guidelines. One can limit donor exposure by using multiple small packs from a single donor to multi transfuse a preterm infant, thus reducing donor exposure.

Embedding best transfusion practice and blood management in neonatal intensive care

BackgroundTransfusion is a common procedure for neonates receiving intensive care management. Recognising a paucity of patient blood management (PBM) programmes in neonates, we aimed to embed blood management and best...

Functional echocardiographic evaluation of the effect of placental transfusion in full-term newborns who need resuscitation

Background At the time of delivery, newborn babies have to pass through transitional changes in many of their life supporting systems. A more successful transition at the level of the cardiovascular system, hence an overall better transition, could be reached if placental transfusion is implicated. Aim To study the feasibility of doing intact umbilical cord milking (I-UCM) as a method of placental transfusion in term neonates who were born depressed and needed resuscitation and to study its hemodynamic effects using echocardiography. Patients and methods A randomized controlled study involving 66 patients over a period of 6 months was conducted. The studied population was assigned to receiving I-UCM or immediate cord clamping. Laboratory parameters, resuscitation interventions, and finally, functional echocardiographic were studied in both groups. Results It was feasible to perform I-UCM in the delivered babies in the assigned group. Such group was found to have faster time for the first breath (45 vs. 60 s), higher Apgar score (5, 8, 10 vs. 4, 7, 9), and no need for more advanced resuscitation interventions compared with the group with immediate cord clamping. Higher levels of hemoglobin (17.20 vs. 15.85) were noticed with less need to transfusion in the intervention group. Better echocardiographic assessments were shown regarding ejection fraction, tricuspid annular plane systolic excursion, and lower incidence of pulmonary hypertension in the I-UCM group (70 vs. 66%, 1.02 vs. 0.87 cm, and 33.3 vs. 62.5%, respectively). Conclusions The practicality of UCM was easy and feasible in both depressed and nondepressed newborns. UCM as a method for placental does not affect resuscitative measures and results in better cardiac performance in asphyxiated babies.

Exchange transfusion for neonatal hyperbilirubinemia: A multicenter, prospective study of Turkish Neonatal Society.

The frequency of neonatal exchange transfusion has declined in recent years, but is still performed in many countries. The procedure is associated with complications. The aim of the study was to determine the clinical features and etiologies of infants with hyperbilirubinemia who underwent exchange transfusion and evaluate the adverse events and clinical outcomes. We performed a secondary analysis of the multicenter Turkish Neonatal Jaundice Online Registry data. Otherwise healthy newborns born ≥35 weeks of gestation who were hospitalized for jaundice and underwent exchange transfusion were included. One-hundred thirty-two patients with a mean serum bilirubin level on admission of 24.9±9.1 mg/dL were enrolled in the study. The most common cause for exchange transfusion was hemolytic jaundice (63.6%), followed by lack of proper feeding (12.9%). It was found that the infants with lack of proper feeding were discharged earlier from the maternity ward (p=0.02), but they were admitted to hospital later (p<0.001) with a higher bilirubin level (p=0.001), and geater weight loss (p=0.04). The reported rate of adverse events associated with exchange transfusion was 11.4%. The most common complication was thrombocytopenia (40%). None of the infants died during the procedure. Acute bilirubin encephalopathy was reported in 13 (9.8%) patients. Severe hyperbilirubinemia requiring exchange transfusion and acute bilirubin encephalopathy are still challenging problems in neonatal periodin our country. The policies including blood group analysis of pregnant women, programs informing parents about breastfeeding and jaundice, and monitoring bilirubin levels of high-risk newborns should be developed to reduce the necessitating for exchange transfusion and to avoid related complications.

Audit on neonatal exchange transfusion in the Neonatology Unit of Assiut University applying American Academy of Pediatrics 2004 guidelines

Introduction: Exchange transfusion (ET) still has an important role in the Neonatal ICU of Assiut University Children Hospital as an emergency procedure for management of severe cases of hyperbilirubinemia. Therefore, this audit study was done on 26 patients for 1 year to detect the adherence to the American Academy of Pediatrics (AAP) 2004 guidelines, which are already implanted in the unit. The procedure involves incremental removal of the infant's blood having high bilirubin levels and/or antibody-coated red blood cells and simultaneous replacement with fresh donor blood providing fresh albumin with binding sites for bilirubin. Patients and methods: This study included 26 infants admitted at the Neonatal ICU of Assiut University Children Hospital for whom ET was done over 12 months from firstt day of September 2017 to the end of August 2018. The data were collected by recording the investigations done before and after ET and observation by the Neonatal ICU of Assiut University Children Hospital staff during ET in comparison with the checklist, which is already implanted in the unit and is based on the AAP 2004 guidelines. Results: Of the 26 studied infants, 73% had ABO incompatibility, where 19.3% had RH incompatibility and 7.7% have other diagnosed breast milk jaundice by exclusion of other causes, subgroup incompatibility, and polycythemia. Coombs test was done in 31% and not done in 69% of the studied cases. All the studied cases were given medication during ET in the form of calcium gluconate intravenously. Conclusion: AAP 2004 guidelines have been partially followed in ET in the studied cases, but there were some shortcomings that can affect the outcome. The study recommends avoiding these shortcomings.

A new approach to neonatal medical management that could transform the prevention of retinopathy of prematurity: Theoretical considerations

Retinopathy of prematurity (ROP) is a disease of the immature retina and is the leading global cause of blindness in children. Two postnatal phases of the disease are distinguished, the first phase is thought to be caused by hyperoxia. One of the most relevant ROP risk factor in routine clinical practice is blood transfusion which leads to the introduction into the neonatal circulation of ‘non-physiological’ adult haemoglobin (HbA) rather than the physiological foetal haemoglobin (HbF). Due to their different affinities for oxygen, HbA will release into retina more oxygen than HbF. It can be expected that this much greater influx of oxygen from HbA may be sensed by the relevant retinal receptors as hyperoxia. Based on the above considerations, I propose that the introduction of non-physiological HbA from adult donors during blood transfusion for anaemia is of key importance in the development and progression of ROP. This hypothesis predicts that there is an HbA limit, beyond which the sequence of events described in the pathogenesis of ROP is triggered.To prevent ROP, I propose launching a new medical field: neonatal transfusion medicine. This system would involve the collection and preparation of umbilical cord blood from the placenta of healthy newborns (containing almost 100% HbF), which would then be administered to premature newborns (who are at risk of ROP) instead of adult blood.

Platelet Administration During Cardiopulmonary Bypass in Neonates: A Universal Therapy Applied in a Novel Way.

Advances in pharmaceuticals (eg, factor concentrates), laboratory testing (eg, rotational thromboelastometry), and processes (eg, transfusion protocols) have contributed to improved outcomes regarding transfusion in neonates undergoing surgical repair for congenital heart disease. A novel strategy, platelets administered during the rewarming phase of cardiopulmonary bypass, as a solution to improved hemostasis, was prospectively evaluated in 42 neonates. Improved intraoperative and postoperative hemostasis was observed in neonates given platelets during the rewarming phase of cardiopulmonary bypass.

The association between isolated oligohydramnios at term and placental pathology in correlation with pregnancy outcomes

IntroductionIsolated term oligohydramnios (ITO) is an obstetrical complication of which the etiology, management, and clinical importance are controversial. In attempt to deepen our understanding, we aimed to study placental pathology and pregnancy outcomes in pregnancies complicated by ITO. Materials and methods– Maternal demographics, neonatal outcomes, and placental histopathology reports of all pregnancies complicated by ITO at 370/7 to 410/7 weeks were reviewed. Excluded were cases complicated by hypertensive disorders, intrauterine fetal growth restriction, placental abruption, and deliveries of undiagnosed small for gestational age neonates. Results were compared between the ITO group and a control group matched for gestational age and mode of delivery. Placental lesions were classified according to the current “Amsterdam” criteria. Composite adverse neonatal outcome was defined as one or more of the following early complications: neonatal intensive care unit admission, sepsis, blood transfusion, phototherapy, respiratory morbidity, cerebral morbidity, necrotizing enterocolitis, or death. ResultsThe study group included 108 patients with ITO that were compared to matched controls. Placentas from the ITO group were characterized by higher rates of placental weights <10th centile (p < 0.001), abnormal cord insertion (p < 0.001), and maternal vascular malperfusion (MVM) lesions (p < 0.001). Neonates from the ITO group had lower birth weights (p < 0.002), and worse composite adverse neonatal outcome (p = 0.028) compared to controls. Conclusion– The current study demonstrates higher rates of placental MVM lesions, and worse neonatal outcome in pregnancies complicated by ITO. These novel findings suggest that ITO should be seen as part of the “placental insufficiency” spectrum.

Severity of Thrombocytopenia at the Time of Platelet Transfusion Influences Post-Transfusion Platelet Kinetics and the Effects of Platelets on Plasma Cytokines in a Model of Murine Neonatal Sepsis

Thrombocytopenia affects 20-30% of neonates admitted to the Neonatal Intensive Care Unit (NICU) and up to 70% of those born extremely prematurely, with sepsis being one of the most frequent causes. Since preterm neonates also have a high bleeding risk, it has been widely accepted that they should receive platelet transfusions at higher platelet count (PC) thresholds than older children or adults. However, there is no consensus regarding what the appropriate threshold should be, particularly in critically ill infants. Surveys and observational studies have revealed extraordinary world-wide variability in neonatal platelet transfusion thresholds, with North-American neonatologists typically using more liberal thresholds (i.e. PC&amp;lt;100x109/L) than European neonatologists. Here we hypothesized that the severity of thrombocytopenia at the time of platelet transfusion would influence the post-transfusion platelet kinetics and the effects of platelets on the inflammatory response of septic newborn mice. To test these hypotheses, we used a validated model of neonatal sepsis/peritonitis, consisting of injecting cecal slurry (CS) or 15% glycerol (control) IP into post-natal day 10 (P10) mice. The CS dose used in these studies induced severe sepsis with a high mortality. c-MPL KO pups (which lack the TPO receptor, pre-infection PC 92±38 x 103/µL) and WT B6 pups (pre-infection PC 748±169 x 103/µL) were used to model severe and mild thrombocytopenia at the time of transfusion, respectively. Two hours after infection, mice from both genotypes were transfused with washed platelets from adult GFP mice (5x107platelets/gram) or with Tyrode's buffer. PCs and GFP% were measured by flow cytometry 2 and 22 hrs post-transfusion. At 2 hours, as expected, transfused septic mice of both genotypes had higher PCs than non-transfused septic littermates (217±118 vs 24±9 x103/µL for c-MPLKO mice, p&amp;lt;0.0001, and 764±193 vs. 549±155 x103/µL for WT mice, p&amp;lt;0.01). By 22 hours post-transfusion, transfused septic c-MPL KO mice still had significantly higher PCs than their non-transfused septic littermates (127±71 vs. 21±12 x103/µL, p&amp;lt;0.01; n=7 per group), but there were no significant differences between transfused and non-transfused septic WT mice (415±139 vs. 310±113 x 103/µL, p=0.1;n=7 per group). Between 2 and 22 hrs post-transfusion, PCs dropped at a nearly three-fold higher rate in transfused septic WT mice than in transfused septic c-MPL KO mice (by 17±8 vs. 6±5 x103 platelets/µL/h). In that interval, adult transfused platelets (GFP+) decreased by a larger percentage than neonatal platelets (GFP-) in transfused septic mice of both genotypes (by 64±14% vs. 46±21% in WT mice, and by 53±27% vs. 28±28% in c-MPL KO mice, both p&amp;lt;0.01), although these observations don't account for ongoing neonatal platelet production. Examination of a panel of plasma cytokines 24h after infection revealed significantly increased levels of pro-inflammatory (IL-6, TNF-alpha, and MCP-1) and anti-inflammatory (IL-10) cytokines in non-transfused septic neonates of both genotypes, compared to controls. Interestingly, platelet transfusions significantly reduced the levels of these cytokines in septic WT mice compared to non-transfused littermates, but had no effect on the cytokine levels of septic c-MPLKO mice. Platelets have been recently shown to reduce TNF-alpha production by murine macrophages at high LPS concentrations (Xiang, 2013) and to sequester both pro- and anti-inflammatory cytokines released by monocytes in response to LPS (Carestia, 2019). Our findings suggest that, in neonatal sepsis, this might require PCs to be above a certain threshold. The consequences of these differences on the outcomes of neonatal sepsis are being investigated. Disclosures Stowell: Grifols: Honoraria. Sola-Visner:Sysmex America, Inc.: Other: Laboratory equipment on loan, Research Funding.

Is There a Role for Titre Monitoring in Kell Alloimmunized Pregnancies?

Background: Kell and Rhesus (Rh) maternal red blood cell (RBC) alloimmunization are the most common causes of severe fetal haemolytic disease. Widespread use of anti-D immune globulin has dramatically reduced the incidence of Rh(D) alloimmunization, leaving K alloimmunization responsible for a significant proportion of cases of fetal anemia requiring intrauterine transfusion ( ). K antigens are expressed on fetal erythrocytes at 10-11 weeks and k antigens at 6-7 weeks gestation (Tovey et al, 1986). In alloimmunized women, erythroid specific antibodies traverse the placenta, causing immune destruction of fetal erythroid cells leading to progressive haemolytic anaemia. The mechanism of fetal anaemia in K alloimmunization differs somewhat from that in Rh-D, in that anti-K antibodies cause suppression of fetal erythropoiesis (Gariod et al, 2004; Weiner et al, 1996). Whilst IUT of RBCs has improved fetal and neonatal survival, important information such as the critical anti-K titres to guide appropriate timing and frequency of IUT, is somewhat conflicting. Currently anti-K alloimmunized pregnancies do not have a standardized protocol for titer monitoring throughout pregnancy and, once alloimmunized, patients are usually referred to a regional fetal center for close ultrasound (US) surveillance. Our primary objective is to determine from a retrospective analysis of our population whether there is a critical anti-K titer that should trigger intensive US monitoring or intervention and to investigate the rate of progression of fetal anemia following IUTs. Methods: This is a retrospective single-center study at Mount Sinai Hospital (MSH), Toronto, Canada, of all pregnant patients with anti-K as the primary alloimmunizing antibody, between 1991 and 2018. MSH is the largest fetal medicine center in Canada and the largest referral center for IUTs. Ethical approval was granted by the Research Ethics Board (REB # 12-0113-C). Data were obtained from a database of patient medical records, US reports and the transfusion medicine laboratory, including maternal demographics, pregnancy history, presence of other alloantibodies and hemoglobin concentration before and after all IUTs. Neonatal outcomes included survival, mode of delivery, gestational age (GA) at delivery, birth weight and need for neonatal exchange transfusion, phototherapy or IVIG. Data were analyzed using GraphPad Prism 6 and linear correlations are expressed as a p-value. Results: Thirty-eight women underwent 163 IUTs in 44 pregnancies where K was the predominant antibody. Two patients in whom anti-K was a secondary antibody were excluded. In 5 of these pregnancies, 2 had a total of three alloantibodies and 5 had 2 alloantibodies each. The median maternal age was 31 (29 - 35) years. Four women had a history of intrauterine fetal death (IUFD) and 9 of neonatal haemolytic disease. The median GA at 1st IUT was 24.2 weeks (14.9-34.7), and there was a median of 4 IUTs per patient. There were seven cases of hydrops fetalis. The number of IUTs a patient received throughout pregnancy was correlated directly with the anti-K titer (Figure 1). Every 4-fold dilution resulted in a further increase in the IUT number by 2.2 above the mean of 2.5 at a titer of 1:32 (p=0.0137). Figure 2 illustrates the correlation between the GA at 1st IUT and antibody titer. IUTs were required at earlier GAs if the titers were higher. Following a 1:32 titer, every 2-fold titer increase reduced the mean gestational age at 1st IUT by 2 weeks (p&lt;0.0001). No pregnancy required an intervention with an anti-K titer &lt; 1:32. The median fetal Hb at the first IUT was 48 (8-91) g/L with an average daily decrease of hemoglobin of 4.7 g/L/day between the first and second IUT (Figure 3), which is similar to the 4.1 g/L/day previously reported in Rh(D) alloimmunization. The median GA was 37.1 (24-39.7) weeks at delivery with median birth weight centile of 59.5%; 8.9% of neonates required a blood transfusion and 24.4% required phototherapy. There were four IUFDs and one neonatal . Conclusion: Our data support a critical anti-K titer of 1:32 and support a role for anti-K titer monitoring as a predictor of disease severity, counselling women appropriately and establishing a balance between paternal K antigen typing, US middle cerebral artery peak systolic velocity monitoring of the fetus and IUTs. Disclosures Garbowski: Vifor Pharma: Consultancy; Imara: Consultancy.