Guidelines on transfusion for fetuses, neonates and older children

The guideline is a revision of the 2004 British Committee for Standards in Haematology (BCSH) guideline on transfusion in neonates and older children (BCSH, 2004). Although there has been little evidence on which to base paediatric clinical transfusion decisions in the past, there have been a number of studies and national audits published over recent years that contribute to decision-making in this area. In addition there have been changes to other guidance, including the management of neonatal jaundice National Institute for Health and Clinical Excellence (NICE, 2010) and the requirement for cytomegalovirus (CMV) seronegative components. The clinical section focuses largely on aspects relating to transfusion indications and administration, whereas the laboratory section contains most of the information relating to pre-transfusion testing and component selection. Details relating to blood component specification and typical transfusion volumes and rates may be found in Appendix 1. The guideline writing group was selected to be representative of UK-based medical experts including specialists from fetal medicine, neonatology, paediatric intensive care, cardiac anaesthesia, paediatric haematology, clinical and laboratory transfusion medicine. The guideline is based on a systematic literature search subsequent to the 2004 guideline up to November 2014 together with other relevant papers identified. The search strategy is presented in Appendix 2. Information from other relevant international guidelines has also been considered. The writing group produced a draft guideline, which was subsequently revised by consensus following comment by members of the Transfusion Task Force of the BCSH and by a sounding board including UK haematologists, paediatricians/neonatologists. The 'GRADE' system was used to quote levels and grades of evidence (http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html). Recommendations entirely extrapolated from evidence from adult studies have been given a lower grade for children. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of transfusion in fetuses, neonates and older children. The guidelines represent recommended UK practice. The guidance may not be appropriate for patients with certain rare disorders and does not cover unusual procedures, such as extracorporeal membrane oxygenation (ECMO). In all cases, individual patient circumstances may dictate an alternative approach. Appropriate transfusion of fetal and paediatric patients of all ages is vital in order to balance transfusion benefits against risks. These risks include transfusion of an incorrect blood component due to errors, such as mistaken patient identity, or unpredictable acute transfusion reactions (Stainsby et al, 2008). Recent studies suggest that a significant percentage of paediatric transfusion recipients receive only one transfusion during their admission (Slonim et al, 2008; New et al, 2014), raising the possibility that some may be avoidable. Specialized components are available for transfusion to different paediatric patient groups and for different clinical indications. Plasma components have been imported for all patients born on or after 1 January 1996 in order to reduce the risk of transfusion transmission of variant Creutzfeldt–Jakob disease (vCJD; see Section 9). Additional component safety measures are applied for fetal and neonatal patients, who are particularly vulnerable recipients because of their small size and developmental immaturity and who also have the longest potential lifespan. Information on components and their transfusion volumes is included in Section 9 and Appendix 1, with additional detail in the text where relevant. Standard definitions of neonates (up to 28 d of postnatal age) and infants (>28 d to <1 year) are used. The definition of a child is <18 years, but in many cases children are admitted to adult wards from 16 years of age, and for these patients local blood transfusion administration transfusion policies for adults may be followed. Thresholds for transfusion are typically based on the haemoglobin concentration (Hb), platelet count and/or coagulation screen results (Venkatesh et al, 2013). These are surrogates for clinical transfusion need (and coagulation ranges in neonates are particularly difficult to interpret) but in most cases are the most pragmatic solution until there is evidence for better clinical measures. The term 'clinically significant bleeding' has been used for some of the recommendations in the guideline. The most widely recognized approach to standardizing bleeding events in transfusion is the system is based on the World Health Organization (WHO) bleeding scale, which assigns different types and severities of bleeds to different grades between 1 and 4. Significant bleeding is typically considered at grades 2–4 (for example Stanworth et al, 2013; NICE, 2015). Although the WHO bleeding scale is more commonly used for clinical research in adults, we suggest that a pragmatic modification may be used to help guide transfusion decisions based on bleeding risk, taking into account the types of bleeding and changes in haemodynamic parameters appropriate for neonatal and paediatric patients in different clinical situations (see Section 4 for cardiac surgery). Intrauterine transfusions (IUTs) are invasive procedures with a risk of fetal death of 1–3% per procedure and up to 20% for hydropic fetuses, depending on the underlying aetiology of the anaemia (Lee & Kaufman, 2011). IUTs are only undertaken in specialized fetal medicine units with the requisite interventional skills and expertise. The National Clinical Reference Group has recommended that such centres are defined as those performing at least 15 procedures per year, with a minimum of two specialists. Although technically challenging, fetal blood sampling (FBS) and IUTs can be performed as early as 16 weeks gestation. IUTs can be performed as late as 34–35 weeks gestation, however the increased risk/benefit ratio must be considered with very late interventions. Complications of FBS/IUT include miscarriage/preterm labour, fetal bradycardia, cord haematoma, vessel spasm, bleeding from the puncture site and fetal death. The procedure is carried out under continuous ultrasound guidance with facilities for immediate analysis of the fetal blood Hb and haematocrit (Hct) or platelet count, allowing any decision to transfuse the fetus to be made concurrently. Good multidisciplinary communication is essential between fetal medicine units undertaking the IUTs, the hospital transfusion laboratory and their counterparts in the hospital where the baby will be delivered. Red cell IUTs are performed for the treatment of fetal anaemia, most commonly due to haemolytic disease of the fetus and newborn (HDN) caused by anti-D, -c or -K (Royal College of Obstetricians and Gynaecologists, 2014; BCSH, 2016a), or fetal parvovirus infection. Ultrasound monitoring using middle cerebral artery peak systolic velocities (MCA PSV) is generally done on a weekly basis for pregnancies at risk. MCA PSV monitoring is the standard technique for non-invasive diagnosis of fetal anaemia (Pretlove et al, 2009) and can predict moderate or severe fetal anaemia with 88% sensitivity and a false positive rate of 18% (Oepkes et al, 2006). If MCA monitoring suggests anaemia (MCA PSV >1·5 multiples of the median), FBS and possibly IUT are indicated. MCA PSV monitoring should be used with caution after 36 weeks as its sensitivity for the detection of fetal anaemia decreases. If there are concerns beyond this gestation because of raised MCA PSV, further advice should be sought from a fetal medicine specialist experienced in managing fetal anaemia. IUT procedures may be required every 2–3 weeks, the frequency minimized by transfusing red cells of high Hct and the maximum volume. The aim of each transfusion is to raise the Hct to 0·45. In general, for red cell antibodies that could cause fetal anaemia but which have been stable throughout pregnancy and where the MCA PSV is normal, delivery should take place between 37 and 38 weeks of gestation. If an IUT has not been required but antibody levels are rising and there is evidence of fetal anaemia, then consideration of earlier delivery may be necessary. If an IUT has been required, the timing of delivery will depend on the degree of fetal anaemia, time from IUT, rate of fall in fetal Hb/Hct and gestation. It is important to ensure that antigen-negative blood is available at delivery for known pregnancies with HDN if it is anticipated that the baby will be anaemic. After delivery, neonates with HDN following IUTs may become anaemic due to haemolysis or bone marrow suppression (Millard et al, 1990) and require monitoring for several weeks post-delivery (see 4.2.1). Anaemia persisting for a few weeks after birth is usually the result of passively acquired maternal antibodies causing continued haemolysis, in which case the baby will be jaundiced and the blood film will show evidence of haemolysis. Late anaemia may develop due to a transient suppression of neonatal erythropoiesis by transfusion. Babies who have required several IUTs are at particular risk. All babies who have had an IUT require admission to a neonatal unit for early phototherapy and investigation for on-going haemolysis or anaemia. Intrauterine platelet transfusions are usually given to correct fetal thrombocytopenia caused by platelet alloimmunization: 'neonatal alloimmune thrombocytopenia' (NAIT). Alloantibodies to human platelet antigens (HPA)-1a, HPA-5b and HPA-3a account for almost all cases of NAIT, the commonest being anti-HPA-1a (80–90% of cases). In most cases fetal transfusion can be avoided by treating the mother with intravenous immunoglobulin (IVIg) and/or corticosteroids (Peterson et al, 2013). Compatible platelets should be available at the time of diagnostic fetal sampling for NAIT, in order to prevent fetal haemorrhage if severe thrombocytopenia is detected, the risk of which increases substantially with platelet counts <50 × 109/l. Key practice points Transfusion triggers for neonates will vary depending on the clinical context, including the gestational age at birth. Neonatal transfusion guidelines have generally been developed as a result of neonatal studies predominantly of very low birth weight (VLBW; <1·5 kg) babies. In neonatal intensive care units (NICUs) most transfusions are given to preterm neonates (mostly <32 weeks gestational age; National Comparative Audit of Blood Transfusion, 2010), some of whom will require transfusion beyond 28 d of life. In general, babies of all gestational and postnatal ages on NICUs will tend to be transfused using the same guidelines although there is little evidence specifically related to term babies. The majority of extremely preterm neonates (<28 weeks gestation) receive at least one red cell transfusion as they frequently become anaemic, partly caused by phlebotomy losses (note: a 0·5 ml blood sample in a 500 g infant (1 ml/kg), is roughly equivalent to a 70 ml sample in a 70 kg adult), sometimes with sample volumes larger than required (Lin et al, 2000). Use of cord blood for initial blood tests for VLBW neonates has been advocated in order to reduce the need for transfusion (Baer et al, 2013), but results should be interpreted with caution if there are sampling difficulties. Neonatal transfusions are usually given as small-volume 'top-up' transfusions, to maintain the Hb above a particular threshold or because of the presence of surrogate markers of anaemia, such as poor growth, lethargy or increased episodes of apnoea. Potential benefits of transfusion in this group include improved tissue oxygenation and a lower cardiac output to maintain the same level of oxygenation (Fredrickson et al, 2011). These benefits need to be weighed against possible adverse outcomes (Christensen & Ilstrup, 2013). In addition to the standard risks associated with transfusion, necrotizing enterocolitis (NEC) may follow neonatal transfusion, although a causal link has not been demonstrated (Christensen, 2011; Paul et al, 2011; Mohamed & Shah, 2012). The use of paedipacks reduces donor exposure for these multiply transfused preterm infants (Wood et al, 1995; Fernandes da Cunha et al, 2005; Strauss, 2010a). Although sequential use of paedipacks may result in the use of older blood, the Age of Red Blood Cells in Premature Infants (ARIPI) trial reported no effects on clinical outcomes for preterm neonates using red cells of different storage ages (Fergusson et al, 2012). Key practice points Exchange blood transfusion (EBT) is performed to manage a high or rapidly rising bilirubin not responsive to intensive phototherapy or IVIg (NICE, 2010), or for severe anaemia. EBT is mainly used in the treatment of HDN to prevent bilirubin encephalopathy by removing the antibody-coated red cells and excess bilirubin. It may also be required for neonatal hyperbilirubinaemia due to other causes, such glucose-6-phosphate dehydrogenase (G6PD) deficiency. Exchange blood transfusion is a specialist procedure with associated risks (Ip et al, 2004; Smits-Wintjens et al, 2008) and is now infrequently performed in most neonatal units mainly as a result of the reduction in HDN following routine antenatal anti-D prophylaxis for D-negative women (BCSH, 2014a) and the ready availability of intensive phototherapy. EBT must take place in an intensive care setting with intensive physiological and biochemical monitoring, carried out by staff trained in the procedure, following written informed parental consent (www.bapm.org/publications/documents/guidelines/procedures.pdf). A single blood volume EBT will remove 75% of the neonatal red cells, and a double volume (160–200 ml/kg depending on gestational age) up to 85–90% red cells (Lathe, 1955; Sproul & Smith, 1964), and up to 50% of circulating bilirubin (Forfar et al, 1958). A double-volume exchange transfusion should be more successful in removing antibody-sensitized neonatal red cells and reduce the need for a subsequent EBT, but there is little direct evidence (Thayyil & Milligan, 2006). Key practice point Prior to and following discharge, babies who received EBT (and/or IUT) should have on-going close monitoring, both clinically and haematologically (with full blood count, reticulocytes, blood film and, if necessary, serum bilirubin), until the haemolysis resolves and the Hb starts to rise (see also 1.2). While these babies still have evidence of haemolysis they should receive folic acid supplementation. Polycythaemia and hyperviscosity can occur in situations of chronic fetal hypoxia, e.g. growth restricted infants, and following twin-to-twin transfusion. Although neonatal hyperviscosity has been implicated as a cause of long-term neurodevelopmental delay (Delaney-Black et al, 1989; Drew et al, 1997), the use of haemodilution (described by neonatologists as 'partial exchange transfusion') for the treatment of polycythaemia is controversial. There is no evidence of long-term benefit and the procedure has been associated with up to an 11-fold increase in risk of NEC (Dempsey & Barrington, 2006; Özek et al, 2010), although the confidence intervals are wide. For the haemodilution procedure there is minimal difference in the effectiveness of plasma, 5% albumin or crystalloid in reducing haematocrit and no difference in viscosity or symptom relief (de Waal et al, 2006). Therefore to minimize risks associated with use of blood products, normal saline should be used if haemodilution is undertaken. The use of haemodilution (partial exchange transfusion) for treatment of polycythaemia is not supported by evidence, and not recommended in the asymptomatic patient (1A). Its use in the symptomatic patient requires clinical judgement to assess the risks and benefits (2C). The majority of red cell transfusions to neonates are top-up transfusions of small volumes (traditionally 10–20 ml/kg, typically 15 ml/kg over 4 h) given to replace phlebotomy losses in the context of anaemia of prematurity, particularly for preterm VLBW neonates. There is very limited evidence to define optimal volumes for neonatal red cell transfusions, particularly relating to long-term outcomes. Volumes greater than 20 ml/kg may increase the risk of volume overload in non-bleeding patients. Therefore, in the context of data supporting restrictive transfusion thresholds from patients of all age groups including neonates, and the recommendations for older children (see 5.1), it seems prudent to use top-up transfusion volumes of 15 ml/kg for non-bleeding neonates in most cases. There is evidence that having a blood transfusion policy and a method of ensuring its implementation has an impact in reducing the number of red cell transfusions (Baer et al, 2011). Hb levels are widely used as a marker of need for transfusion despite the limitations (Banerjee & Aladangady, 2014). Specific thresholds of Hb at which neonates are transfused vary according to the cardiorespiratory status and postnatal age of the infant, partly following the normal physiological reduction in Hb over the first few weeks of life (National Comparative Audit of Blood Transfusion, 2010; Whyte & Kirpalani, 2011). Since publication of the previous BCSH guidelines (BCSH, 2004), three randomized studies addressing 'restrictive' versus 'liberal' transfusion thresholds for neonatal red cell transfusion in VLBW babies have been published (Iowa study, Bell et al, 2005; Premature Infants in Need of Transfusion (PINT), Kirpalani et al, 2006; Chen et al, 2009, and these are included in updated systematic reviews (Whyte & Kirpalani, 2011; Venkatesh et al, 2012). Liberal transfusion thresholds were those more typically applied in the past, by comparison to policies describing more restricted use of red cells (at lower 'restrictive' thresholds by Hb or Hct). The trials in neonates reported a small and variable reduction in the number of transfusions with restrictive regimens. For the restrictive group (transfused at lower Hbs), at short-term follow-up the Iowa study (Bell et al, 2005) reported an increase in episodes of apnoea, and at 18–21 month follow-up the PINT study found a statistically significant cognitive delay in a post-hoc analysis (Whyte et al, 2009). For the liberally transfused group, the Iowa study patients had significantly poorer learning outcomes (McCoy et al, 2011) and reduced brain volume on magnetic resonance imaging (Nopoulos et al, 2011). However, information on long term outcomes is limited and contradictory and overall there is no evidence that restrictive transfusion policies have a significant impact on mortality or major morbidity (Whyte & Kirpalani, 2011). It should be noted that safety of Hb thresholds below those used in the trials is unknown. Suggested red cell transfusion thresholds for very preterm neonates are given in Table 1. They have been developed from the restrictive thresholds of the recent randomized controlled trials of VLBW babies (gestational ages mostly <31 weeks gestation) and are consistent with the neonatal transfusion data from the National Comparative Audit of Blood Transfusion (2010). The precise thresholds used will depend on the clinical situation. Further evidence based on short-term and long-term outcomes should become available from the multicentre randomized controlled trial (RCT) ETTNO (Effects of Transfusion Thresholds on Neurocognitive Outcome of extremely low birth weight infants; ETTNO Investigators, 2012), and the TOP-trial (Transfusion of Prematures trial; Clinicaltrials.gov NCT01702805). There is no specific evidence relating to transfusion of infants with chronic lung disease (CLD; defined as oxygen dependency beyond 28 d of age). Ex-preterm infants with CLD should be transfused as suggested in Table 1, taking into account their clinical status. Some clinicians may accept Hbs as low as 80 g/l with adequate reticulocytes. There is no justification for top-up transfusion simply because the baby is about to be discharged. Table 1 does not include suggested thresholds for moderate to late preterm (≥32 weeks gestational age at birth) or term neonates, as there is little evidence regarding the appropriate thresholds for these groups. Clinicians may consider similar thresholds to those used for preterm babies off oxygen. There are several systematic reviews and over 30 trials of EPO use in neonates (Aher & Ohlsson, 2012, 2014; Ohlsson & Aher, 2014). EPO may reduce red cell transfusion requirements in neonates but its effect appears to be relatively modest whether given early or late. EPO has been suggested to have broader neuroprotection roles, but risks include the development of retinopathy of prematurity (ROP) related to pathological neovascularization (Aher & Ohlsson, 2014). Although underpowered for ROP, a recent RCT of EPO and darbepoeitin alfa (a novel erythropoiesis stimulating agent) in 102 preterm infants reported a significant reduction in transfusion requirements and donor exposures in both the EPO and darbepoeitin alfa groups compared with placebo (Ohls et al, 2013). EPO may be considered for preterm babies of parents who object to transfusion, e.g. Jehovah's Witnesses, but may not prevent the need for transfusion. Delayed cord clamping (DCC) of at least 1 min is recommended for the term and preterm neonate not requiring resuscitation (Wyllie et al, 2015). Systematic reviews of DCC in term neonates have shown significantly increased Hb after birth and decreased iron deficiency at 2–6 months of age (Hutton & Hassan, 2007; McDonald et al, 2013). There was a significant increase in asymptomatic polycythaemia (Hct >65%) and a tendency to increased blood viscosity following DCC (Hutton & Hassan, 2007). In preterm neonates with DCC, the Hb is higher after birth, together with higher blood pressure and reduced red cell transfusion requirement (Rabe et al, 2012; Ghavam et al, 2014). However, although Rabe et al (2012) found reduction in intraventricular haemorrhage (IVH) (all grades together) the numbers were too small to comment on the clinically significant IVHs (grade 3 or 4), and there is paucity of evidence about the long-term neurodevelopmental outcomes. Further RCT evidence is needed for DCC in the very preterm neonate and those in need of resuscitation at birth, e.g. Australian Placental Transfusion Study (APTS); (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335752). For surgery in neonates, the thresholds given in Table 1 may be used, as there is no evidence that higher perioperative Hbs are required (for neonates on cardiopulmonary bypass see Section 6). Large volume transfusion, defined as at least equivalent to a single circulating blood volume (approximately 80 ml/kg for neonates) over 24 h or 50% of the circulating volume within 3 h, may be needed for specific types of neonatal surgery, e.g. craniofacial or liver surgery. If major blood loss (>40 ml/kg) is anticipated, consideration should be given to the use of antifibrinolytic agents, such as tranexamic acid, although there is little published evidence in neonates undergoing non-cardiac surgery. Cell salvage for neonates with large volume blood loss is technically feasible and could be used to reduce allogeneic transfusion as in older children (Section 5.2.6). For situations of massive haemorrhage in neonates, it seems reasonable to apply the principles of the management of major bleeding in children (Section 7) although there is little evidence for this age group (Diab et al, 2013). There is a risk of hyperkalaemia following large volume transfusions, particularly if infused rapidly (Strauss, 2010b; Vraets et al, 2011; Lee et al, 2014), so it is recommended that red cells for large volume neonatal and infant transfusions (Appendix 1, Table b) are used before the end of Day 5 following donation (and within 24 h of irradiation) in order to reduce this risk in the recipient (see Sections 6.1 and 9.1.5). Rapid transfusion via a central line may represent a particular risk, and the alternative use of large bore (greater than 23 g) peripheral lines in small babies may not always be technically feasible. Serum electrolyte concentrations should be monitored frequently, including calcium (to prevent hypocalcaemia secondary to citrate overload) and potassium. All large volume transfusions should be given via a blood warmer to avoid the development of hypothermia and the core temperature should be monitored, as recommended for adults (NICE, 2008). Transfuse red cells for large volume neonatal and infant transfusion before the end of Day 5 following donation (1C). The use of platelet transfusions for neonates with thrombocytopenia and active bleeding is considered appropriate, but there is uncertainty and practice variation in the wider use of platelet transfusions for prophylaxis in the absence of bleeding. In an evidence-based review of the use of platelets, Lieberman et al (2014a) noted that most studies explored the relationships between thrombocytopenia and clinical outcomes rather than the direct effects of platelet transfusions. In a multicentre prospective observational study of 169 neonates with platelet counts of less than 60 × 109/l, most transfusions were prophylactic and given to pre-term neonates, and many were given after the period when major bleeding, including IVH, occurs most frequently. Most infants received platelet transfusions within a range of pre-transfusion platelet counts between 25 and 50 × 109/l (Stanworth et al, 2009). There has been only one RCT in neonates to assess a threshold level for the effectiveness of prophylactic platelet transfusions (to compare prophylactic platelet thresholds of 50 vs. 150 × 109/l) (Andrew et al, 1993), and the recruited patient population in that trial, conducted over 20 years ago, may be of limited relevance to current neonatal practice. A randomized trial of prophylactic platelet thresholds is on going in the UK, Ireland and the Netherlands (International Standard Randomized Controlled Trial Number [ISRCTN] 87736839; www.planet-2.com; Curley A. et al, 2014). Other studies are required to address gestational age- and postnatal age-specific effects on neonatal platelet function (Ferrer-Marin et al, 2013). In the absence of results from RCTs in this patient group, recommendations for prophylactic platelet transfusion are made on the basis of clinical experience. Suggested thresholds for pre-term infants and those with NAIT are summarized in Table 2. While these may also apply to term neonates (e.g. those admitted to paediatric intensive care units (PICUs)), many paediatricians might consider more liberal use of platelets in unstable preterm neonates and more restrictive use in stable term infants. In the absence of specific evidence on platelet thresholds for prophylaxis before invasive procedures, recommendations for older children may be followed (see Table 3). Information on neonates undergoing cardiac surgery is described later (Section 6.7). Severe mucositis Sepsis Laboratory evidence of DIC in the absence of bleedinga Anticoagulant therapy Risk of bleeding due to a local tumour infiltration Insertion of a non-tunnelled central venous line Moderate haemorrhage (e.g. gastrointestinal bleeding) including bleeding in association with DIC Surgery, unless minor (except at critical sites) Major haemorrhage or significant post-operative bleeding (e.g. post cardiac surgery) Surgery at critical sites: central nervous system including eyes NAIT results most commonly from maternally derived anti- HPA-1a or 5b platelet antibodies. All neonates with NAIT (or suspected NAIT) and thrombocytopenia after birth should be discussed with a haematologist. Severely thrombocytopenic neonates with suspected NAIT should receive platelet transfusions at thresholds depending on bleeding symptoms or family history (see Table 2). The suggested threshold of 25 × 109/l in the absence of bleeding is the same as that for neonates without NAIT, but it is acknowledged that this is not evidence-based. Results of diagnostic serological tests may not be available immediately, but the UK Blood Services stock platelets that are negative for HPA-1a/5b antigens, antibodies to which are responsible for over 90% of cases. A post-transfusion platelet count should be measured to check the increment. The baby should be monitored for intracranial haemorrhage (ICH) by cranial ultrasound and, if there is evidence of ICH, platelet transfusions should be given to maintain platelet counts between 50 and 100 × 109/l for the period that the baby is felt to be at highest risk of on going haemorrhage. If HPA-1a/5b-negative platelets are unavailable or ineffective in producing a platelet rise (Department of Health, 2008), random donor platelets and/or IVIg may be used, which may reduce the need for platelet transfusions until spontaneous recovery in platelet count occurs 1–6 weeks after birth (see also Section 9.2). There is considerable uncertainty about appropriate use of FFP in neonates, which reflects the lack of evidence in this area. National audits have shown high proportions of FFP transfusions are given for prophylaxis: 42% of infant FFP transfusions in a UK audit (Stanworth et al, 2011) and 63% in a similar Italian audit (Motta et al, 2014). Prophylactic use of FFP, including prior to surgery, is of unproven benefit and uncertainty is compounded by the difficulty in defining a significant coagulopathy in this age group. A large RCT reported by the Northern Neonatal Nursing Initiative (NNNI Trial Group, 1996) reported no benefit from prophylactic FFP given to neonates to prevent ICH, although the study did not assess coagulopathy and the gestational age distribution of enrolled babies would