Associations Between Early Red Blood Cell Transfusion and Severe Intraventricular Hemorrhage, and Between Late Red Blood Cell Transfusion and Necrotizing Enterocolitis Robert D. Christensen, MD Transfusion of banked donor erythrocytes can be life saving for small and ill neonates with severe anemia or active hemorrhage. However, risks of transfusions exist and must be weighed against potential benefits each time a transfusion is considered. The present review seeks to bring together the published data supporting 2 newly postulated risks of transfusions among very low-birth-weight neonates. The first is an association between early red blood cell transfusions, those administered in the first few days after birth, and the subsequent occurrence of a grade 3 or 4 intraventricular hemorrhage. The second is an association between late RBC transfusions and the subsequent occurrence of necrotizing enterocolitis. Much remains to be discovered about the pathogenetic links between transfusion and these adverse outcomes. Moreover, work is needed to clearly establish whether transfusions are causatively associated with these adverse outcomes or are covariables. The purpose of this chapter is to review the associations between transfusion and intraventricular hemorrhage and between transfusions and necrotizing enterocolitis and to use these associations to hypothesize that evidence-based improvements in transfusion practice have the potential to improve neonatal intensive care unit outcomes. Semin Perinatol 36:283-289 2012 Published by Elsevier Inc. KEYWORDS cord stripping, delayed cord clamping, intraventricular hemorrhage, necrotizing enterocolitis, transfusion The Women and Newborns Program, Intermountain Healthcare, Salt Lake City, UT. Address reprint requests to Robert D. Christensen, MD, NICU, 4th Floor, McKay-Dee Hospital Center, 4401 Harrison Boulevard, Ogden, UT 84403. E-mail: Robert.christensen@imail.org Transfusions of banked donor erythrocytes are critically important to neonatal intensive care medicine. Indeed, in certain instances, red blood cell (RBC) transfusions are life saving. However, each transfusion administered conveys risks and benefits. Some transfusion risks have been well defined, others less so, and perhaps yet other risks are not even usually recognized as transfusion-related events, but are seen only as a clinical deterioration in the complex intensive care course. This chapter will present the published associations between RBC transfusions and 2 significant neonatal morbidities severe intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). These 2 associations are statistically sound and robust. However, disentangling causeand-effect relationships from co-morbidities can be problematic; yet, this is critical to understanding whether changes in transfusion practices are likely to reduce the prevalence of severe IVH and NEC. Early RBC Transfusion and Severe IVH Large periventricular hemorrhagic infarctions in very lowbirth-weight (VLBW) neonates presage adverse outcomes. 1-4 The odds of developing a large hemorrhagic brain infarction increase significantly with decreasing gestational age at birth and, to a certain extent, with increasing level of illness in the first days after birth. 1,2,4 Mechanistic explanations for the gestational age-associated propensity to severe IVH include the paucity of pericytes (mesenchymal cells) wrapping and giving structural support to the capillaries in the periventricular subependyma and germinal matrix. 5,6 Because of this pau- 0146-0005/12/$-see front matter 2012 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.semperi.2012.04.009 283
284 R.D. Christensen Table 1 Testing Potential Pathogenic Mechanisms Predisposing VLBW Neonates to Severe IVH Group PT (seconds) aptt (seconds) Fibrinogen (mg/dl) Platelets <50 10 9 /L ( ) Blood Culture Cord ph Mechanical Ventilation Cases (n 54) 18.7 6.1 57 19 251 155 1/54 (2%) 3/54 (6%) 7.25 0.14 54/54 (100%) Controls (n 101) 17.9 2.7 60 26 235 134 1/101 (1%) 1/101 (1%) 7.26 0.15 101/101 (100%) P value 0.333 0.440 0.507 0.457 0.122 0.498 1.000 Modified with permission from Baer et al. 9 aptt, activated partial thromboplastin time; IVH, intraventricular hemorrhage; PT, prothrombin time; VLBW, very low-birth-weight. city, wide fluctuations in blood pressure and blood flow through the immature capillary beds are more likely to induce rupture and hemorrhage. Bednarek and colleagues 7 reported a trend toward a higher incidence of severe IVH in neonatal intensive care units (NICUs) administering RBC transfusions liberally, compared with other NICUs using transfusions in a more restricted manner. Following up on that observation, our group studied 54 consecutive VLBW neonates who had 1 or more normal head ultrasound examinations followed by an examination showing a grade 3 or 4 IVH. The temporal sequence of events was as follows: (1) no IVH, (2) RBC transfusion, and (3) severe IVH. 8,9 To evaluate this apparent association between RBC transfusion and subsequent severe IVH, we performed a casecontrol study matching the 54 cases (severe IVH) with controls (no IVH) on demographics, Apgar scores, maternal steroids, and level of illness indicators. We hypothesized (Table 1) that the cases were more likely to have had antecedent coagulopathy, thrombocytopenia, infection, acidosis, or use of mechanical ventilation. Contrary to our hypothesis, these were not more common among the cases than among the controls (Table 1). 8 A sensitivity analysis (Fig. 1) indicated that RBC transfusion, by itself, is an independent risk factor for developing a severe Figure 1 Diagram of a sensitivity analysis designed to assess the likelihood that RBC transfusions are causally related to subsequently developing a severe IVH. Relationships are shown schematically between the following 3 factors: (1) RBC transfusions (given before the IVH occurred), (2) development of a severe IVH, and (3) unknown or unmeasured factors that could influence both (1) and (2). The solid line labeled R is the correlation between the unmeasured factors and RBC transfusion. The solid line labeled G is the correlation between unmeasured factors and developing a severe IVH. The dashed line with the question mark represents the question, Does a direct relationship exist between RBC transfusion and subsequently developing a severe IVH, or can the association be explained by a very large R and G? (Modified with permission from Baer et al. 9 ) IVH, intraventricular hemorrhage; RBC, red blood cell. IVH. Only if the relationships G and R (as shown in Fig. 1) both exceed a correlation of 0.95 (correlations that high are exceedingly rare in biology and medicine), would transfusion be a comorbidity only, not an independent contributor to the risk of hemorrhage. Thus, given any reasonable assumptions for G and R in VLBW neonates, early RBC transfusions are an independent risk factor for developing a severe IVH. As a further step toward assessing a potential role of early RBC transfusions in the pathogenesis of severe IVH, we analyzed VLBW neonates who had a grade 1 IVH and sought antecedents of extension to a grade 3 or 4 IVH. 9 Specifically, in some cases where a grade 1 IVH is detected, subsequent ultrasound studies show it has resolved completely, whereas in other cases, it has enlarged to become a grade 3 or 4. We identified 55 VLBW neonates in whom a grade 1 evolved into a grade 3 or 4, and compared these with controls, matched for demographic and level of illness variables, who had a grade 1 IVH that resolved completely with no extension to a higher grade. Using logistic regression, the most significant variable we identified, associated with likelihood of extension to a severe IVH, was the administration of an RBC transfusion while the hemorrhage was still grade 1. 9 Certainly, not all instances of severe IVH are the result of a donor RBC transfusion. This is clear because not all neonates with a severe IVH had a preceding transfusion, and not all early RBC transfusions to VLBW neonates are followed by a severe IVH. Thus, at most, it can be postulated that early RBC transfusions are causally associated with some cases of severe IVH. Surely, the proclivity of any given neonate to develop a severe IVH is multifactorial, involving environmental, developmental, and genetic factors. However, if the association between early RBC transfusion and severe IVH is indeed a cause and effect relationship in some cases, then successful efforts to reduce or eliminate early RBC transfusions during the first days after VLBW delivery should reduce the prevalence of severe IVH. Does it? Three lines of evidence suggest the answer is yes it does. Specifically, instituting programs that reduce early RBC transfusions among VLBW neonates result in a lower prevalence of IVH. These 3 methods are delayed clamping of the umbilical cord, milking or striping of the umbilical cord, and drawing all NICU baseline laboratory blood tests from fetal blood in the placenta, thereby initially drawing no blood from the neonate. Delayed Clamping of the Umbilical Cord Most mammals at birth do not immediately sever the umbilical cord; rather, a long cord segment remains attached
Associations between RBC transfusions and IVH and NEC 285 to the neonate, and this segment withers and falls off in a few days. In contrast, in most hospital births, the cord is clamped and severed immediately after delivery. The present chapter will not review this issue as it applies to deliveries at term, but will focus only on this issue among VLBW deliveries. Delayed clamping has been advocated for decades, but few studies have sought to test this in VLBW deliveries as a means of improving outcomes. Mercer et al 10 conducted an important trial where women about to deliver prematurely were randomized to immediate versus delayed clamping of the umbilical cord. The immediate clamping occurred at 6.9 4.2 seconds after delivery and the delayed clamping after 32.1 12.6 seconds (P 0.001). Blood hemoglobin concentrations 24 hours after birth were not reported, and early RBC transfusions were not specifically reported. However, during the entire hospitalization, 61% of those with immediate clamping received an RBC transfusion versus 50% of those with delayed cord clamping. IVH was more common in those with immediate (36%) than delayed clamping (14%, P 0.03). Similar findings, including improved neurodevelopmental outcomes, have been reported by Rabe et al, 11 Oh et al, 12 and in a follow-up study by Mercer et al. 13 Two meta-analyses by Rabe et al 14,15 examined outcomes of studies performing immediate versus delayed clamping among preterm pregnancies. In their Cochrane review, 7 studies (297 neonates) were included that used a delay in clamping ranging from 30 to 120 seconds. Delayed clamping was associated with statistically higher hematocrit values 4 hours after birth, fewer early transfusions, and less prevalence of IVH. 15 The World Health Organization 16 published the following summary on this topic, In preterm infants, delaying cord clamping by 30-120 seconds seems to be associated with less need for blood transfusion and less intraventricular hemorrhage. The beneficial effects of delayed cord clamping may yield the greatest benefits in settings where access to health care is limited. Milking or Striping of the Umbilical Cord One perceived problem with applying the delayed cord clamping technique during a VLBW delivery is the obligatory delay in neonatal resuscitation. 17 As a potentially quicker means of accomplishing a placental transfusion, Hosono et al 18 proposed striping or milking the cord. This is accomplished, just after delivery but before placental delivery, by grasping the umbilical cord toward the placental end and gently moving blood within the umbilical vessels toward the neonate. This stripping or milking maneuver is generally performed 1-4 times after which the cord is clamped and cut in the usual manner. Hosono et al s original report involved 40 singleton infants born between 24 and 28 weeks gestation, half were randomly assigned to cord striping and half to early clamping. The milked group had higher hemoglobin levels (by about 2 g/dl), higher mean blood pressures at NICU admission (by about 6 mm Hg), and a shorter duration of ventilation. Hosono et al also reported that VLBW neonates with a higher initial hemoglobin level had lower odds of requiring a RBC transfusion and lower odds of developing an IVH. 19 Rabe et al 20 directly compared delayed cord clamping with cord striping in a randomized trial of 58 deliveries before 33 weeks gestation. Of the 58 neonates included, those who were randomized to clamping had 30 seconds of delay, whereas those randomized to stripping had 4 gentle milking maneuvers performed. The authors found no differences between the groups in hemoglobin levels, transfusions, or morbidities, and concluded that milking the cord in this manner achieved a similar volume of transfusion, as did delaying the cord clamping for 30 seconds. 21 NICU Admission Laboratory Tests Drawn From the Placenta There is much practice variation regarding exactly which blood tests are drawn from VLBW neonates on admission to the NICU. It is common to draw at least 1 ml for an initial blood culture, although as Connell et al 22 have advocated, inoculating a larger volume of blood is much more likely to identify low concentrations of circulating organisms. A complete blood count with a differential cell count and a platelet count can be useful baseline assessments, and as demonstrated by Carroll et al, 23 the values do not differ in paired cord versus neonatal blood samples. Also, some centers obtain the state metabolic screen before instituting an amino acid containing intravenous solution, which often necessitates initially drawing an additional 1 ml or so. Occasionally, other blood tests are also drawn on NICU admission, but because of the volume of blood required, these are generally kept to a minimum (Fig. 2). The blood desired for testing at NICU admission can almost always be obtained using fetal blood drawn after pla- Figure 2 The blood samples that are sometimes drawn from very low-birth-weight infants on admission to the neonatal intensive care unit for blood culture, blood gas, type and cross match (or type and screen), coagulation studies (not commonly obtained on neonatal intensive care unit admission), complete blood count with differential count and platelet count, and state metabolic screen. (Color version of figure is available online.)
286 R.D. Christensen Analysis of the entire group of 200, using case-control methodology, is currently under way, although an interim analysis at n 65 showed the same pattern as the first 10 deliveries (Table 2). Figure 3 Preparation for drawing fetal blood from the umbilical vein of an otherwise discarded placenta at 30 weeks gestation, a few minutes after placental delivery. The umbilical vein, at the point of attachment of the cord and placenta, has been painted with povadone iodine and is held by the operator s left hand, and a needle puncture is obtained using the right hand to obtain blood for the neonatal intensive care unit admission laboratory tests. (Color version of figure is available online.) cental delivery, from the umbilical vein on the clamped placental end of the cord or on the surface of the placenta. 24 Using this method, there is no need for blood to be initially drawn from the neonate (Fig. 3). To assess the potential value of applying this technique, we obtained blood in this way in 10 VLBW deliveries compared with 10 matched controls, where the blood tests were drawn in the standard way (from the neonate). As shown in Table 2, this technique resulted in a higher hemoglobin level at 24 hours. Because transfusions are generally given according to guidelines that use the hemoglobin level, fewer early transfusions were given to this group. As with the other 2 means of reducing early transfusions (delayed clamping and striping), this technique was associated with a lower prevalence of IVH as assessed on day 7 of life. 24 At the time of this writing, the blood drawing technique had been used successfully on 200 deliveries at Intermountain Healthcare hospitals. The great majority of these were VLBW, whereas a few were term or late preterm deliveries with known fetal anemia, severe abruption, or other reasons where this technique was considered of value to the neonate. Combining These Techniques Delayed cord clamping and cord stripping are generally considered mutually exclusive techniques. The 2 techniques are viewed as alternative methods of accomplishing the same goal, increasing the volume of placental-neonatal transfusion. No reports are available where both techniques were used together. In contrast, the third technique, obtaining all initial blood tests from the placenta, can be performed after delayed clamping or after cord stripping. Additional study is needed to assess any added benefits to the neonate of using one or the other cord transfusion techniques followed by the placental laboratory draw. Predictably, this combination would result in a yet higher 24-hour hemoglobin concentration and, on that basis, presumably yet lower odds of receiving an early RBC transfusion, as well as, in theory, yet lower odds of developing a severe IVH. Taken together, this group of studies suggests that the statistical association between early RBC transfusion and severe IVH does indeed have clinical relevance. Moreover, this work provides new means of reducing, although surely not completely eliminating, severe IVH among VLBW neonates. Late RBC Transfusion and NEC McGrady et al reported a cluster of NEC cases in a single NICU during a 3-month period in the 1980s. NEC was diagnosed in 31% of VLBW neonates and in 11% of those weighing 1500 g. 25 The Centers for Disease Control investigated this outbreak and found only 1 significant association RBC transfusion. The association was highly significant, with an odds ratio (OR) for NEC after transfusion of 15.1 (95% confidence interval: 2.6-92.5). Almost 10 years later, Bednarek et al 7 found a similar association in 6 NICUs in the Boston area, reporting that 2 NICUs transfused about 70 ml/kg more RBC, over the NICU course, than did the 2 lowest transfusing NICUs. VLBW neonates in the high-transfusing NICUs had significantly greater odds of developing NEC, with a 7% prevalence (15/232) in the high-transfusing NICUs (adjusted OR: 1.1 [0.5-2.2]) compared with a 2% prevalence (5/280) in Table 2 Outcomes of 20 VLBW Neonates Where all Initial Blood Tests Were Drawn From Fetal Blood in the Placenta (n 10) Versus Matched Controls Where all Were Drawn From the Neonate (n 10) Group Birth Weight Grams Mean (Range) Total Phlebotomy on First Day (ml) Mean Change in Hemoglobin for the First 24 hours Total Number RBC Transfusions Given in the First 7 days IVH Present at day 7 Cases (n 10) 1072 (480-1461) 1.5 2.3 Increase by 1 g/dl 4 0 Controls (n 10) 1000 (455-1390) 7.5 5.2 Decrease by 1 g/dl 16 6* P value 0.640 0.007 0.005 0.02 0.01 Modified with permission from Christensen et al. 24 *Four had grade 1 and 2 had grade 3.
Associations between RBC transfusions and IVH and NEC 287 Table 3 NEC and Concomitant Eosinophilia (Blood Eosinophil Concentration >95th Reference Range) can Occur After an RBC Transfusion (Transfusion-associated NEC) or can Occur With no Antecedent Transfusion. The Latter is Generally a More Benign Condition, Possibly Allergic Enterocolitis Group Stage III NEC Death From NEC Eosinophilia and NEC after 5/24 (24%) 3/24 (13%) RBC transfusion Eosinophilia and NEC with 0/30 (0%) 0/30 (0%) no antecedent RBC transfusion P value 0.013 0.081 Modified with permission from Christensen et al. 29 NEC, necrotizing enterocolitis. Table 4 Annual RBC Transfusion Rate, NEC Rate, and Severe IVH Rate of VLBW Neonates in the NICUs of Intermountain Healthcare in the Years 2007-2010 Group 2007 2008 2009 2010 VLBW neonates (n) 309 321 285 331 RBC transfusion rate 19% 17% 13% 12%* NEC rate (stage >2) 7.8% 8.1% 5.6% 6.3% IVH rate (grade >3) 22.1% 18.0% 10.2% 11.4% A program was began in late 2008 and fully implemented in 2009 to improve compliance with the NICU transfusion guidelines. 41-43 This program resulted in a significant reduction in RBC transfusion rate, which was accompanied by a trend toward a lower NEC rate and a significant reduction in IVH rate. NICU, neonatal intensive care unit. *P value (before vs after practice change) <0.001. P value (before vs after practice change) <0.090. P value (before vs after practice change) <0.001. the low-transfusing units (adjusted OR: 0.3 [0.1-0.8], P 0.05). After the publication by Bednarek et al, case reports and retrospective studies by Mally et al 26 and Agwu and Narchi 27 described this same association. Focusing exclusively on Bell stage III NEC, where surgical and pathologic evidence confirmed that the disease entity under study was indeed NEC, we also found such an association, with 40 of 112 NEC cases occurring within 48 hours (mean 18 hours) after an RBC transfusion. 28,29 Josephson et al, 30 Blau et al, 31 dos Santos et al, 32 Singh et al, 33 and Paul et al 34 reported a similar association. Most cases of NEC are unrelated to RBC transfusion. Most NICU RBC transfusions are not followed by NEC, and most cases of NEC do not immediately follow an RBC transfusion. Given these certainties, it is clear that transfusions are not the cause of NEC. However, it is reasonably clear that some cases of NEC, probably 25% or so of cases, do indeed present within about 1 day of an RBC transfusion. Despite remaining uncertainties in the pathogenesis of NEC, several common elements are found among the largest studies reporting transfusion-associated NEC. These common elements include the following: (1) approximately 25% of NEC cases follow reasonably closely after an RBC transfusion (2-48 hours, but generally nearer 12 hours); (2) neonates with transfusion-associated NEC are generally born at earlier gestation than those who develop NEC unrelated to transfusion; (3) neonates with transfusion-associated NEC have had 1 or more previous RBC transfusions; and (4) the age of the blood transfused (days since donor draw) is not different among those with transfusion-associated NEC than among matched controls who were transfused but did not develop NEC. The potential pathogenic mechanism(s) resulting in transfusion-associated NEC are addressed in other chapters of this edition of Clinics in Perinatology. These mechanisms include the variables for which the transfusion was ordered, immunologic mechanisms, and impaired biomechanical properties of the banked erythrocytes. A mechanism involving a targeted immune response is supported by the finding of eosinophilia in some cases. 35 In fact, when eosinophilia accompanies NEC, those with an antecedent transfusion seem to have a more clinically severe form of NEC (Table 3). Indeed, the various immunologic and biomechanical mechanisms used to explain post-transfusion NEC might not be mutually exclusive; perhaps, multiple pathogenic elements can be operative. An important clinical issue, as of yet incompletely addressed, is whether withholding feedings during the time the RBC are infusing diminishes the risk of transfusion-associated NEC. El-Dib et al 36 from Children s National Medical Center noted recently that following a practice change of withholding feedings during RBC transfusions, prevalence of NEC reduced from 5.3% of VLBW infants to 1.3% (P 0.05). In any pre- versus postanalysis of a practice change, it is difficult to exclude the Hawthorne effect. Thus, any benefit of withholding feedings during RBC transfusion remains speculative. Moreover, the length of time to withhold feedings before and after transfusion is an important, but untested, variable. In theory, one way to prevent transfusion-associated NEC is to eliminate late transfusions. Indeed, if 25% of NEC cases are due to transfusion-associated NEC, eliminating late transfusions would reduce the NEC prevalence by 25%. Similarly, reducing the rate of late transfusion in half the cases would reduce the overall NEC prevalence by about 12.5%. Unlike early transfusions, which are generally given for low hemoglobin concentrations due to repeated phlebotomy in the first days, late transfusions are generally given because of low hemoglobin concentration associated with the hyporegenerative normocytic, normochromic anemia of prematurity. 37 If vulnerable VLBW neonates are treated with an erythropoietic-stimulating agent, such as darbepoetin rather receiving a late transfusion, fewer cases of NEC should be the result. 38-41 This theory requires prospective testing, but is supported by the transfusion-reduction programs instituted in the NICUs of Intermountain Healthcare in 2009, 42,43 where a reduction in RBC transfusion rate was accompanied by a trend toward fewer cases of NEC and a significant decline in severe IVH (Table 4).
288 R.D. Christensen Acknowledgments The author thanks Erick Henry, MPH, for data acquisition and analysis and Vickie L. Baer, RN, and Diane K. Lambert, RN, for data management and display, photography, and editorial assistance in all of the Intermountain Healthcare Transfusion Medicine research projects reviewed in this report. References 1. Linder N, Haskin O, Levit O, et al: Risk factors for intraventricular hemorrhage in very low birth weight premature infants: A retrospective case-control study. Pediatrics 111:e590-e595, 2003 2. Lee JY, Kim HS, Jung E, et al: Risk factors for periventricular-intraventricular hemorrhage in premature infants. J Korean Med Sci 25:418-424, 2010 3. Groenendaal F, Termote JU, van der Heide-Jalving M, et al: Complications affecting preterm neonates from 1991 to 2006: What have we gained? Acta Paediatr 99:354-358, 2010 4. 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Singh R, Visintainer PF, Frantz ID 3rd, et al: Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants. J Perinatol 31:176-182, 2011 34. Paul DA, Mackley A, Novitsky A, et al: Increased odds of necrotizing enterocolitis after transfusion of red blood cells in premature infants. Pediatrics 127:635-641, 2011 35. Christensen RD, Lambert DK, Gordon PV, et al: Neonates presenting with bloody stools and eosinophilia can progress to two different types of necrotizing enterocolitis. J Perinatol 2011 [Epub ahead of print] 36. El-Dib M, Narang S, Lee E, et al: Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants. J Perinatol 31:183-187, 2011 37. Ohls RK: Human recombinant erythropoietin in the prevention and treatment of anemia of prematurity. Paediatr Drugs 4:111-121, 2002 38. Warwood TL, Ohls RK, Wiedmeier SE, et al: Single-dose darbepoetin administration to anemic preterm neonates. 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Associations between RBC transfusions and IVH and NEC 289 41. Baer VL, Lambert DK, Schmutz N, et al: Adherence to NICU transfusion guidelines: Data from a multihospital healthcare system. J Perinatol 28:492-497, 2008 42. Baer VL, Henry E, Lambert DK, et al: Implementing a program to improve compliance with neonatal intensive care unit transfusion guidelines was accompanied by a reduction in transfusion rate: A prepost analysis within a multihospital health care system. Transfusion 51:264-269, 2011 43. Christensen RD, Henry E, Ilstrup S, et al: A high rate of compliance with neonatal intensive care unit transfusion guidelines persists even after a program to improve transfusion guideline compliance ended. Transfusion 51:2519-2520, 2011