EDITORIAL Retinopathy of prematurity and transfusion practice
I
n the United States, 3.9 million babies are born each year, of which approximately 28,000 (0.7%) weigh less than 1250 g at birth. Approximately half of these small preterm infants become affected, to a lesser or greater extent, by retinopathy of prematurity (ROP), and therefore screening examinations are part of routine care.1 ROP, previously known as retrolental fibroplasia, is a disorder of disorganized growth of developing retinal blood vessels and can result in fibrovascularization and retinal detachment. In approximately 90% of neonates who develop ROP, the disorder resolves, requires no specific treatment, and leaves no permanent damage. However, the 10% with the most severe forms of ROP go on to have impaired vision or even blindness.2 In fact, 1100 to 1500 infants annually in the United States develop ROP severe enough to require specific treatment and 400 to 600 of these become legally blind.3 The development of ROP historically has involved both elements of high oxygen saturation and relative hypoxia.4 Besides these oxygen stresses, fluctuating oxygen levels and poor infant growth are also now recognized as contributing elements, but many gaps exist in understanding pathogenesis and susceptibility factors. Randomized, masked trials in the United States, Australia, New Zealand, Canada, and the United Kingdom indicated that lower targets of oxygen saturation (85%-89%) using pulse oximeters reduced the rate of treatment for ROP (10.6% vs. 13.5%; RR, 0.79; 95% CI, 0.63-1.00; p = 0.045). However the lower-target group had a higher rate of death than those in the higher-target group (saturations 91%95%; 23.1% vs. 15.9%; RR in the lower-target group, 1.45; 95% confidence interval [CI], 1.15-1.84; p = 0.002).5 Evidence for genetic susceptibility to ROP is strong, but the identity of the gene(s) involved and the molecular mechanisms remain uncertain. In a recent meta-analysis including seven studies, Liu and colleagues6 concluded that advanced ROP is significantly associated with VEGF (vascular endothelial growth factor) gene polymorphisms. Analyzing monozygotic versus dizygotic twins using mixed-effects logistic regression, Bizzarro and colleagues7 concluded that 30% of the pathogenesis of ROP can be accounted for by clinical factors (including hyperoxia) with genetic factors accounting for 70%. Sanghi and colleagues8 studied 35 pairs of identical twins where both developed ROP and found that 20% had the same or approximately the same severity of ROP while 80% were widely discordant in severity, suggesting that both genetic © 2014 AABB TRANSFUSION 2014;54:960-961. 960
TRANSFUSION Volume 54, April 2014
and environmental factors are relevant. Early dosing of recombinant erythropoietin (rEPO) to preterm infants was once thought to be a risk factor for ROP development,9 but animal models,10 human studies,11,12 and a revision of the original meta-analysis data (Ohls and Widness, personal communication, 2013) all indicate that rEPO dosing is not a risk factor for developing ROP. Beginning in the 1980s many reports concluded that RBC transfusion was a risk factor for ROP.13-16 Recent publications also report this association,17-19 but it is difficult to sort out the effect of RBC transfusions from the fact that the most severely ill neonates receive more RBC transfusions. This increased transfusion requirement is largely due to the relationship between the number of blood tests needed for intensive care monitoring and the number of RBC transfusions given.20,21 It has been postulated that damaging effects of transfusions on the immature retina are mediated by an increase in free iron.22 However, whether this is so and whether reducing RBC transfusions of neonates susceptible to ROP reduces their ROP risk are not known.23 In this issue of TRANSFUSION, Dani and colleagues24 from Florence, Italy, report an intriguing observation relevant to ROP pathogenesis and prevention. Reviewing their single-center data from 1999 through 2008, they found that neonates born at less than 29 weeks’ gestation who received fresh-frozen plasma (FFP) infusions during their first week after birth were less likely to develop ROP. Their data indicated that receiving at least two infusions of FFP diminished the risk of ROP by approximately one-half (relative risk [RR], 0.46; 95% CI, 0.23-0.93). The FFP was administered to these neonates generally because of prolonged clotting studies or signs of bleeding. The authors list the appropriate cautions that the study was retrospective and that FFP administration was not administered with the intent of diminishing the ROP risk. Also, the neonates who received FFP differed in known and unknown ways from those who did not, and those differences may be relevant to the outcomes. If FFP has the capacity to supply preterm infants with something of value toward ROP prevention, that substance might be IGF-1 or IGFBP-3 as the authors postulate, but it might just as likely be other factors or properties currently untested or unknown. Perhaps their observation, although in need of validation, will help focus ROP research efforts toward preventive approaches supplemental to the current transcutaneous oxygen saturation control programs.1-3 Moreover, if preventive substances from FFP can be identified, perhaps supplying the specific factor(s) in reliable amounts could have substantial advantages over infusing FFP.
EDITORIAL
Importantly, we judge that it would be imprudent to advise a widespread practice change on the basis of this observation; specifically, we do not advocate routinely infusing FFP to the smallest neonates with the hope of reducing their risk of severe ROP. Rather, we maintain that, like many associations discovered in retrospective data analysis, this provocative and potentially important finding should be followed by validation, prospective studies, and other rigorous means of testing efficacy, risk, and benefit.
9. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2012; (9)CD004863. 10. Slusarski JD, McPherson RJ, Wallace GN, et al. High-dose erythropoietin does not exacerbate retinopathy of prematurity in rats. Pediatr Res 2009;66:625-30. 11. Ohls RK, Christensen RD, Kamath-Rayne BD, et al. A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants. Pediatrics 2013;132: e119-27. 12. Zayed MA, Uppal A, Hartnett ME. New-onset maternal gestational hypertension and risk of retinopathy of prematurity. Invest Ophthalmol Vis Sci 2010;51:4983-8.
CONFLICT OF INTEREST The authors report no conflicts of interest or funding sources.
13. Yu VY, Hookham DM, Nave JR. Retrolental fibroplasia— controlled study of 4 years’ experience in a neonatal inten-
1
Robert D. Christensen, MD e-mail: [email protected] Sarah J. Ilstrup, MD2 Mary Elizabeth Hartnett, MD3 1 Women and Newborns Program, Intermountain Healthcare 2 Transfusion Medicine, Intermountain Healthcare 3 University of Utah Moran Eye Center Salt Lake City, UT
REFERENCES
sive care unit. Arch Dis Child 1982;57:247-52. 14. Shohat M, Reisner SH, Krikler R, et al. Retinopathy of prematurity: incidence and risk factors. Pediatrics 1983;72: 159-63. 15. Cats BP, Tan KE. Retinopathy of prematurity: review of a four-year period. Br J Ophthalmol 1985;69:500-3. 16. Cooke RW, Clark D, Hickey-Dwyer M, et al. The apparent role of blood transfusions in the development of retinopathy of prematurity. Eur J Pediatr 1993;152:833-6. 17. van Sorge A, Kerkhoff F, J Halbertsma F, et al. Severe retinopathy of prematurity in twin-twin transfusion syndrome after multiple blood transfusions. Acta Ophthalmol. 2013 Jun 15. doi: 10.1111/aos.12229. [Epub ahead of print].
1. Fierson WM; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists.
18. Hadi AM, Hamdy IS. Correlation between risk factors during the neonatal period and appearance of retinopathy
Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2013;131:189-95. 2. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med 2012;367:2515-26. 3. Quinn GE, Fielder AR. Prevention of ROP blindness. Clin
of prematurity in preterm infants in neonatal intensive care units in Alexandria Egypt Clin Ophthalmol 2013;7: 831-7. 19. Giannantonio C, Papacci P, Cota F, et al. Analysis of risk factors for progression to treatment-requiring ROP in a
Perinatol 2013;40:xvii-xviii. 4. Hartnett ME, Lane RH. Effects of oxygen on the development and severity of retinopathy of prematurity. J AAPOS 2013;17:229-34. 5. BOOST II United Kingdom Collaborative Group; BOOST II Australia Collaborative Group; BOOST II New Zealand Collaborative Group; Stenson BJ, Tarnow-Mordi WO, Darlow BA, et al. Oxygen saturation and outcomes in preterm infants. N Engl J Med 2013;368:2094-104. 6. Liu P, Wu D, Zhou W, et al. Association of VEGF gene polymorphisms with advanced retinopathy of prematurity: a meta-analysis. Mol Biol Rep 2012;39:10731-7. 7. Bizzarro MJ, Hussain N, Jonsson B, et al. Genetic susceptibility to retinopathy of prematurity. Pediatrics 2006;118: 1858-63. 8. Sanghi G, Dogra MR, Dutta S, et al. Intersibling variability of retinopathy of prematurity in twins and its risk factors. Int Ophthalmol 2012;32:113-7.
20.
21.
22.
23.
24.
single neonatal intensive care unit: is the exposure time relevant? J Matern Fetal Neonatal Med 2012;25:471-7. Rosebraugh MR, Widness JA, Nalbant D, et al. A mathematical modeling approach to quantify the role of phlebotomy losses and need for transfusions in neonatal anemia. Transfusion 2013;53:1353-60. Rosebraugh MR, Widness JA, Veng-Pedersen P. Multidose optimization simulation of erythropoietin treatment in preterm infants. Pediatr Res 2012;71:332-7. Dani C, Reali MF, Bertini G, et al. The role of blood transfusions and iron intake on retinopathy of prematurity. Early Hum Dev 2001;62:57-63. Brooks SE, Marcus DM, Gillis D, et al. The effect of blood transfusion protocol on retinopathy of prematurity: a prospective, randomized study. Pediatrics 1999;104:514-8. Dani C, Poggi C, Bresci C, et al. Early fresh-frozen plasma transfusion decreases the risk of retinopathy of prematurity. Transfusion 2014;54:1002-7.
Volume 54, April 2014
TRANSFUSION
961
I
n the United States, 3.9 million babies are born each year, of which approximately 28,000 (0.7%) weigh less than 1250 g at birth. Approximately half of these small preterm infants become affected, to a lesser or greater extent, by retinopathy of prematurity (ROP), and therefore screening examinations are part of routine care.1 ROP, previously known as retrolental fibroplasia, is a disorder of disorganized growth of developing retinal blood vessels and can result in fibrovascularization and retinal detachment. In approximately 90% of neonates who develop ROP, the disorder resolves, requires no specific treatment, and leaves no permanent damage. However, the 10% with the most severe forms of ROP go on to have impaired vision or even blindness.2 In fact, 1100 to 1500 infants annually in the United States develop ROP severe enough to require specific treatment and 400 to 600 of these become legally blind.3 The development of ROP historically has involved both elements of high oxygen saturation and relative hypoxia.4 Besides these oxygen stresses, fluctuating oxygen levels and poor infant growth are also now recognized as contributing elements, but many gaps exist in understanding pathogenesis and susceptibility factors. Randomized, masked trials in the United States, Australia, New Zealand, Canada, and the United Kingdom indicated that lower targets of oxygen saturation (85%-89%) using pulse oximeters reduced the rate of treatment for ROP (10.6% vs. 13.5%; RR, 0.79; 95% CI, 0.63-1.00; p = 0.045). However the lower-target group had a higher rate of death than those in the higher-target group (saturations 91%95%; 23.1% vs. 15.9%; RR in the lower-target group, 1.45; 95% confidence interval [CI], 1.15-1.84; p = 0.002).5 Evidence for genetic susceptibility to ROP is strong, but the identity of the gene(s) involved and the molecular mechanisms remain uncertain. In a recent meta-analysis including seven studies, Liu and colleagues6 concluded that advanced ROP is significantly associated with VEGF (vascular endothelial growth factor) gene polymorphisms. Analyzing monozygotic versus dizygotic twins using mixed-effects logistic regression, Bizzarro and colleagues7 concluded that 30% of the pathogenesis of ROP can be accounted for by clinical factors (including hyperoxia) with genetic factors accounting for 70%. Sanghi and colleagues8 studied 35 pairs of identical twins where both developed ROP and found that 20% had the same or approximately the same severity of ROP while 80% were widely discordant in severity, suggesting that both genetic © 2014 AABB TRANSFUSION 2014;54:960-961. 960
TRANSFUSION Volume 54, April 2014
and environmental factors are relevant. Early dosing of recombinant erythropoietin (rEPO) to preterm infants was once thought to be a risk factor for ROP development,9 but animal models,10 human studies,11,12 and a revision of the original meta-analysis data (Ohls and Widness, personal communication, 2013) all indicate that rEPO dosing is not a risk factor for developing ROP. Beginning in the 1980s many reports concluded that RBC transfusion was a risk factor for ROP.13-16 Recent publications also report this association,17-19 but it is difficult to sort out the effect of RBC transfusions from the fact that the most severely ill neonates receive more RBC transfusions. This increased transfusion requirement is largely due to the relationship between the number of blood tests needed for intensive care monitoring and the number of RBC transfusions given.20,21 It has been postulated that damaging effects of transfusions on the immature retina are mediated by an increase in free iron.22 However, whether this is so and whether reducing RBC transfusions of neonates susceptible to ROP reduces their ROP risk are not known.23 In this issue of TRANSFUSION, Dani and colleagues24 from Florence, Italy, report an intriguing observation relevant to ROP pathogenesis and prevention. Reviewing their single-center data from 1999 through 2008, they found that neonates born at less than 29 weeks’ gestation who received fresh-frozen plasma (FFP) infusions during their first week after birth were less likely to develop ROP. Their data indicated that receiving at least two infusions of FFP diminished the risk of ROP by approximately one-half (relative risk [RR], 0.46; 95% CI, 0.23-0.93). The FFP was administered to these neonates generally because of prolonged clotting studies or signs of bleeding. The authors list the appropriate cautions that the study was retrospective and that FFP administration was not administered with the intent of diminishing the ROP risk. Also, the neonates who received FFP differed in known and unknown ways from those who did not, and those differences may be relevant to the outcomes. If FFP has the capacity to supply preterm infants with something of value toward ROP prevention, that substance might be IGF-1 or IGFBP-3 as the authors postulate, but it might just as likely be other factors or properties currently untested or unknown. Perhaps their observation, although in need of validation, will help focus ROP research efforts toward preventive approaches supplemental to the current transcutaneous oxygen saturation control programs.1-3 Moreover, if preventive substances from FFP can be identified, perhaps supplying the specific factor(s) in reliable amounts could have substantial advantages over infusing FFP.
EDITORIAL
Importantly, we judge that it would be imprudent to advise a widespread practice change on the basis of this observation; specifically, we do not advocate routinely infusing FFP to the smallest neonates with the hope of reducing their risk of severe ROP. Rather, we maintain that, like many associations discovered in retrospective data analysis, this provocative and potentially important finding should be followed by validation, prospective studies, and other rigorous means of testing efficacy, risk, and benefit.
9. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2012; (9)CD004863. 10. Slusarski JD, McPherson RJ, Wallace GN, et al. High-dose erythropoietin does not exacerbate retinopathy of prematurity in rats. Pediatr Res 2009;66:625-30. 11. Ohls RK, Christensen RD, Kamath-Rayne BD, et al. A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants. Pediatrics 2013;132: e119-27. 12. Zayed MA, Uppal A, Hartnett ME. New-onset maternal gestational hypertension and risk of retinopathy of prematurity. Invest Ophthalmol Vis Sci 2010;51:4983-8.
CONFLICT OF INTEREST The authors report no conflicts of interest or funding sources.
13. Yu VY, Hookham DM, Nave JR. Retrolental fibroplasia— controlled study of 4 years’ experience in a neonatal inten-
1
Robert D. Christensen, MD e-mail: [email protected] Sarah J. Ilstrup, MD2 Mary Elizabeth Hartnett, MD3 1 Women and Newborns Program, Intermountain Healthcare 2 Transfusion Medicine, Intermountain Healthcare 3 University of Utah Moran Eye Center Salt Lake City, UT
REFERENCES
sive care unit. Arch Dis Child 1982;57:247-52. 14. Shohat M, Reisner SH, Krikler R, et al. Retinopathy of prematurity: incidence and risk factors. Pediatrics 1983;72: 159-63. 15. Cats BP, Tan KE. Retinopathy of prematurity: review of a four-year period. Br J Ophthalmol 1985;69:500-3. 16. Cooke RW, Clark D, Hickey-Dwyer M, et al. The apparent role of blood transfusions in the development of retinopathy of prematurity. Eur J Pediatr 1993;152:833-6. 17. van Sorge A, Kerkhoff F, J Halbertsma F, et al. Severe retinopathy of prematurity in twin-twin transfusion syndrome after multiple blood transfusions. Acta Ophthalmol. 2013 Jun 15. doi: 10.1111/aos.12229. [Epub ahead of print].
1. Fierson WM; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists.
18. Hadi AM, Hamdy IS. Correlation between risk factors during the neonatal period and appearance of retinopathy
Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2013;131:189-95. 2. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med 2012;367:2515-26. 3. Quinn GE, Fielder AR. Prevention of ROP blindness. Clin
of prematurity in preterm infants in neonatal intensive care units in Alexandria Egypt Clin Ophthalmol 2013;7: 831-7. 19. Giannantonio C, Papacci P, Cota F, et al. Analysis of risk factors for progression to treatment-requiring ROP in a
Perinatol 2013;40:xvii-xviii. 4. Hartnett ME, Lane RH. Effects of oxygen on the development and severity of retinopathy of prematurity. J AAPOS 2013;17:229-34. 5. BOOST II United Kingdom Collaborative Group; BOOST II Australia Collaborative Group; BOOST II New Zealand Collaborative Group; Stenson BJ, Tarnow-Mordi WO, Darlow BA, et al. Oxygen saturation and outcomes in preterm infants. N Engl J Med 2013;368:2094-104. 6. Liu P, Wu D, Zhou W, et al. Association of VEGF gene polymorphisms with advanced retinopathy of prematurity: a meta-analysis. Mol Biol Rep 2012;39:10731-7. 7. Bizzarro MJ, Hussain N, Jonsson B, et al. Genetic susceptibility to retinopathy of prematurity. Pediatrics 2006;118: 1858-63. 8. Sanghi G, Dogra MR, Dutta S, et al. Intersibling variability of retinopathy of prematurity in twins and its risk factors. Int Ophthalmol 2012;32:113-7.
20.
21.
22.
23.
24.
single neonatal intensive care unit: is the exposure time relevant? J Matern Fetal Neonatal Med 2012;25:471-7. Rosebraugh MR, Widness JA, Nalbant D, et al. A mathematical modeling approach to quantify the role of phlebotomy losses and need for transfusions in neonatal anemia. Transfusion 2013;53:1353-60. Rosebraugh MR, Widness JA, Veng-Pedersen P. Multidose optimization simulation of erythropoietin treatment in preterm infants. Pediatr Res 2012;71:332-7. Dani C, Reali MF, Bertini G, et al. The role of blood transfusions and iron intake on retinopathy of prematurity. Early Hum Dev 2001;62:57-63. Brooks SE, Marcus DM, Gillis D, et al. The effect of blood transfusion protocol on retinopathy of prematurity: a prospective, randomized study. Pediatrics 1999;104:514-8. Dani C, Poggi C, Bresci C, et al. Early fresh-frozen plasma transfusion decreases the risk of retinopathy of prematurity. Transfusion 2014;54:1002-7.
Volume 54, April 2014
TRANSFUSION
961
