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The role of erythropoietin in the anemia of prematurity
The Role of Erythropoietin in the Anemia of Prematurity John J. Doyle Neonatal erythropoiesis is limited by a relatively inadequate production of erythropoietin. This is likely the result of dependence on the hepatic production of erythropoietin and an incomplete switchover to renal production. The present model of neonatal erythropoiesis suggests that the use of exogenous erythropoietin should correct the early anemia of premanu.ity that is observed at 6 weeks of age in premature newborns. Randomized, controlled trials of erythropoietin use in very low birthweight infants are reviewed. The data support the conclusion that erythropoietin at doses of ---750 u/kg/wk started at less than 7 days of age results in improved reticulocyte counts and hemoglobin levels, but does not reduce the number of infants who will be exposed to blood products. Erythropoietin at doses of ->600 u/kg/wk started at an average of 21 days of life improves reticulocyte counts and hemoglobin levels, and reduces the number of infants will will require late transfusion, but does nothing for the bulk of infants who are transfused before that age. Copyright 9 1 9 9 7 by W.B. Saunders
Company
n the 1980s and 1990s, erythropoietin (Epo) emerged as a tool for understanding the pathophysiology of the early anemia of prematurity (AOP) and as a drug for treatment of the same disorder. The significance of this anemia, which occurs between 4 and 6 weeks o f life in premature neonates, has been a source of controversy. Disparate opinions have argued that it is not pathological, but simply physiological ~ whereas others have c o m p a r e d it with the "air h u n g e r " experienced at high altitudes. 2 Regardless of this controversy, neonates continue to undergo transfusion for a myriad of symptoms t h o u g h t to be indicative o f symptomatic anemia. 3'4 Improved assays 5 for the measurement of Epo have led to a better understanding of its role in AOP, while the availability of recombinant h u m a n Epo has led to clinical trials of the drug in premature newborns.
I
Neonatal Erythropoiesis T h e relationship between Epo and hemoglobin level in premature newborns is complex. There From the Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario. Address reprint requests toJohn J. Doyle, MD, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8. Copyright 9 1997 by W.B. Saunders Company O146-0005/97/2101-0004505. 00/0
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is not a direct correlation between the two, and other factors (eg, P50, 2,3-DPG, mixed venous oxygen, cardiac output) play a role in determining the Epo response. 6'7 Investigators have clearly shown that premature neonates have adequate numbers of erythroid progenitors with a normal Epo responsiveness, s11 More recently, it has been shown that the macrophages o f premature newborns are as effective as those of older children and adults at the production o f Epo. 12 Despite this, a consistent theme has emerged that the Epo response to hypoxemia is " b l u n t e d " in preterm infants. 13'~4 Forestier et al 1~ showed that in utero levels of Epo are quite low (mean value, 1.6 + 2.5 m I U / m L ) . Brown et a113 and Stockman et al TM have shown persistence of inappropriately low Epo levels in premature infants. From these observations, a model o f neonatal erythropoiesis has emerged in which inadequate Epo response to hypoxemia becomes central to the pathophysiology of the early anemia o f prematurity. In this model, it has been postulated the hepatic sensor mechanism is primarily responsible for driving the premature neonate's Epo response to oxygen delivery. The hepatic mechanism is thought to be relatively insensitive when compared with the renal mechanism and produces proportionately less Epo for unit of oxygen delivered. By 4 to 6 weeks o f postnatal life, this results in the low levels of measured hemoglobin found in premature newborns and hypoxemia. Given that there are sufficient hum-
Seminars in Perinatology, Vol 21, No 1 (February), 1997: pp 20-27
Role of Erythropoietin in Anemia
2l
Table 1. Randomized, Controlled Trials of Epo Administration to Premature Neonates in Which Epo Administration Was Begun Within the First Week of Life
Author, Reference
Blinded
No. (Study~Control)
Day Epo Started (Mean)
Dose (U/kg/wk)
Obladen ~5 Emmerson sl Soubasi "~2 Soubasi 37
No Yes Yes Yes
4 7 <7 1-7
Maier 24 Carnielli 26
Yes No Yes
43/50 16/8 25/19 33/36 28/36 121/120 11/11 10/10
70 100-300 300 300 750 750 1,200 1,400
O h l s s6
3 2 2
Study groups are arranged in order of increasing weekly dosage.
bers of erythroid progenitors available to be stimulated by Epo, it seems reasonable that providing exogenous Epo will correct the defect and lead to a higher h e m o g l o b i n value/5 Clinical Trials Case reports ~e-~s and series 1921 have suggested benefit and risks for the use o f Epo in p r e m a t u r e newborns. Avoidance of transfusions, with the attendant risks of viral infection and volume overload, is primarily the benefit sought. Possible risks of Epo therapy have included neutropenia, iron, and o t h e r nutrient depletion. Randomized, controlled trials (RCT) c o m p a r i n g exogenous administration of Epo with a nonEpo control g r o u p have m o r e clearly defined the benefit and risks of Epo use in the p r e m a t u r e newborn. 22-40 Clinical trials of Epo have targeted small premature infants (generally < 34 weeks of gestation and <1,500 g), but have varied in the age at starting Epo and the dosage used. To facilitate analysis of the studies, in this r e p o r t they have b e e n divided into "early" and " l a t e " studies. In the "early" studies (Table 1), Epo administration began within the first week of life. In the " l a t e " g r o u p (Table 2), Epo administration started on average at 3 weeks of age. Tables 1 through 4 have b e e n organized in o r d e r of increasing weekly erythropoietin dosage. All groups s u p p l e m e n t e d infants with iron, because early studies had shown that iron depletion resulting f r o m increased erythropoietic activity resulted in iron-limited red blood cell production. 2~ Vitamin E, folate, and multivitamin supplements were used variably, and only two groups used protein supplements. 2s'a5 Transfu-
sion criteria were codified for most of the studies, removing the subjective c o m p o n e n t often e n c o u n t e r e d in the decision of when to transfuse.
Early Erythropoietin
Administration
T h e rationale b e h i n d the early administration of Epo lies in the desire to avoid any transfusion in the small newborn. Between 60% and 100% of p r e m a t u r e infants are transfused before 3 weeks of age. 2~'~3'39'42T h e acuity o f these patients makes t h e m less a m e n a b l e to study, because oral feedings may not be established, a n d a substantial n u m b e r and volume of blood samples are n e e d e d to m o n i t o r their clinical condition. T h e r e is a direct correlation between volumes of blood sampled and transfused. 1'24 At Epo doses of less than 300 u / k g / w k (Table 3), there is no evidence of i m p r o v e m e n t in hematopoiesis as shown by changes in reticulocyte n u m b e r s or m e a s u r e d h e m a t o c r i t or hemoglobin. O b l a d e n et al ~5 stratified their study population on the basis o f venfilatory status. T h e r e was no statistically significant difference in either the well (spontaneously breathing) or the sick (ventilated) group. Results at Epo doses of 300 u / k g / wk are conflicting. Several groups showed mildly improved reticulocyte counts 31'32'37 and lower ferritin values, sx'a7 Only Soubasi et al ~7 showed a m o d e s t increase in h e m a t o c r i t values (0.294 vs 0.282) that reached statistical significance but limited clinical value. At Epo doses less than or equal to 300 u / k g / w k , there was no r e p o r t e d decrease in the n u m b e r s of infants requiring transfusions or in the n u m b e r of transfusions given. At Epo doses of greater than or equal to 750
22
J o h n J . Doyle
Table 2. Randomized, Controlled Trials of Epo Administration to Premature Neonates in Which Epo Administration Was Begun About the Third Week of Life Author, Reference
Donato z~ Shannon 24 Donato 22 Bechensteen 2s Chen 38 Ronnestad s~ Shannon 27 Shannon 39 Meyer 3s Ohls 2~ Donato 22 Bader 4~
Blinded
No. (Study~Control)
D a y Epo Started (Mean)
Dose ( U / k g / w k )
Yes Yes Yes No No Yes Yes Yes Yes No Yes No
8/9 10/10 8/9 14/15 26/25/19" 12/12 4/4 77/80 40/40 10/9 8/9 15/14
28 21 28 21 22 14 to 21 20 23 27 42 28 34
150 200 300 300 300 450 500 500 600 700 750 900
* Groups are Epo/transfusions/no Epo, no transfusions. Study groups are arranged in order of increasing weekly dosage.
t r a n s f u s e d , b u t t h o s e in t h e E p o a r m w h o d i d receive t r a n s f u s i o n s r e c e i v e d significantly fewer transfusions. O f n o t e , in t h e l a r g e s t s t u d y to d a t e , ~4 n o statistical d i f f e r e n c e was o b s e r v e d in t h e n u m b e r o f infants t r a n s f u s e d , y e t t h e c o n t r o l infants r e c e i v e d a g r e a t e r n u m b e r o f t r a n s f u s i o n s p e r infant. N o v e l t r a n s f u s i o n strategies, s u c h as " m u l t i - d o s i n g " f r o m t h e s a m e unit, 43'44 c o u l d m a k e this i n c o n s e q u e n t i a l by r e d u c i n g e x p o sures to m u l t i p l e d o n o r s .
u / k g / w k , t h e r e is a c o n v i n c i n g i m p r o v e m e n t in reticulocyte numbers between the treatment and c o n t r o l arms. Similarly, t h e r e is e v i d e n c e o f i r o n d e p l e t i o n as s h o w n b y a g r e a t e r d e c r e a s e in ferritin in t h e t r e a t m e n t a r m . M e a n f e r r i t i n values in t h e t r e a t m e n t g r o u p s d i d n o t fall i n t o t h e defic i e n t r a n g e , likely as a r e s u l t o f i r o n s u p p l e m e n tation. M o s t s t u d i e s at this d o s a g e s h o w e d h i g h e r h e m a t o c r i t o r h e m o g l o b i n values in t h e treatm e n t a r m . I n t h e s t u d i e s o f Soubasi et a137 a n d C a r n i e l l i e t al, 26 significantly fewer E p o - t r e a t e d i n f a n t s u n d e r w e n t t r a n s f u s i o n . I n t h e studies o f M a i e r et a134 a n d O h l s e t a l Y t h e r e was n o t a s i g n i f i c a n t d i f f e r e n c e in t h e n u m b e r s o f i n f a n t s
Late Erythropoietin A d m i n i s t r a t i o n P r e m a t u r e n e w b o r n infants c o n t i n u e to n e e d transfusion therapy during the later part of their
Table 3. Results of Randomized, Controlled Trials of "Early" Epo Administration to Premature Neonates Author, Reference
Obladen 25
Dose U/kg/wk
70
Emmerson 31 100-300 Soubasi ~2 300 Soubasi s7 Maier 34 Carnielli 26 Ohls 36
300 300 750 750 1,200 1,400
Reticulocytes
Ferritin ( # g / L )
5.0 7.7 111 76
vs vs vs vs
3.7% 2.5% 62 • 109/Lt 54 X 109/L
163 252 88 85
vs vs vs vs
170 201 172t 205**
43 5.9 6.9 3.7 4.46 309
vs vs vs vs vs vs
25 X 109/Lt 3.0%t** 3.0%t** 2.0%** 1.49%t 126 • 10~ **
520 237 262 67
vs vs vs vs
490** 462t** 462t** 130t
H g b ( g / L ) or H c t
118 136 108 91
vs vs vs vs
123 127 111 86
99 0.294 0.340 0.361 0.481 0.433
vs vs vs vs vs vs
89 0.282t** 0.282t** 0.300** 0.438t 0.376**
No. o f Patients Transfused
No. of Transfusions
8 vs 15 15 vs 14 6 vs 7 3 vs 6 4 vs 9 No difference, specific data not given 7 vs 16 4 vs 16 t 60 vs 81 104 vs 151 t 9 vs 34 t 2 vs 7 2 vs 14 t
* Patients divided into two groups, top were spontaneously breathing, bottom were on artificial ventilation. t Statistically significant at at least P <.05, all others are not significant. ** Extrapolated from graphical presentation. Note: Comparisons are reported as study group versus control.
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Role of Erythropoietin in Anemia
Table 4. Results of Randomized, Controlled Trials of "Late" Epo Administration to Premature Neonates:
Comparisons are Reported as Study Group Versus Control Author, Reference
Dose U/kg/wk
Reticulocytes
Ferritin ( # g / L )
Donato 22 S h a n n o n 24
150 200
82 vs 79
Donato 2~
300
Bechensteen 2s
300
326 vs 271 • 109/L **
Chen .38
300
5.9 vs 1.7 vs 2.8%'f
116 vs 298 vs 290t
Ronnestad 35 S h a n n o n 27 S h a n n o n s9 Meyer ss Ohls ~3
450 500 500 600 700
4.8 263 315 223 7
132 95 148 63 107
Donato ~ Bader 4~
750 900
360 vs 230 x 109/LJ-
164 vs 158 • 109/L 73 vs 79
vs vs vs vs vs
2.7%t 136 • 109/Lt 206 • 109/Lt 125 • 109/Lt 1.6%t**
vs vs vs vs vs
147 128 189 123t 168
55 vs 79 76 vs 235t
H g b ( g / L ) or H c t
94 0.289 0.281 104 0.348 120 0.358 103 0.306
vs vs vs vs vs vs vs vs vs
109 0.327 0.282 109 0.327 98** 0.290** 198 vs 84 0.323 vs 0.273
0.314 0.320 0.323 0.346 116 0.356 0.340
vs vs vs vs vs vs vs
0.252~0.273~ 0.293t 0.340t** 109 0.327 0.280"f
No. o f Patients Transfused
No. o f Transfusions
3 vs 8 6 vs 8
7 vs 18
5 vs 7
12 vs 18
0 vs 4
4 vs 36 v s 0 1 vs 8 1 vs 3 44 vs 55 6 vs 17t
1 vs 7 t 2 vs 8 t
85 vs 128 7 vs 21t
1 vs 18t
* Patients divided into three groups, study group versus transfused group versus nontransfused, no Epo group. t Statistically significant at at least P < .05, all others are not significant. ** Extrapolated from graphical presentation.
nursery stay. 42 At our center, 232% of newborns are transfused during their newborn stay at greater than 3 weeks of age; however, fewer than 10% are being transfused for the first time. If these infants are targeted for Epo therapy, there will still be the potential of preventing substantial blood product exposure. At doses of less than 300 u / k g / w k (Table 4), there is no evidence of effect from Epo. At doses of 300 u / k g / w k , Donato et a122 and Bechensteen et a128 showed no evidence o f benefit, whereas Chen et al sa showed statistically higher reticulocyte counts and lower ferritin values. None of these studies showed improved hemoglobin levels or avoidance of transfusion therapy. At doses of 450 to 500 u / k g / w k , reticulocyte counts were consistently and statistically higher in the Epo-treated infants over those o f controlsY '35'a9 Hemoglobin or hematocrit values were also statistically different in the treatment group. Ferritin values did not differ between groups, and the numbers o f infants transfused as well as the n u m b e r of transfusions were not different. At doses ranging from 600 to 900 u / k g / w k , reticulocyte counts were again consistently higher in the Epo-treated neonates. 22'~s's3'4~Except for the study of Donato et a l y significant
improvements in hematocrit values were observed. Two groups reported iron depletion at these doses. 3s'4~ All four of the trials used oral iron supplementation at a dose of 6 m g / k g / d of elemental iron. Significandy fewer infants received transfusions in the Epo-treated groups, and fewer transfusions were given in total to the treated groups. Adverse Effects
Halp6rin et al 2~ observed that premature neonates treated with Epo at doses of 75 to 300 u / kg/wk developed a slight decline in neutrophil numbers during and up to 2 months from completion o f Epo therapy. All patients developed neutrophil counts of <1.0 • 109/L at some point during their therapy, and five o f seven developed counts <0.5 • 109/L at least once during their treatment. This was a n o n r a n d o m i z e d study leading to uncertainty as to whether neutropenia was the result of Epo therapy or the natural course for these small neonates. Ohls and Christensen, ~3 in their RCT o f Epo at doses of 700 u / k g / w k , reported a significant decrease in the absolute neutrophil count o f the Epotreated infants. This was supported by the observation o f a decreased neutrophil storage pool in the b o n e marrow of several infants. Despite this,
24
~hn~ D ~
the large n u m b e r s of r e p o r t e d trials to date have observed no difference in neutrophil n u m b e r s between Epo-treated n e o n a t e s and the control
arms.22,24,26-28,31-39,45
In one of the largest studies, Maier et al a4 r e p o r t e d a difference in weight gain favoring the control arm. Multiple o t h e r studies have observed no difference in weight gain. 2~'2s'~a'32, a5,a7,3s,40 In the study of C h e n et al, 3s there were two control groups; o n e received transfusion therapy and the second received neither Epo n o r transfusion t h r o u g h the study period. The latter control g r o u p showed significantly p o o r e r weight gain than either of the other arms, which showed equal weight gain. O f uncertain benefit is the increase in h e m o g l o b i n F levels observed in Epo-treated neonates. Several groups have n o t e d an increase in h e m o g l o b i n F or h e m o g l o b i n F-containing cells. 24'27'29'31'32'37 Bechensteen et a129 and Bard and Widness 46 p r e s e n t e d data showing that the h e m o g l o b i n F level in Epo-treated neonates was no greater than the levels observed in control infants who were not transfused. This is supp o r t e d by the data of S h a n n o n et a124 and Soubasi et al a2 that correlated the decrease in hemoglobin F levels with transfusion. Thus, rather than Epo resulting in continuing "fetal erythropoiesis," it seems that the effect of therapy is the result of transfusion of p r e d o m i n a n t l y adult blood. In n o n e of the studies was the increase in fetal h e m o g l o b i n shown to be of h a r m despite the theoretical disadvantage of p o o r e r oxygen unloading f r o m the h e m o g l o b i n F molecule.
Conclusions High doses of erythropoietin are capable of increasing neonatal erythropoiesis. In most studies, it is not possible to show that Epo ameliorates the signs and symptoms assigned to the anemia of prematurity, because control infants were transfused before significant symptoms. T h e study of Chen et al, 3s in which there was a no Epo and no transfusion control arm, showed that b o t h interventions (Epo a n d transfusion) improved weight gain a n d r e d u c e d apneas and bradycardias. These trials show that the use of transfusion can be diminished and possibly avoided t h r o u g h the use of erythropoietin therapy, but not that the n u m b e r of d o n o r exposures are significantly decreased.
W h e n therapy is started at less than 7 days of age in a p r e m a t u r e infant of less than 1,500 g, doses of 750 u / k g / w k are able to improve the reticulocyte count and h e m o g l o b i n level. T h a t this is d o n e through active erythropoiesis, is shown by the increase in iron utilization (decrease in serum ferritin). This strategy reduces the n u m b e r of transfusions that are given, but does not diminish the n u m b e r of newborns being exposed to d o n o r blood. It is also less effective in sicker newborns (requiring ventilation), limiting its usefulness to well infants. T h e r a p y started in older infants (about 21 days of life) at doses o f greater than or equal to 600 u / k g / w k will improve the reticulocyte count and h e m o g l o b i n levels. Doses of oral iron in the range of 6 m g / k g / d (elemental iron) will not prevent a decrease in iron stores (serum ferritin), but does prevent most treated infants from falling into the iron-deficient range. This strategy reduces the n u m b e r of children who receive transfusions as well as the a m o u n t of b l o o d transfused; however, most of these infants will have received some transfusion before Epo therapy. Both the "early" and " l a t e " strategies seem to be safe, with no significant short- or long-term effects. T h e use of exogenous erythropoietin does not h i n d e r the e n d o g e n o u s d e v e l o p m e n t of the n o r m a l erythron or create any later erythropoietic defect. T h e iron depletion that can occur seems m a n a g e a b l e by the prophylactic use of higher iron dosage. Concerns regarding neutropenia a n d weight loss have not b e e n b o r n e out by the majority of trials. In the trial of Emm e r s o n et al, 31 two cases of sudden infant death syndrome occurred in the t r e a t m e n t g r o u p after c o m p l e t i o n of the trial. This has not b e e n n o t e d in o t h e r trials. On the whole, erythropoietin administration has b e e n associated with remarkably few side effects. Despite these data, the role of erythropoietin in patient m a n a g e m e n t remains uncertain. Although high doses can decrease the n u m b e r of neonates receiving transfusions, it does n o t prevent the early n e e d for transfusions. Creative transfusion practices, such as "multi-dosing" f r o m a single unit until it reaches its expiry, 43'44 and directed parental donation reduce the number o f d o n o r exposures associated with transfusion. I m p r o v e d screening further improves the safety of the current b l o o d products. 47 Two studies have e x a m i n e d the cost-effective-
Role of Erythropoietin in Anemia
ness of erythropoietin therapy as c o m p a r e d with that of transfusion. Maier et al s4 calculated the relative costs of erythropoietin 750 u / k g / w k versus transfusion therapy and added in cost factors for the later estimated costs o f hepatitis C and acquired i m m u n e deficiency syndrome secondary to viral transmission. T h e estimated cost of treating a newborn with erythropoietin was $1,262 (US), and for the controls was $1,203 (US). In the studies of Ohls et al, 36 the cost of erythropoietin at 1,400 u / k g / w k was c o m p a r e d with that of transfusion therapy. T h e cost of erythropoietin and transfusions in the treatment arm was $129 (US) per patient and $256 (US) per patient for transfusions in the control arm. Given the modest cost savings from the use of erythropoietin, the restricted target population (well, very low birth weight infants) and the available alternatives for transfusion therapy, the general use of erythropoietin cannot be recomm e n d e d for the m a n a g e m e n t of AOP. Individual nurseries will need to examine their patient mix, ease o f obtaining blood products, the potential for "multi-dosing" from a single unit of packed RBCs, and the specific costs in their setting of using this drug.
Other Roles for Erythropoietin in the Newborn Bronchopulmonary dysplasia is accompanied by a hyporegenerative anemia. In a randomized, double-blind, controlled trial o f erythropoietin (200 u / k g / d ) for 10 days versus placebo, Ohls et a145showed increased hematocrit and reticulocyte values in the Epo-treated arm. Lactate levels were not changed. In the control arm, lactate levels increased significantly. In the 30 days after completion of drug administration, four infants in the control arm required transfusion versus one in the treatment arm (P <.001). No adverse effects were observed in the treatment arm. The mean age at study entry was 99 days for the treatment arm and 91 days for the placebo recipients. The investigators concluded that the anemia of b r o n c h o p u l m o n a r y dysplasia is responsive to erythropoietin therapy, and that further study is n e e d e d to determine the significance of these observations. Scaradavou et a148 presented a series o f four infants with suppressed erythropoiesis (as a result of intrauterine transfusions for Rh hemolytic
25
disease) treated with erythropoietin at doses of 600 u / k g / w k . Therapy was started between 1 and 7.5 weeks of age. Between 2 and 4 weeks after starting erythropoietin therapy, all infants showed a reticulocytosis and increase in hemoglobin level. In one infant, the hemoglobin level decreased after stopping erythropoietin and again improved with reinstitution o f therapy. No adverse effects were observed. In a more theoretical structure, erythropoietin has been postulated to work as an antioxidant. 49 Premature rabbits in an oxygen-enriched atmosphere suffered less oxidant-mediated lung damage when treated with erythropoietin than controls. T h e investigators postulated that by stimulating erythropoiesis, non-heme iron was mobilized and there was less transient metal-facilitated oxidative injury. A further interesting observation is the presence o f erythropoietin receptors within the fetal spinal cord. 5~T h e presence of erythropoietin receptor mRNA in fetal spinal cord cells was shown using a polymerase chain reaction technique. Immunohistochemical techniques were then used to show the presence o f the erythropoietin receptor in spinal tissue. Uptake was shown in cells radiating from the ependymal canal toward the anterior and posterior median sulci. The physiological role of these receptors is unknown.
References 1. Blanchette VS, Zipursky A: Assessment of anemia in newborn infants. Clin Perinatol 11:489, 1984 2. Holland BM, Jones JG, Wardrop CAJ: Lessons from the anemia of prematurity. Hematol/Oncol Clin North Am 1:355, 1987 3. Levy GJ, Strauss RG, Hume H, et al: National survey of neonatal transfusion practices: I. Red blood cell therapy. Pediatr 91:523, 1993 4. Stute H, Greiner B, Linderkamp O: Effect of blood transfusion on cardiorespiratory abnormalities in preterm infants. Arch Dis Child 72:F194, 1995 5. Cohen RA, Clemons G, Ebbe S: Correlation between bioassay and radioimmunoassay for erythropoietin in human serum and urine concentrates. Proc Soc Exp Biol Med 179:296, 1985 6. Stockman JA, III., Garcia JF, Oski FA: The anemia of prematurity. Factors governing the erythropoietin response. N EnglJ Med 296:647, 1977 7. HAgAP, Meberg A, Halvorsen S: Plasma erythropoietin concentrations during the early anemia of prematurity. Acta Pediatr Scand 72:827, 1983 8. Rhondeau SM, Christensen RD, Ross MP, et al: Responsiveness to recombinant human erythropoietin of m a r -
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10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
22.
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24.
25.
26.
JohnJ. Doyle
row erythroid progenitors from infants with the "anemia of prematurity." J Pediatr 112:935, 1988 Shannon KM, Naylor GS, TorkilsonJC, et al: Circulating erythroid progenitors in the anemia of prematurity. N EnglJ Med 317:728, 1987 Forestier F, Daffos F, Catherine N, et al: Developmental hematopoiesis in normal human fetal blood. Blood 77:2360, 1991 Emmerson AJB, Westwood NB, Rackham RA, et al: Erythropoietin responsive progenitors in anaemia of prematurity. Arch Dis Child 66:810, 1991 Ohls RK, LiY, Trautman S, et al: Erythropoietin production by macrophages from preterm infants: Implications regarding the cause of the anemia of prematurity. Pediatr Res 35:169, 1994 Brown MS, Garcia JF, Phibbs RH, et al: Decreased response of plasma immunoreactive erythropoietin to "available oxygen" in anemia of prematurity. J Pediatr 105:793, 1984 Stockman JA, III., Graeber JE, Clark DA, et al: Anemia of prematurity: determinants of the erythropoietin respoiase. J Pediatr 105:786, 1984 Shannon KM: Anemia ofprematurity: Progress and prospects. A m J Pediatr Hematol Oncol 12:14, 1990 Davis P, Herbert M, Davies DP, et al: Erythropoietin for anaemia in a preterm Jehovah's Witness baby. Early Human Dev 28:279, 1992 Fernandes CJ, Hagan R, Frieberg A, et al: Erythropoietin in very preterm infants. J Paediatr Child Health 30:356, 1994 Yu VYH, Bacsain MB: Avoidance of red blood cell transfusion in an extremely preterm infant given recombinant human erythropoietin therapy. J Paediatr Child Health 30:360, 1994 Beck D, Masserey E, Meyer M, et al: Weekly intravenous administration of recombinant human erythropoietin in infants with the anemia of prematurity. Eur J Pediatr 150:767, 1991 Halp6rin DS, Wacker P, Lacourt G, et al: Effects of recombinant human erythropoietin in infants with the anemia of prematurity: A pilot study. J Pediatr 116:779, 1990 Halp6fin DS, F61ix M, Wacker P, et al: Recombinant human erythropoietin in the treatment of infants with anaemia of prematurity. EurJ Pediatr 151:661, 1992 Donato H, Rendo P, Vivas N, et al: Recombinant human erythropoiefin in the treatment of anemia of prematurity: A randomized, double-blind, placebo-controlled trial comparing three different doses. IntJ Pediatr Hematol/Oncol 3:279, 1996 Ohls RK, Christensen RD: Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity. J Pediatr 119:781, 1991 Shannon KM, Mentzer WC, Abels RI, et al: Recombinant human erythropoietin in the anemia of prematurity: Results of a placebo-controlled pilot study. J Pediatr 118:949, 1991 Obladen M, Maier R, Segerer H, et al: Efficacy and safety of recombinant human erythropoietin to prevent anaemias of prematurity. European randomized multicenter trial. Contrib Nephrol 88:314, 1991 Carnielli V, Monfini G, Da Riol R, et al: Effect of high
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42,
doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants.J Pediatr 121:98, 1992 Shannon KM, Mentzer WC, Abels RI, et al: Enhancement of erythropoiesis by recombinant human erythropoiefin in low birth weight infants: A pilot study. J Pediatr 120:586, 1992 Bechensteen AG, H~tg~tP, Halvorsen S, et al: Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Arch Dis Child 69:19, 1993 Bechensteen AG, Refsum HE, Halvorsen S, et al: Effects of recombinant human erythropoiefin on fetal and adult hemoglobin in preterm infants. Pediatr Res 38:729, 1995 Bechensteen AG, Halvorsen S, H~tg~tP, et al: Erythropoietin (Epo), protein and iron supplementation and the prevention of anaemia of prematurity: Effects on serum immunoreactive Epo, growth and protein and iron metabolism. Acta Paediatr 85:490, 1996 Emmerson AJB, Coles HJ, Stern CMM, et al: Double blind trial of recombinant human erythropoietin in preterm infants. Arch Dis Child 68:291, 1993 Soubasi V, Kremenopoulos G, Diamandi E, et al: In which neonates does early recombinant human erythropoiefin treatment prevent anemia of prematurity? Results of a randomized controlled study. Pediatr Res 34:675, 1993 Meyer MP, Meyer JH, Commerford A, et al: Recombinant human erythropoietin in the treatment of the anemia of prematurity: Results of a double-blind, placebocontrolled study. Pediatrics 93:918, 1994 Maier P.F, Obladen M, Scigalla P, et al: The effect of epoetin beta (recombinant human erythropoiefin) on the need for transfusion in very-low-birth-weight infants. N EnglJ Med 330:1173, 1994 Ronnestad A, Moe PJ, Breivik N: Enhancement of erythropoiesis be erythropoiefin, bovine protein and energy fortified mother's milk during anaemia of prematurity. Acta Paediatr 83:809, 1994 Ohls RK, Osborne KA, Christensen RD: Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: A randomized placebo-controlled trial.J Pediatr 126:421, 1995 Soubasi V, Kremenopoulos G, Diamanti E, et al: Followup of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. J Pediatr 127:291, 1995 Chen J-Y, Wu T-S, Chanlai S-P: Recombinant human erythropoietin in the treatment of anemia of prematurity. Am J Perinatol 12:314, 1995 Shannon KM, KeithJF, III, Mentzer WC, et al: Recombinant human erythropoiefin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 95:1, 1995 Bader D, Blondheim O,Jonas R, et al: Decreased ferritin levels, despite iron supplementation, during erythropoiefin therapy in anaemia of prematurity. Acta Paediatr 85:496, 1996 MesserJ, HaddadJ, Donato L, et al: Early treatment of premature infants with recombinant human erythropoietin. Pediatr 92:519, 1993 Brown MS, Berman ER, Luckey D: Prediction of the
Role of Eothropoietin in Anemia
43.
44.
45.
46.
need for transfusion during anemia of prematurity. J Pediatr 116:773, 1990 Liu EA, Mannino FL, Lane TA: Prospective, randomized trial of the safety and efficacy of a limited donor exposure transfusion program for premature neonates.J Pediatr 125:92, 1994 Lee DA, Siagle TA, Jackson TM, et al: Reducing blood donor exposures in low birth weight infants by the use of older, unwashed packed red blood cells. J Pediatr 126:280, 1995 Ohls RK, Hunter DD, Christensen RD: A randomized, double-blind placebo-controlled trial of recombinant erythropoietin in treatment of the anemia of bronchopulmonary dysplasia. J Pediatr 123:996, 1993 Bard H, WidnessJA: Effect of recombinant human eryth-
47.
48.
49.
50.
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ropoietin on the switchover from fetal to adult hemoglobin synthesis in preterm infants.J Pediatr 127:478, 1995 Schreiber GB, Busch MB, Kleinman SH, et al: The risk of transfusion-transmitted viral infections. N Engl J Med 334:1685, 1996 Scaradavou A, Inglis S, Peterson P, et al: Suppression of erythropoiesis by intrauterine transfusions in hemolytic disease of the newborn: Use of erythropoietin to treat the late anemia. J Pediatr 123:279, 1993 Bany-Mohammed FM, Slivka S, Hallman M: Recombinant human erythropoietin: Possible role as an antioxidant in premature rabbits. Pediatr Res 40:381, 1996 Li Y, Juui SE, Morris-Wiman JA, et al: Erythropoietin receptors are expressed in the central nervous system of mid-trimester h u m a n fetuses. Pediatr Res 40:376, 1996
Company
n the 1980s and 1990s, erythropoietin (Epo) emerged as a tool for understanding the pathophysiology of the early anemia of prematurity (AOP) and as a drug for treatment of the same disorder. The significance of this anemia, which occurs between 4 and 6 weeks o f life in premature neonates, has been a source of controversy. Disparate opinions have argued that it is not pathological, but simply physiological ~ whereas others have c o m p a r e d it with the "air h u n g e r " experienced at high altitudes. 2 Regardless of this controversy, neonates continue to undergo transfusion for a myriad of symptoms t h o u g h t to be indicative o f symptomatic anemia. 3'4 Improved assays 5 for the measurement of Epo have led to a better understanding of its role in AOP, while the availability of recombinant h u m a n Epo has led to clinical trials of the drug in premature newborns.
I
Neonatal Erythropoiesis T h e relationship between Epo and hemoglobin level in premature newborns is complex. There From the Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario. Address reprint requests toJohn J. Doyle, MD, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8. Copyright 9 1997 by W.B. Saunders Company O146-0005/97/2101-0004505. 00/0
20
is not a direct correlation between the two, and other factors (eg, P50, 2,3-DPG, mixed venous oxygen, cardiac output) play a role in determining the Epo response. 6'7 Investigators have clearly shown that premature neonates have adequate numbers of erythroid progenitors with a normal Epo responsiveness, s11 More recently, it has been shown that the macrophages o f premature newborns are as effective as those of older children and adults at the production o f Epo. 12 Despite this, a consistent theme has emerged that the Epo response to hypoxemia is " b l u n t e d " in preterm infants. 13'~4 Forestier et al 1~ showed that in utero levels of Epo are quite low (mean value, 1.6 + 2.5 m I U / m L ) . Brown et a113 and Stockman et al TM have shown persistence of inappropriately low Epo levels in premature infants. From these observations, a model o f neonatal erythropoiesis has emerged in which inadequate Epo response to hypoxemia becomes central to the pathophysiology of the early anemia o f prematurity. In this model, it has been postulated the hepatic sensor mechanism is primarily responsible for driving the premature neonate's Epo response to oxygen delivery. The hepatic mechanism is thought to be relatively insensitive when compared with the renal mechanism and produces proportionately less Epo for unit of oxygen delivered. By 4 to 6 weeks o f postnatal life, this results in the low levels of measured hemoglobin found in premature newborns and hypoxemia. Given that there are sufficient hum-
Seminars in Perinatology, Vol 21, No 1 (February), 1997: pp 20-27
Role of Erythropoietin in Anemia
2l
Table 1. Randomized, Controlled Trials of Epo Administration to Premature Neonates in Which Epo Administration Was Begun Within the First Week of Life
Author, Reference
Blinded
No. (Study~Control)
Day Epo Started (Mean)
Dose (U/kg/wk)
Obladen ~5 Emmerson sl Soubasi "~2 Soubasi 37
No Yes Yes Yes
4 7 <7 1-7
Maier 24 Carnielli 26
Yes No Yes
43/50 16/8 25/19 33/36 28/36 121/120 11/11 10/10
70 100-300 300 300 750 750 1,200 1,400
O h l s s6
3 2 2
Study groups are arranged in order of increasing weekly dosage.
bers of erythroid progenitors available to be stimulated by Epo, it seems reasonable that providing exogenous Epo will correct the defect and lead to a higher h e m o g l o b i n value/5 Clinical Trials Case reports ~e-~s and series 1921 have suggested benefit and risks for the use o f Epo in p r e m a t u r e newborns. Avoidance of transfusions, with the attendant risks of viral infection and volume overload, is primarily the benefit sought. Possible risks of Epo therapy have included neutropenia, iron, and o t h e r nutrient depletion. Randomized, controlled trials (RCT) c o m p a r i n g exogenous administration of Epo with a nonEpo control g r o u p have m o r e clearly defined the benefit and risks of Epo use in the p r e m a t u r e newborn. 22-40 Clinical trials of Epo have targeted small premature infants (generally < 34 weeks of gestation and <1,500 g), but have varied in the age at starting Epo and the dosage used. To facilitate analysis of the studies, in this r e p o r t they have b e e n divided into "early" and " l a t e " studies. In the "early" studies (Table 1), Epo administration began within the first week of life. In the " l a t e " g r o u p (Table 2), Epo administration started on average at 3 weeks of age. Tables 1 through 4 have b e e n organized in o r d e r of increasing weekly erythropoietin dosage. All groups s u p p l e m e n t e d infants with iron, because early studies had shown that iron depletion resulting f r o m increased erythropoietic activity resulted in iron-limited red blood cell production. 2~ Vitamin E, folate, and multivitamin supplements were used variably, and only two groups used protein supplements. 2s'a5 Transfu-
sion criteria were codified for most of the studies, removing the subjective c o m p o n e n t often e n c o u n t e r e d in the decision of when to transfuse.
Early Erythropoietin
Administration
T h e rationale b e h i n d the early administration of Epo lies in the desire to avoid any transfusion in the small newborn. Between 60% and 100% of p r e m a t u r e infants are transfused before 3 weeks of age. 2~'~3'39'42T h e acuity o f these patients makes t h e m less a m e n a b l e to study, because oral feedings may not be established, a n d a substantial n u m b e r and volume of blood samples are n e e d e d to m o n i t o r their clinical condition. T h e r e is a direct correlation between volumes of blood sampled and transfused. 1'24 At Epo doses of less than 300 u / k g / w k (Table 3), there is no evidence of i m p r o v e m e n t in hematopoiesis as shown by changes in reticulocyte n u m b e r s or m e a s u r e d h e m a t o c r i t or hemoglobin. O b l a d e n et al ~5 stratified their study population on the basis o f venfilatory status. T h e r e was no statistically significant difference in either the well (spontaneously breathing) or the sick (ventilated) group. Results at Epo doses of 300 u / k g / wk are conflicting. Several groups showed mildly improved reticulocyte counts 31'32'37 and lower ferritin values, sx'a7 Only Soubasi et al ~7 showed a m o d e s t increase in h e m a t o c r i t values (0.294 vs 0.282) that reached statistical significance but limited clinical value. At Epo doses less than or equal to 300 u / k g / w k , there was no r e p o r t e d decrease in the n u m b e r s of infants requiring transfusions or in the n u m b e r of transfusions given. At Epo doses of greater than or equal to 750
22
J o h n J . Doyle
Table 2. Randomized, Controlled Trials of Epo Administration to Premature Neonates in Which Epo Administration Was Begun About the Third Week of Life Author, Reference
Donato z~ Shannon 24 Donato 22 Bechensteen 2s Chen 38 Ronnestad s~ Shannon 27 Shannon 39 Meyer 3s Ohls 2~ Donato 22 Bader 4~
Blinded
No. (Study~Control)
D a y Epo Started (Mean)
Dose ( U / k g / w k )
Yes Yes Yes No No Yes Yes Yes Yes No Yes No
8/9 10/10 8/9 14/15 26/25/19" 12/12 4/4 77/80 40/40 10/9 8/9 15/14
28 21 28 21 22 14 to 21 20 23 27 42 28 34
150 200 300 300 300 450 500 500 600 700 750 900
* Groups are Epo/transfusions/no Epo, no transfusions. Study groups are arranged in order of increasing weekly dosage.
t r a n s f u s e d , b u t t h o s e in t h e E p o a r m w h o d i d receive t r a n s f u s i o n s r e c e i v e d significantly fewer transfusions. O f n o t e , in t h e l a r g e s t s t u d y to d a t e , ~4 n o statistical d i f f e r e n c e was o b s e r v e d in t h e n u m b e r o f infants t r a n s f u s e d , y e t t h e c o n t r o l infants r e c e i v e d a g r e a t e r n u m b e r o f t r a n s f u s i o n s p e r infant. N o v e l t r a n s f u s i o n strategies, s u c h as " m u l t i - d o s i n g " f r o m t h e s a m e unit, 43'44 c o u l d m a k e this i n c o n s e q u e n t i a l by r e d u c i n g e x p o sures to m u l t i p l e d o n o r s .
u / k g / w k , t h e r e is a c o n v i n c i n g i m p r o v e m e n t in reticulocyte numbers between the treatment and c o n t r o l arms. Similarly, t h e r e is e v i d e n c e o f i r o n d e p l e t i o n as s h o w n b y a g r e a t e r d e c r e a s e in ferritin in t h e t r e a t m e n t a r m . M e a n f e r r i t i n values in t h e t r e a t m e n t g r o u p s d i d n o t fall i n t o t h e defic i e n t r a n g e , likely as a r e s u l t o f i r o n s u p p l e m e n tation. M o s t s t u d i e s at this d o s a g e s h o w e d h i g h e r h e m a t o c r i t o r h e m o g l o b i n values in t h e treatm e n t a r m . I n t h e s t u d i e s o f Soubasi et a137 a n d C a r n i e l l i e t al, 26 significantly fewer E p o - t r e a t e d i n f a n t s u n d e r w e n t t r a n s f u s i o n . I n t h e studies o f M a i e r et a134 a n d O h l s e t a l Y t h e r e was n o t a s i g n i f i c a n t d i f f e r e n c e in t h e n u m b e r s o f i n f a n t s
Late Erythropoietin A d m i n i s t r a t i o n P r e m a t u r e n e w b o r n infants c o n t i n u e to n e e d transfusion therapy during the later part of their
Table 3. Results of Randomized, Controlled Trials of "Early" Epo Administration to Premature Neonates Author, Reference
Obladen 25
Dose U/kg/wk
70
Emmerson 31 100-300 Soubasi ~2 300 Soubasi s7 Maier 34 Carnielli 26 Ohls 36
300 300 750 750 1,200 1,400
Reticulocytes
Ferritin ( # g / L )
5.0 7.7 111 76
vs vs vs vs
3.7% 2.5% 62 • 109/Lt 54 X 109/L
163 252 88 85
vs vs vs vs
170 201 172t 205**
43 5.9 6.9 3.7 4.46 309
vs vs vs vs vs vs
25 X 109/Lt 3.0%t** 3.0%t** 2.0%** 1.49%t 126 • 10~ **
520 237 262 67
vs vs vs vs
490** 462t** 462t** 130t
H g b ( g / L ) or H c t
118 136 108 91
vs vs vs vs
123 127 111 86
99 0.294 0.340 0.361 0.481 0.433
vs vs vs vs vs vs
89 0.282t** 0.282t** 0.300** 0.438t 0.376**
No. o f Patients Transfused
No. of Transfusions
8 vs 15 15 vs 14 6 vs 7 3 vs 6 4 vs 9 No difference, specific data not given 7 vs 16 4 vs 16 t 60 vs 81 104 vs 151 t 9 vs 34 t 2 vs 7 2 vs 14 t
* Patients divided into two groups, top were spontaneously breathing, bottom were on artificial ventilation. t Statistically significant at at least P <.05, all others are not significant. ** Extrapolated from graphical presentation. Note: Comparisons are reported as study group versus control.
23
Role of Erythropoietin in Anemia
Table 4. Results of Randomized, Controlled Trials of "Late" Epo Administration to Premature Neonates:
Comparisons are Reported as Study Group Versus Control Author, Reference
Dose U/kg/wk
Reticulocytes
Ferritin ( # g / L )
Donato 22 S h a n n o n 24
150 200
82 vs 79
Donato 2~
300
Bechensteen 2s
300
326 vs 271 • 109/L **
Chen .38
300
5.9 vs 1.7 vs 2.8%'f
116 vs 298 vs 290t
Ronnestad 35 S h a n n o n 27 S h a n n o n s9 Meyer ss Ohls ~3
450 500 500 600 700
4.8 263 315 223 7
132 95 148 63 107
Donato ~ Bader 4~
750 900
360 vs 230 x 109/LJ-
164 vs 158 • 109/L 73 vs 79
vs vs vs vs vs
2.7%t 136 • 109/Lt 206 • 109/Lt 125 • 109/Lt 1.6%t**
vs vs vs vs vs
147 128 189 123t 168
55 vs 79 76 vs 235t
H g b ( g / L ) or H c t
94 0.289 0.281 104 0.348 120 0.358 103 0.306
vs vs vs vs vs vs vs vs vs
109 0.327 0.282 109 0.327 98** 0.290** 198 vs 84 0.323 vs 0.273
0.314 0.320 0.323 0.346 116 0.356 0.340
vs vs vs vs vs vs vs
0.252~0.273~ 0.293t 0.340t** 109 0.327 0.280"f
No. o f Patients Transfused
No. o f Transfusions
3 vs 8 6 vs 8
7 vs 18
5 vs 7
12 vs 18
0 vs 4
4 vs 36 v s 0 1 vs 8 1 vs 3 44 vs 55 6 vs 17t
1 vs 7 t 2 vs 8 t
85 vs 128 7 vs 21t
1 vs 18t
* Patients divided into three groups, study group versus transfused group versus nontransfused, no Epo group. t Statistically significant at at least P < .05, all others are not significant. ** Extrapolated from graphical presentation.
nursery stay. 42 At our center, 232% of newborns are transfused during their newborn stay at greater than 3 weeks of age; however, fewer than 10% are being transfused for the first time. If these infants are targeted for Epo therapy, there will still be the potential of preventing substantial blood product exposure. At doses of less than 300 u / k g / w k (Table 4), there is no evidence of effect from Epo. At doses of 300 u / k g / w k , Donato et a122 and Bechensteen et a128 showed no evidence o f benefit, whereas Chen et al sa showed statistically higher reticulocyte counts and lower ferritin values. None of these studies showed improved hemoglobin levels or avoidance of transfusion therapy. At doses of 450 to 500 u / k g / w k , reticulocyte counts were consistently and statistically higher in the Epo-treated infants over those o f controlsY '35'a9 Hemoglobin or hematocrit values were also statistically different in the treatment group. Ferritin values did not differ between groups, and the numbers o f infants transfused as well as the n u m b e r of transfusions were not different. At doses ranging from 600 to 900 u / k g / w k , reticulocyte counts were again consistently higher in the Epo-treated neonates. 22'~s's3'4~Except for the study of Donato et a l y significant
improvements in hematocrit values were observed. Two groups reported iron depletion at these doses. 3s'4~ All four of the trials used oral iron supplementation at a dose of 6 m g / k g / d of elemental iron. Significandy fewer infants received transfusions in the Epo-treated groups, and fewer transfusions were given in total to the treated groups. Adverse Effects
Halp6rin et al 2~ observed that premature neonates treated with Epo at doses of 75 to 300 u / kg/wk developed a slight decline in neutrophil numbers during and up to 2 months from completion o f Epo therapy. All patients developed neutrophil counts of <1.0 • 109/L at some point during their therapy, and five o f seven developed counts <0.5 • 109/L at least once during their treatment. This was a n o n r a n d o m i z e d study leading to uncertainty as to whether neutropenia was the result of Epo therapy or the natural course for these small neonates. Ohls and Christensen, ~3 in their RCT o f Epo at doses of 700 u / k g / w k , reported a significant decrease in the absolute neutrophil count o f the Epotreated infants. This was supported by the observation o f a decreased neutrophil storage pool in the b o n e marrow of several infants. Despite this,
24
~hn~ D ~
the large n u m b e r s of r e p o r t e d trials to date have observed no difference in neutrophil n u m b e r s between Epo-treated n e o n a t e s and the control
arms.22,24,26-28,31-39,45
In one of the largest studies, Maier et al a4 r e p o r t e d a difference in weight gain favoring the control arm. Multiple o t h e r studies have observed no difference in weight gain. 2~'2s'~a'32, a5,a7,3s,40 In the study of C h e n et al, 3s there were two control groups; o n e received transfusion therapy and the second received neither Epo n o r transfusion t h r o u g h the study period. The latter control g r o u p showed significantly p o o r e r weight gain than either of the other arms, which showed equal weight gain. O f uncertain benefit is the increase in h e m o g l o b i n F levels observed in Epo-treated neonates. Several groups have n o t e d an increase in h e m o g l o b i n F or h e m o g l o b i n F-containing cells. 24'27'29'31'32'37 Bechensteen et a129 and Bard and Widness 46 p r e s e n t e d data showing that the h e m o g l o b i n F level in Epo-treated neonates was no greater than the levels observed in control infants who were not transfused. This is supp o r t e d by the data of S h a n n o n et a124 and Soubasi et al a2 that correlated the decrease in hemoglobin F levels with transfusion. Thus, rather than Epo resulting in continuing "fetal erythropoiesis," it seems that the effect of therapy is the result of transfusion of p r e d o m i n a n t l y adult blood. In n o n e of the studies was the increase in fetal h e m o g l o b i n shown to be of h a r m despite the theoretical disadvantage of p o o r e r oxygen unloading f r o m the h e m o g l o b i n F molecule.
Conclusions High doses of erythropoietin are capable of increasing neonatal erythropoiesis. In most studies, it is not possible to show that Epo ameliorates the signs and symptoms assigned to the anemia of prematurity, because control infants were transfused before significant symptoms. T h e study of Chen et al, 3s in which there was a no Epo and no transfusion control arm, showed that b o t h interventions (Epo a n d transfusion) improved weight gain a n d r e d u c e d apneas and bradycardias. These trials show that the use of transfusion can be diminished and possibly avoided t h r o u g h the use of erythropoietin therapy, but not that the n u m b e r of d o n o r exposures are significantly decreased.
W h e n therapy is started at less than 7 days of age in a p r e m a t u r e infant of less than 1,500 g, doses of 750 u / k g / w k are able to improve the reticulocyte count and h e m o g l o b i n level. T h a t this is d o n e through active erythropoiesis, is shown by the increase in iron utilization (decrease in serum ferritin). This strategy reduces the n u m b e r of transfusions that are given, but does not diminish the n u m b e r of newborns being exposed to d o n o r blood. It is also less effective in sicker newborns (requiring ventilation), limiting its usefulness to well infants. T h e r a p y started in older infants (about 21 days of life) at doses o f greater than or equal to 600 u / k g / w k will improve the reticulocyte count and h e m o g l o b i n levels. Doses of oral iron in the range of 6 m g / k g / d (elemental iron) will not prevent a decrease in iron stores (serum ferritin), but does prevent most treated infants from falling into the iron-deficient range. This strategy reduces the n u m b e r of children who receive transfusions as well as the a m o u n t of b l o o d transfused; however, most of these infants will have received some transfusion before Epo therapy. Both the "early" and " l a t e " strategies seem to be safe, with no significant short- or long-term effects. T h e use of exogenous erythropoietin does not h i n d e r the e n d o g e n o u s d e v e l o p m e n t of the n o r m a l erythron or create any later erythropoietic defect. T h e iron depletion that can occur seems m a n a g e a b l e by the prophylactic use of higher iron dosage. Concerns regarding neutropenia a n d weight loss have not b e e n b o r n e out by the majority of trials. In the trial of Emm e r s o n et al, 31 two cases of sudden infant death syndrome occurred in the t r e a t m e n t g r o u p after c o m p l e t i o n of the trial. This has not b e e n n o t e d in o t h e r trials. On the whole, erythropoietin administration has b e e n associated with remarkably few side effects. Despite these data, the role of erythropoietin in patient m a n a g e m e n t remains uncertain. Although high doses can decrease the n u m b e r of neonates receiving transfusions, it does n o t prevent the early n e e d for transfusions. Creative transfusion practices, such as "multi-dosing" f r o m a single unit until it reaches its expiry, 43'44 and directed parental donation reduce the number o f d o n o r exposures associated with transfusion. I m p r o v e d screening further improves the safety of the current b l o o d products. 47 Two studies have e x a m i n e d the cost-effective-
Role of Erythropoietin in Anemia
ness of erythropoietin therapy as c o m p a r e d with that of transfusion. Maier et al s4 calculated the relative costs of erythropoietin 750 u / k g / w k versus transfusion therapy and added in cost factors for the later estimated costs o f hepatitis C and acquired i m m u n e deficiency syndrome secondary to viral transmission. T h e estimated cost of treating a newborn with erythropoietin was $1,262 (US), and for the controls was $1,203 (US). In the studies of Ohls et al, 36 the cost of erythropoietin at 1,400 u / k g / w k was c o m p a r e d with that of transfusion therapy. T h e cost of erythropoietin and transfusions in the treatment arm was $129 (US) per patient and $256 (US) per patient for transfusions in the control arm. Given the modest cost savings from the use of erythropoietin, the restricted target population (well, very low birth weight infants) and the available alternatives for transfusion therapy, the general use of erythropoietin cannot be recomm e n d e d for the m a n a g e m e n t of AOP. Individual nurseries will need to examine their patient mix, ease o f obtaining blood products, the potential for "multi-dosing" from a single unit of packed RBCs, and the specific costs in their setting of using this drug.
Other Roles for Erythropoietin in the Newborn Bronchopulmonary dysplasia is accompanied by a hyporegenerative anemia. In a randomized, double-blind, controlled trial o f erythropoietin (200 u / k g / d ) for 10 days versus placebo, Ohls et a145showed increased hematocrit and reticulocyte values in the Epo-treated arm. Lactate levels were not changed. In the control arm, lactate levels increased significantly. In the 30 days after completion of drug administration, four infants in the control arm required transfusion versus one in the treatment arm (P <.001). No adverse effects were observed in the treatment arm. The mean age at study entry was 99 days for the treatment arm and 91 days for the placebo recipients. The investigators concluded that the anemia of b r o n c h o p u l m o n a r y dysplasia is responsive to erythropoietin therapy, and that further study is n e e d e d to determine the significance of these observations. Scaradavou et a148 presented a series o f four infants with suppressed erythropoiesis (as a result of intrauterine transfusions for Rh hemolytic
25
disease) treated with erythropoietin at doses of 600 u / k g / w k . Therapy was started between 1 and 7.5 weeks of age. Between 2 and 4 weeks after starting erythropoietin therapy, all infants showed a reticulocytosis and increase in hemoglobin level. In one infant, the hemoglobin level decreased after stopping erythropoietin and again improved with reinstitution o f therapy. No adverse effects were observed. In a more theoretical structure, erythropoietin has been postulated to work as an antioxidant. 49 Premature rabbits in an oxygen-enriched atmosphere suffered less oxidant-mediated lung damage when treated with erythropoietin than controls. T h e investigators postulated that by stimulating erythropoiesis, non-heme iron was mobilized and there was less transient metal-facilitated oxidative injury. A further interesting observation is the presence o f erythropoietin receptors within the fetal spinal cord. 5~T h e presence of erythropoietin receptor mRNA in fetal spinal cord cells was shown using a polymerase chain reaction technique. Immunohistochemical techniques were then used to show the presence o f the erythropoietin receptor in spinal tissue. Uptake was shown in cells radiating from the ependymal canal toward the anterior and posterior median sulci. The physiological role of these receptors is unknown.
References 1. Blanchette VS, Zipursky A: Assessment of anemia in newborn infants. Clin Perinatol 11:489, 1984 2. Holland BM, Jones JG, Wardrop CAJ: Lessons from the anemia of prematurity. Hematol/Oncol Clin North Am 1:355, 1987 3. Levy GJ, Strauss RG, Hume H, et al: National survey of neonatal transfusion practices: I. Red blood cell therapy. Pediatr 91:523, 1993 4. Stute H, Greiner B, Linderkamp O: Effect of blood transfusion on cardiorespiratory abnormalities in preterm infants. Arch Dis Child 72:F194, 1995 5. Cohen RA, Clemons G, Ebbe S: Correlation between bioassay and radioimmunoassay for erythropoietin in human serum and urine concentrates. Proc Soc Exp Biol Med 179:296, 1985 6. Stockman JA, III., Garcia JF, Oski FA: The anemia of prematurity. Factors governing the erythropoietin response. N EnglJ Med 296:647, 1977 7. HAgAP, Meberg A, Halvorsen S: Plasma erythropoietin concentrations during the early anemia of prematurity. Acta Pediatr Scand 72:827, 1983 8. Rhondeau SM, Christensen RD, Ross MP, et al: Responsiveness to recombinant human erythropoietin of m a r -
26
9.
10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
JohnJ. Doyle
row erythroid progenitors from infants with the "anemia of prematurity." J Pediatr 112:935, 1988 Shannon KM, Naylor GS, TorkilsonJC, et al: Circulating erythroid progenitors in the anemia of prematurity. N EnglJ Med 317:728, 1987 Forestier F, Daffos F, Catherine N, et al: Developmental hematopoiesis in normal human fetal blood. Blood 77:2360, 1991 Emmerson AJB, Westwood NB, Rackham RA, et al: Erythropoietin responsive progenitors in anaemia of prematurity. Arch Dis Child 66:810, 1991 Ohls RK, LiY, Trautman S, et al: Erythropoietin production by macrophages from preterm infants: Implications regarding the cause of the anemia of prematurity. Pediatr Res 35:169, 1994 Brown MS, Garcia JF, Phibbs RH, et al: Decreased response of plasma immunoreactive erythropoietin to "available oxygen" in anemia of prematurity. J Pediatr 105:793, 1984 Stockman JA, III., Graeber JE, Clark DA, et al: Anemia of prematurity: determinants of the erythropoietin respoiase. J Pediatr 105:786, 1984 Shannon KM: Anemia ofprematurity: Progress and prospects. A m J Pediatr Hematol Oncol 12:14, 1990 Davis P, Herbert M, Davies DP, et al: Erythropoietin for anaemia in a preterm Jehovah's Witness baby. Early Human Dev 28:279, 1992 Fernandes CJ, Hagan R, Frieberg A, et al: Erythropoietin in very preterm infants. J Paediatr Child Health 30:356, 1994 Yu VYH, Bacsain MB: Avoidance of red blood cell transfusion in an extremely preterm infant given recombinant human erythropoietin therapy. J Paediatr Child Health 30:360, 1994 Beck D, Masserey E, Meyer M, et al: Weekly intravenous administration of recombinant human erythropoietin in infants with the anemia of prematurity. Eur J Pediatr 150:767, 1991 Halp6rin DS, Wacker P, Lacourt G, et al: Effects of recombinant human erythropoietin in infants with the anemia of prematurity: A pilot study. J Pediatr 116:779, 1990 Halp6fin DS, F61ix M, Wacker P, et al: Recombinant human erythropoietin in the treatment of infants with anaemia of prematurity. EurJ Pediatr 151:661, 1992 Donato H, Rendo P, Vivas N, et al: Recombinant human erythropoiefin in the treatment of anemia of prematurity: A randomized, double-blind, placebo-controlled trial comparing three different doses. IntJ Pediatr Hematol/Oncol 3:279, 1996 Ohls RK, Christensen RD: Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity. J Pediatr 119:781, 1991 Shannon KM, Mentzer WC, Abels RI, et al: Recombinant human erythropoietin in the anemia of prematurity: Results of a placebo-controlled pilot study. J Pediatr 118:949, 1991 Obladen M, Maier R, Segerer H, et al: Efficacy and safety of recombinant human erythropoietin to prevent anaemias of prematurity. European randomized multicenter trial. Contrib Nephrol 88:314, 1991 Carnielli V, Monfini G, Da Riol R, et al: Effect of high
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42,
doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants.J Pediatr 121:98, 1992 Shannon KM, Mentzer WC, Abels RI, et al: Enhancement of erythropoiesis by recombinant human erythropoiefin in low birth weight infants: A pilot study. J Pediatr 120:586, 1992 Bechensteen AG, H~tg~tP, Halvorsen S, et al: Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Arch Dis Child 69:19, 1993 Bechensteen AG, Refsum HE, Halvorsen S, et al: Effects of recombinant human erythropoiefin on fetal and adult hemoglobin in preterm infants. Pediatr Res 38:729, 1995 Bechensteen AG, Halvorsen S, H~tg~tP, et al: Erythropoietin (Epo), protein and iron supplementation and the prevention of anaemia of prematurity: Effects on serum immunoreactive Epo, growth and protein and iron metabolism. Acta Paediatr 85:490, 1996 Emmerson AJB, Coles HJ, Stern CMM, et al: Double blind trial of recombinant human erythropoietin in preterm infants. Arch Dis Child 68:291, 1993 Soubasi V, Kremenopoulos G, Diamandi E, et al: In which neonates does early recombinant human erythropoiefin treatment prevent anemia of prematurity? Results of a randomized controlled study. Pediatr Res 34:675, 1993 Meyer MP, Meyer JH, Commerford A, et al: Recombinant human erythropoietin in the treatment of the anemia of prematurity: Results of a double-blind, placebocontrolled study. Pediatrics 93:918, 1994 Maier P.F, Obladen M, Scigalla P, et al: The effect of epoetin beta (recombinant human erythropoiefin) on the need for transfusion in very-low-birth-weight infants. N EnglJ Med 330:1173, 1994 Ronnestad A, Moe PJ, Breivik N: Enhancement of erythropoiesis be erythropoiefin, bovine protein and energy fortified mother's milk during anaemia of prematurity. Acta Paediatr 83:809, 1994 Ohls RK, Osborne KA, Christensen RD: Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: A randomized placebo-controlled trial.J Pediatr 126:421, 1995 Soubasi V, Kremenopoulos G, Diamanti E, et al: Followup of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. J Pediatr 127:291, 1995 Chen J-Y, Wu T-S, Chanlai S-P: Recombinant human erythropoietin in the treatment of anemia of prematurity. Am J Perinatol 12:314, 1995 Shannon KM, KeithJF, III, Mentzer WC, et al: Recombinant human erythropoiefin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 95:1, 1995 Bader D, Blondheim O,Jonas R, et al: Decreased ferritin levels, despite iron supplementation, during erythropoiefin therapy in anaemia of prematurity. Acta Paediatr 85:496, 1996 MesserJ, HaddadJ, Donato L, et al: Early treatment of premature infants with recombinant human erythropoietin. Pediatr 92:519, 1993 Brown MS, Berman ER, Luckey D: Prediction of the
Role of Eothropoietin in Anemia
43.
44.
45.
46.
need for transfusion during anemia of prematurity. J Pediatr 116:773, 1990 Liu EA, Mannino FL, Lane TA: Prospective, randomized trial of the safety and efficacy of a limited donor exposure transfusion program for premature neonates.J Pediatr 125:92, 1994 Lee DA, Siagle TA, Jackson TM, et al: Reducing blood donor exposures in low birth weight infants by the use of older, unwashed packed red blood cells. J Pediatr 126:280, 1995 Ohls RK, Hunter DD, Christensen RD: A randomized, double-blind placebo-controlled trial of recombinant erythropoietin in treatment of the anemia of bronchopulmonary dysplasia. J Pediatr 123:996, 1993 Bard H, WidnessJA: Effect of recombinant human eryth-
47.
48.
49.
50.
27
ropoietin on the switchover from fetal to adult hemoglobin synthesis in preterm infants.J Pediatr 127:478, 1995 Schreiber GB, Busch MB, Kleinman SH, et al: The risk of transfusion-transmitted viral infections. N Engl J Med 334:1685, 1996 Scaradavou A, Inglis S, Peterson P, et al: Suppression of erythropoiesis by intrauterine transfusions in hemolytic disease of the newborn: Use of erythropoietin to treat the late anemia. J Pediatr 123:279, 1993 Bany-Mohammed FM, Slivka S, Hallman M: Recombinant human erythropoietin: Possible role as an antioxidant in premature rabbits. Pediatr Res 40:381, 1996 Li Y, Juui SE, Morris-Wiman JA, et al: Erythropoietin receptors are expressed in the central nervous system of mid-trimester h u m a n fetuses. Pediatr Res 40:376, 1996