Published online November 1, 2004
PEDIATRICS Vol. 114 No. 5 November 2004, pp. 1287-1291 (doi:10.1542/peds.2003-1129-L)
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Neurodevelopmental Outcome and Growth at 18 to 22 Months' Corrected Age in Extremely Low Birth Weight Infants Treated With Early Erythropoietin and Iron

Robin K. Ohls, MD*, Richard A. Ehrenkranz, MD{ddagger}, Abhik Das, PhD§, Anna M. Dusick, MD||, Kimberly Yolton, MD, Elaine Romano, MSN, CPNP§, Virginia Delaney-Black, MD#, Lu-Ann Papile, MD*, Neal P. Simon, MD**, Jean J. Steichen, MD{ddagger}{ddagger}, Kimberly G. Lee, MD§§,|||| for the National Institute of Child Health and Human Development Neonatal Research Network

* Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico
{ddagger} Department of Pediatrics, Yale University, New Haven, Connecticut
§ Research Triangle Institute, Research Triangle Park, North Carolina
|| Department of Pediatrics, Indiana University, Indianapolis, Indiana
Newborn Center, University of Tennessee, Memphis, Tennessee
# Division of Neonatal and Perinatal Medicine, Wayne State University, Detroit, Michigan
** Department of Pediatrics, Emory University, Atlanta, Georgia
{ddagger}{ddagger} Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
§§ Joint Program in Neonatology, Harvard University, Boston, Massachusetts
|||| National Institute of Child Health and Human Development, Bethesda, Maryland


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background. Clinical trials evaluating the use of erythropoietin (Epo) have demonstrated a limited reduction in transfusions; however, long-term developmental follow-up data are scarce.

Objective. We compared anthropometric measurements, postdischarge events, need for transfusions, and developmental outcomes at 18 to 22 months' corrected age in extremely low birth weight (ELBW) infants treated with early Epo and supplemental iron therapy with that of placebo/control infants treated with supplemental iron alone.

Methods. The National Institute of Child Health and Human Development Neonatal Research Network completed a randomized, controlled trial of early Epo and iron therapy in preterm infants ≤1250 g. A total of 172 ELBW (≤1000-g birth weight) infants were enrolled (87 Epo and 85 placebo/control). Of the 72 Epo-treated and 70 placebo/control ELBW infants surviving to discharge, follow-up data (growth, development, rehospitalization, transfusions) at 18 to 22 months' corrected age were collected on 51 of 72 Epo-treated infants (71%) and 51 of 70 placebo/controls (73%) by certified examiners masked to the treatment group. Statistical significance was determined using {chi}2 analysis.

Results. There were no significant differences between treatment groups in weight or length or in the percentage of infants weighing <10th percentile either at the time of discharge or at follow-up, and no difference was found in the mean head circumference between groups. A similar percentage of infants in each group was rehospitalized (38% Epo and 35% placebo/control) for similar reasons. There were no differences between groups with respect to the percentage of infants with Bayley-II Mental Developmental Index <70 (34% Epo and 36% placebo/control), blindness (0% Epo and 2% placebo/control), deafness or hearing loss requiring amplification (2% Epo and 2% placebo/control), moderate to severe cerebral palsy (16% Epo and 18% placebo/control) or the percentage of infants with any of the above-described neurodevelopmental impairments (42% Epo and 44% placebo/control).

Conclusions. Treatment of ELBW infants with early Epo and iron does not significantly influence anthropometric measurements, need for rehospitalization, transfusions after discharge, or developmental outcome at 18 to 22 months' corrected age.

Key Words: erythropoietin • parenteral iron • neurodevelopment • preterm infant

Abbreviations: Epo, erythropoietin • ELBW, extremely low birth weight • NICHD, National Institute of Child Health and Human Development • CSF, cerebral spinal fluid • BPD, bronchopulmonary dysplasia • IVH, intraventricular hemorrhage • NEC, necrotizing enterocolitis • NDI, neurodevelopmental impairment • MDI, Mental Developmental Index • PDI, Psychomotor Developmental Index

We previously reported the results of a randomized, double-masked, placebo-controlled trial of early human recombinant erythropoietin (Epo) and iron treatment in infants of ≤1250 g birth weight.1 In that study, infants were randomized to Epo (400 U/kg 3 times weekly, given intravenously or subcutaneously) or placebo/control initiated by 96 hours of age and continued through the 35th postmenstrual week. Epo recipients on parenteral nutrition received supplemental parenteral iron at a dose of 5 mg/kg once a week, whereas placebo/control infants received 1 mg/kg once a week. All infants received enteral iron when tolerating 60 mL/kg per day enterally. Transfusions were administered in accordance with a conservative transfusion protocol.

Although the combination of early Epo and iron therapy stimulated erythropoiesis and was not associated with an increased incidence of neonatal morbidities or adverse events, there was a measurable but minor impact on the overall transfusion requirements of these infants. Multiple randomized, controlled trials have reported a range of similar to more significant results; thus, treatment of preterm infants with Epo varies from center to center.2–5 Limited data have been reported concerning the long-term effects of Epo therapy.6,7

We previously reported that there were no differences between groups in anthropomorphic measurements, hospital days, or neonatal morbidities. The purpose of this study was to evaluate and compare measures of morbidity, including neurodevelopmental and anthropometric outcomes and the number of rehospitalizations at 18 to 22 months' corrected age, in the extremely low birth weight (ELBW) (≤1000-g) infant survivors who participated in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network Epo trial. We therefore hypothesized that there would be no difference in neurodevelopmental outcome evaluated at 18 to 22 months' corrected age between treated and placebo/control infants. We also hypothesized that because Epo-treated infants had higher hematocrit levels, fewer Epo-treated infants would be <10th percentile for the corresponding intrauterine birth weight-postmenstrual age and that Epo-treated infants would achieve greater catch-up growth by 18 to 22 months' corrected age than placebo/control infants. Finally, we hypothesized that because both groups of infants were discharged with adequate hematocrits and endogenous Epo production is not suppressed by Epo treatment,6 there would be no difference between Epo-treated and placebo/control infants in the number of postdischarge blood transfusions or rehospitalizations.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Enrolled in the NICHD Neonatal Research Network Trial (see Appendix) between August 1997 and March 1998 were 172 ELBW infants. Eighty-seven infants were randomized to the Epo-treatment group and 85 to the placebo/control group. Epo-treated infants received an average of 23 ± 10 doses of Epo administered over an 8- to 10-week period, of which 53% were administered intravenously. Epo-treated infants also received an average of 2 ± 1 parenteral iron doses (5 mg/kg) weekly, whereas infants in the placebo group received an average of 2 ± 1 parenteral iron doses (1 mg/kg) weekly. Fifteen infants in each group expired before discharge. Of those surviving to discharge, 51 of 72 (71%) of the Epo-treated and 51 of 70 (73%) of the placebo/control infants were evaluated at 18 to 22 months' corrected age in the NICHD Neonatal Research Network ELBW follow-up program.


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  		APPENDIX NICHD Neonatal Research Network Early Epo Therapy Study

 
Discharge data were collected on all surviving study participants. Data reported are a subset of those previously presented.1 The percentage of infants with discharge weight <10th percentile based on Alexander's reference intrauterine growth curves was determined.8 Information on neonatal morbidities was collected and included incidence of late-onset sepsis (a positive blood or cerebral spinal fluid [CSF] culture obtained in the presence of compatible signs of septicemia after 72 hours of age or culture-negative clinical infection after 72 hours of age for which the infant received antibiotics for ≥5 days), bronchopulmonary dysplasia (BPD) (oxygen administration at 36 weeks' postmenstrual age), retinopathy of prematurity (stage 3 or higher9), severe intraventricular hemorrhage (IVH, grades 3 and 410), and necrotizing enterocolitis (NEC, Bell's stage II or higher11).

Assessments were performed by certified examiners masked to the infant's treatment group and included a standardized neurologic examination, an evaluation using the Bayley Scales of Infant Development-II Revised, structured parent interviews about medical and social history, and functional performance and anthropometric measurements. Information about medical history included incidence and reason for rehospitalizations and number of erythrocyte transfusions administered.

Hearing information was obtained from parental report supplemented with the results of audiologic evaluations when available. Deafness was defined as hearing disability requiring amplification. Vision status and information from any postdischarge ophthalmologic examinations were obtained from the parent and supplemented by information from the medical record. A standard eye examination was performed to evaluate tracking, nystagmus, and roving eye movements. Blindness was defined as no functional vision in both eyes. The overall outcome of survival with neurodevelopmental impairment (NDI) was defined as survival to 18 to 22 months' corrected age with ≥1 of the following: Mental Developmental Index (MDI) < 70, Psychomotor Developmental Index (PDI) < 70, moderate or severe cerebral palsy, blindness, or deafness.

Comparisons were made between the Epo and placebo/control groups using {chi}2 or Fisher's exact tests for categorical variables and t tests for continuous variables. Statistical significance was defined as a P value < .05. Institutional review board approval and informed consent were obtained at each of the participating centers.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
All surviving infants seen at 18 to 22 months' corrected age were included in analysis. There were no differences in anthropometric measurements during hospitalization or in outcome characteristics between treatment groups at the time of discharge, and except for the incidence of BPD and discharge length, there were no differences in those parameters between the infants seen at 18 to 22 months' corrected age compared with those not seen (Table 1). The incidence of BPD was higher in the infants seen at follow-up, especially in the Epo group, compared with those infants not seen, and the discharge length of the Epo-treated infants seen at follow-up was significantly greater than for the Epo-treated infants who were not seen. There were 15 deaths in each group before 120 days. The causes of death were similar between the Epo (respiratory distress/chronic lung disease, 3; sepsis/NEC, 8; severe IVH, 1; other, 3) and placebo/control (respiratory distress/chronic lung disease, 4; sepsis/NEC, 6; severe IVH, 1; other, 4) groups.1 An additional 2 infants in the placebo/control group expired between 120 days of age and the 18- to 22-month follow-up examination.


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  		TABLE 1. Characteristics of NICHD Epo Study Survivors

 
With the exception of the percentage of infants with head circumference <10th percentile being lower in the Epo group, there were no significant differences in anthropometric measurements at 18 to 22 months' corrected age (Table 2). The percentage of infants with head circumference <10th percentile at the time of follow-up was 15% in the Epo group and 34% in placebo/controls (P < .05); however, there was no difference in the mean head circumference between groups.


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  		TABLE 2. Growth at 18 to 22 Months' Corrected Age Follow-up

 
The incidence of NDIs at 18 to 22 months' corrected age in the treatment groups is listed in Table 3. There were no differences between groups with respect to the percentage of infants with MDI < 70 (34% Epo and 36% placebo/control), blindness (0% Epo and 2% placebo/control), deafness or hearing loss requiring amplification (2% Epo and 2% placebo/control), or the percentage of infants with any of the above-mentioned NDIs (42% Epo and 44% placebo/control). Fourteen infants in the Epo group had a PDI < 70 compared with 6 infants in the placebo/control group (P < .05). Despite this finding, there was no difference in the mean PDI scores between groups, and the percentage of infants with moderate to severe cerebral palsy as determined by functional motor assessment was the same in both groups (16% Epo and 18% placebo/control).


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  		TABLE 3. Neurodevelopmental Outcomes at 18 to 22 Months' Corrected Age

 
There were no significant differences between groups with respect to need for rehospitalization (Table 4). The reasons for rehospitalization did not differ between groups. None of the infants in the study received a transfusion after discharge. No postdischarge adverse events related to Epo or iron therapy were reported in either group.


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  		TABLE 4. Postdischarge Events

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Numerous preterm infants have been involved in studies evaluating Epo administration; however, follow-up has been limited. This study evaluated the largest population to date of Epo-treated infants followed for neurodevelopmental and anthropometric parameters. In a smaller study, Newton et al7 evaluated neurodevelopmental outcome in 40 infants who had participated in 1 of 3 randomized studies at the University of California, San Francisco, and found no difference in developmental outcomes between the 20 Epo-treated infants and the 20 controls. They excluded infants with grade III or IV IVH or periventricular leukomalacia, and only 12 of the 20 Epo-treated infants received therapeutic doses.

In our study population, anthropometric measurements and neurodevelopmental outcomes at 18 to 22 months' corrected age were similar in all but 2 aspects. For Epo recipients, a greater percentage had a PDI < 70, whereas a greater percentage of placebo/control infants had a head circumference <10th percentile. However, there were no statistically significant differences in mean head circumference or mean PDI scores between the Epo and placebo/control groups nor any difference in the incidence of significant cerebral palsy or MDI < 70. The group with a greater percentage of head circumference <10th percentile did not have a greater percentage of infants with PDI < 70. Because it is unlikely that these differences are clinically significant, we conclude that, overall, the treatment of ELBW infants with early Epo and iron did not significantly influence anthropometric measurements or neurodevelopmental outcomes at 18 to 22 months' corrected age. A prospectively designed study with a larger sample size would be required to determine the significance of some of the small differences observed in our study.

A limitation of this study was the fact that only 70% of study survivors were evaluated at 18 to 22 months' corrected age. Follow-up investigators generally sought to assess at least 80% of the potential study population to ensure that findings are generalizable, not affected by acquisition bias, and not prone to type I or II errors. Although 5-year or school-age evaluations would provide valuable information about new therapies given to preterm neonates such as Epo, these assessments are often unfeasible because they require costly long-term tracking and interim assessments. In addition, the assessment results are strongly influenced by the family's socioeconomic status.12

Hematopoietic follow-up of infants receiving Epo has also been limited. Soubasi et al6 looked at red cell indices after 6 and 12 months in preterm infants receiving Epo and observed no differences in onset of endogenous erythropoiesis between Epo-treated and control infants. In our study, none of the infants received transfusions after discharge. Reports of red cell aplasia in adults receiving Epo have occurred in the last 2 years.13 This rare side effect has not been reported in any preterm infant receiving Epo; however, the development of anti-Epo antibodies has not been tested specifically in a neonatal population. Moreover, although the development of vascular malformations has been linked to the use of Epo in 2 neonates,14 this was not seen in our patients. The creation of Epo registries might assist in tracking side effects in infants over a 2- to 5-year period.

Research during the past several years has demonstrated that in addition to hematopoietic properties, Epo plays a developmental role in angiogenesis and in neurogenesis.15,16 Epo and Epo receptors are present in nonhematopoietic developing neural tissue in animals and humans.17–19 Similar to its action in erythropoiesis, Epo binds to its receptor in nonhematopoietic tissues, activating cellular mechanisms that include cell maturation, division, and inhibition of apoptosis.18,20 Studies evaluating Epo in adult and neonatal animal models report the prevention of hypoxic-ischemic brain injury, a decrease in infarction volume, reduced vasoconstriction, decreased neuronal apoptosis, and decreased neurologic deterioration in animals treated with high doses of Epo.21–25

In animal models, Epo administered intraperitoneally results in CSF concentrations that are 5% to 10% of serum concentrations. Recent animal studies evaluating the use of Epo to reduce hypoxic-ischemic injury evaluated doses of Epo of 1000 to 5000 U/kg, resulting in CSF concentrations between 10 and 20 mU/mL.23 In humans, CSF Epo concentrations are <1% of those found in serum.26 Therefore, it is not likely that Epo administered at lower doses to neonates would produce direct central nervous system effects. Our findings that Epo did not influence neurodevelopmental outcome at 18 to 22 months' corrected age are consistent with this result.

Iron deficiency in the fetus and neonate can also affect later neurodevelopment, including loss of memory and attention deficits.27–29 The inclusion of parenteral supplemental iron in our study did not seem to affect neurodevelopment, because similar rates of NDI have been previously reported in NICHD Neonatal Research Network follow-up studies of ELBW infants.30 Differences were not expected between groups in this study based on iron supplementation, because ferritin concentrations were adequate in both groups at the end of the study.1 Although iron stores were likely enhanced in infants enrolled in the study, the study was not powered to detect differences in outcome based on iron stores. Additional evaluation is required to determine the impact of sufficient iron supplementation on neurodevelopmental outcome in ELBW infants.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Early Epo and iron therapy did not affect anthropometric measurements or neurodevelopment. Anthropometric measurements at hospital discharge and at 18 to 22 months' corrected age were similar between the study groups. In addition, early Epo and iron therapy did not seem to influence the need for late transfusions or for hospitalization after newborn intensive care unit discharge. We conclude that treatment of ELBW infants with early Epo and iron does not significantly influence anthropometric measurements or developmental outcome at 18 to 22 months' corrected age.


   ACKNOWLEDGMENTS
 
This work was supported by a grant from the National Institutes of Health, National Institute of Child Health and Human Development, through cooperative agreements with the authors' institutions: U10 HD27881 (R.K.O. and L.-A.P.), U10 HD27871 (R.A.E. and E.R.), U01 HD36790 (A.D.), U10 HD27856 (A.M.D.), U10 HD21415 (K.Y.), U10 HD21385 (V.D.-B.), U10 HD27851 (N.P.S.), U10 HD27853 (J.J.S.), and U10 HD34167 (K.G.L.) and General Clinical Research Centers M01 RR 00997 (R.K.O. and L.-A.P.), M01 RR 06022 (R.A.E. and E.R.), M01 RR 00750 (A.M.D.), M01 RR 08084 (J.J.S.), and M01 RR02635, M01 RR 02172, and M01 RR 01032 (K.G.L.).

We acknowledge Charlotte Gard for assistance in statistical analysis and Carolyn Petrie for administrative assistance.


   FOOTNOTES
 
Accepted Apr 28, 2004.

Address correspondence to Robin K. Ohls, MD, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131. E-mail: rohls{at}unm.edu


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics



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