PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Pediatr. Author manuscript; available in PMC Mar 1, 2011.
Published in final edited form as:
PMCID: PMC2827634
NIHMSID: NIHMS161841
In utero Iron Status and Auditory Neural Maturation in Premature Infants as Evaluated by Auditory Brainstem Response
Sanjiv B. Amin, MD,# Mark Orlando, PhD,* Ann Eddins, PhD,* Matthew MacDonald, AuD,* Christy Monczynski, AuD,* and Hongye Wang, Ph.D**
# Department of Pediatrics, Division of Neonatology, The University of Rochester School of Medicine and Dentistry
* Department of Otolaryngology and Department of Audiology, The University of Rochester School of Medicine and Dentistry
** Department of Biostatistics, The University of Rochester School of Medicine and Dentistry
Corresponding Author: Sanjiv B Amin, MD, MS, Department of Pediatrics, PO Box 651, 601 Elmwood Avenue, Rochester, NY -14642, Tel: 585-275-2972, Fax: 585-461-3614, Sanjiv_Amin/at/urmc.rochester.edu
Edited by AJ and WFB
Objective
To determine if cord ferritin (CF) concentration, an index of in utero iron status, is associated with auditory neural maturation in premature infants.
Study design
A prospective cohort study was performed to compare auditory neural maturation between infants with latent iron deficiency (CF 11–75 ng/ml) and infants with normal iron status (CF > 75 ng/ml) at birth. Our inclusion criteria were 27–33 weeks gestational age infants admitted to the Neonatal Intensive Care Unit between July, 2007 and November, 2008 within 12 hours after birth and had cord blood collected. Infants with TORCH infections, chromosomal disorders, cranio-facial anomalies, culture proven sepsis, and/or unstable conditions were excluded. CF concentrations were measured using a chemiluminescence immuno-assay method. Bilateral monaural auditory brainstem evoked responses (ABR) were performed using 80 dB nHL click stimuli at a repetition rate of 29.9/sec within 48 hours after birth.
Results
Of 80 infants studied, 35 infants had latent iron deficiency. After controlling for confounders, infants with latent iron deficiency had significantly prolonged absolute wave latencies I, III, and V and decreased frequency of mature ABR waveform compared with infants with normal iron status.
Conclusion
Premature infants with in utero latent iron deficiency have abnormal auditory neural maturation compared with infants with normal in utero iron status.
Keywords: Auditory brainstem evoked response, latent iron deficiency, cord ferritin, brain development
Iron is crucial for fetal brain development and substantial iron accretion occurs during the last trimester of pregnancy.(15) Although there is active transport of iron across the placenta, several clinical conditions are known to negatively affect fetal iron status including severe maternal iron deficiency, intrauterine growth restriction, pregnancy-induced hypertension, maternal smoking, and maternal diabetes mellitus.(1, 2, 612) Iron deficiency during the critical period of brain development affects multiple developmental processes including myelination, dendritic growth, synaptic function, monoamine metabolism, and energy metabolism.(4, 7, 13, 14)
Cord ferritin (CF) concentration, a measure of tissue iron stores, is currently considered the best indicator of in utero fetal iron status, and remains the most widely used measure of iron status for neonatal outcome studies. (1517) Neonatal observational studies suggest that latent or brain iron deficiency during in utero life as evaluated by CF concentration is associated with long-term adverse effects on the developing brain in near-term and term infants. (16, 17) However, no data exist regarding acute concomitant effects of in utero latent iron deficiency on the developing brain in premature infants.
Auditory brainstem evoked response (ABR) is a non-invasive neurophysiologic assessment of auditory neural maturation, a surrogate outcome for brain maturation, in premature infants.(5, 18, 19) The ABR waveform in term neonates is comprised of 3 waves (I, III, and V). (19) Wave I is generated peripherally in the auditory nerve.(20) Wave III reflects the firing of axons exiting the cochlear nuclear complex in the brainstem, and wave V primarily reflects an action potential generated by axons from the lateral leminiscus at a more rostral brainstem location.(20) There is a rapid maturation of the ABR during the perinatal period that is influenced by the degree of myelination, neuronal development, synaptic function, and axonal growth in the auditory nervous system.(19, 21) With increasing gestational age (GA), maturation of the ABR waveform is characterized by improving detectability of the response peaks and shortening of the absolute wave latencies.(19) The decrease in wave I latency reflects the maturation of the auditory pathway at auditory nerve level, and the decreases in waves III & V latencies reflect the maturation of the auditory pathway at the brainstem level.(20) Since waves I, III, & V are not always detectable in premature infants ≤ 33 weeks GA, the ABR waveform can also be categorized as a Response Type based on the replicability of the response and the presence of wave III or wave V.(19) The Response Type also demonstrates progressive maturation with increasing GA.(19) Therefore, categorization of the ABR waveform provides a useful approach and has been previously used to evaluate effects of perinatal factors on auditory neural maturation in extremely premature infants. (18, 22) ABR has also been previously used to study effects of iron deficiency anemia in infants more than 6 months old. (23) This study seeks to determine if in utero iron status influences auditory neural maturation in 27–33 weeks GA infants.
A prospective cohort study comparing auditory neural maturation of premature infants with latent iron deficiency (CF 11–75 ng/ml) with premature infants with normal iron status (CF > 75 ng/ml) was conducted. We chose a cord ferrtin concentration of 75 ng/ml as a cut off level to define latent iron deficiency because this cut-off level has been used by previous studies and was shown to be associated with neurodevelopment outcomes in term and premature infants.(15, 17) Parental consent was obtained for each subject enrolled in the study. The study was approved by the Institutional Human Subject Review Board.
All infants 27–33 weeks GA at birth who were delivered and admitted to the Neonatal Intensive Care Unit (NICU) of University of Rochester Medical Center (URMC) between July, 2007 and November, 2008 were eligible for the study if cord blood was collected at the time of delivery. Infants with craniofacial anomalies, chromosomal disorders, TORCH infections (toxoplasmosis, other infections, rubella, cytomegalovirus infection and herpes simplex), culture proven sepsis, or those who were too clinically unstable for ABR testing between 24–48 hours after birth were excluded.
GA was assessed by obstetrical dating criteria, or when obstetrical data was inadequate, by Ballard exam. Data were prospectively collected on demographics, maternal diabetes, pregnancy induced hypertension, chorioamnionitis, in utero exposure to cocaine and other illicit drugs, use of antenatal magnesium sulfate, antenatal steroid exposure, mode of delivery, 5 minute Apgar ≤ 3, respiratory distress syndrome, and total serum bilirubin concentrations prior to ABR testing.
Exposure Variable - CF Measurements
The institutional policy is to collect cord blood on all newborn infants delivered at the URMC for evaluation of infants’ blood group. The cord blood collected in a red top tube is routinely stored at 4°C in a refrigerator by the institutional blood bank for two weeks. Soon after obtaining the consent for the study, the cord blood on each subject was transferred from the blood bank to the adjacent clinical chemistry laboratory for immediate measurement of serum ferritin concentrations using the chemiluminescence immunoassay method.
Outcome Variable - Auditory Brainstem Evoked Response
ABRs were recorded with a Biologic Navigator Evoked Response System with the subjects lying supine in the isolette and skin temperture > 35.5°C. Testing was performed by audiologists skilled in the administration of ABR tests to NICU infants. Electrode sites were mastoid (reference), midline on high forehead or crown of the head (active), and shoulder (ground). Electrode gel was applied to silver/silver chloride electrodes. Bilateral monaural ABR tests were performed between 24 and 48 hours after birth using 80 dB nHL broadband click stimuli with insert earphones. The clicks were presented at a repetition rate of 29.9/sec, and three runs of 2000 repetitions were recorded for each ear. The 2 most replicable runs for each ear were averaged and used for analysis. The ABRs were analyzed by the audiologists without knowledge of GA or CF concentrations. The ABR findings from the better ear in each subject were used for the final analyses of absolute latencies.
In addition, typmanometry using a 1000 Hz probe was performed in each subject to rule out middle ear disease. Transient otoacoustic emission tests were performed to rule out outer hair cell dysfunction.
Since ABR waves I, III, and V cannot be detected in all premature infants ≤ 33 weeks GA, ABR waveforms were categorized into Response Types based on response replicability and peak identification: Type 1, a waveform with normal morphology and replicable waves III and V (mature response type); Type 2, a replicable response with either a wave III or V; Type 3, a replicable response with neither a wave III or V; Type 4, a waveform with no replicable response.(19) The categories from Type 4 to Type 1 are in order from immature to mature ABR waveform. If the waveform was Type 1 or Type 2, latencies for waves I, III, & V were measured. If the Response Type was 1 in both ears, it was considered a mature ABR Response Type for that particular subject.
Statistical Analyses
Analyses were performed using SAS (version 9.1, SAS Institute Inc, Cary, NC). The subjects with latent iron deficiency and those with normal iron status were compared using 2-sample t-tests for continuous variables and the Chi-square or Fisher’s exact test as appropriate for categorical variables. Repeated measure analysis using linear mixed model was carried out to test the difference in better ear absolute latencies between latent iron deficiency and normal iron status groups, with I, III, and V absolute latencies as multiple outcomes for each subject. Variables associated with iron status or auditory maturation on bivariate analysis (p < 0.1) were considered potential confounders and included in regression analysis. Unstructured variance covariance matrix was specified. The significance level of the data analysis was set at 0.05.
A total of 153 infants, 27–33 weeks GA, were born and admitted to the NICU at URMC between July 2007 and November 2008. Of these, 13 infants were excluded (4 infants died within 24 hours after birth, 7 were unstable, 1 infant had chromosomal syndrome and 1 infant had craniofacial anomaly). Of remaining 140 infants, 108 infants had cord blood collected soon after delivery. Of these 108 infants, 80 consented and were enrolled. The mean GA of infants who did not consent was 29.2 weeks and was not different from those who consented. Thirty five (44%) infants were categorized to have in utero latent iron deficiency (CF concentration 11–75 ng/ml, mean 42 ng/ml, median 41ng/ml) and 45 premature infants had normal in utero iron statuts (CF concentration > 75 ng/ml, mean 164 ng/ml, median 118 ng/ml). Mothers of all enrolled subjects had good prenatal care and only two were diagnosed with iron deficiency anemia during pregnancy. Each subject had a hematocrit > 35 at birth and none were anemic before ABR evaluation. None of the subjects had hypoglycemia prior to ABR evaluation. None of the subjects were diagnosed with hypothyroidism during the neonatal period. The characteristics of study patients as a function of in utero iron status are shown in Table I. There were no significant differences between the two groups in demographic and perinatal factors except for cesarean section, maternal history of diabetes, and unconjugated hyperbilirubinemia.
Table 1
Table 1
Characteristics of Study Population as a Function of In Utero Iron Status
Wave Latencies
None of the study subjects had an abnormal oto-acoustic emision test or tympanometry. The stratified analysis for the effect of iron status on each of the absolute latencies are provided in Table II. Infants with latent iron deficiency had significantly prolonged absolute latencies III and V (using better ear for each infant) compared with infants with normal iron status (Table II). There was a non-significant trend for absolute latency I to be prolonged in infants with latent iron deficiency compared with infants with normal iron status. By fitting linear mixed effects model with better ear absolute latencies I, III, and V as multiple responses for each subject, infants with latent iron deficiency had significantly prolonged absolute latencies I, III, and V as compared with infants with normal iron status after controlling for cesarean section, maternal diabetes, and total serum bilirubin concentration (p = 0.01).
Table 2
Table 2
Absolute Latencies and Mature ABR Response Type as a Function of In Utero Iron Status
ABR Response Types
Infants with normal iron status had a trend for a higher frequency of mature ABR Response Type compared with infants with latent iron deficiency as shown in Table II (p = 0.08). Among infants with normal iron status, 35% of infants had a complete ABR waveform (all three absolute waves present), and only 14% of infants with latent iron deficiency had a complete ABR waveform (p = 0.2).
Iron deficiency is the most common nutrient deficiency in the world.(24) Although ample evidence exists from animal studies regarding the role of iron for fetal and neonatal brain development, little human data exists regarding in utero iron status and its concomitant effect on brain development.(35, 14) Our findings suggest that CF concentration, an index measurement for in utero iron status, is associated with auditory neural maturation when evaluated by ABR soon after birth in premature infants.
Progressive development is seen in the fetal auditory nervous system during the last trimester of pregnancy and iron is an essential nutrient for this critical development of the nervous system.(4, 21) ABR has been used as a non-invasive tool to assess auditory neural maturation in premature infants as a function of enteral feedings, taurine supplementation, hypothyroxinemia, and antenatal steroid exposure.(18, 22, 2527) By evaluating the wave latencies, which are influenced by the degree of myelination, axonal growth, dendritic growth, and synaptic function, inferences can be made about the possible effects of iron status on auditory neural maturation, a surrogate outcome for brain maturation.
Several previous observational studies in infants and older children have used ABR to evaluate the effect of iron deficiency anemia on brain development.(23, 2832) Although these studies demonstrated an association between ABR changes and iron status, they involved older infants with iron deficiency anemia which is a late manifestation of iron deficiency. Therefore, these studies also failed to answer the question whether iron deficiency without anemia causes neurological impairment. The ABR changes were irreversible despite correction of iron status and anemia with iron therapy.(28) Several studies have demonstrated that brain and other tissues are depleted long before red blood cells are depleted and, therefore, early identification and treatment of iron deficiency before anemia develops may be essential.(9, 11, 16)
Compared with studies in older children which evaluated specific neurodevelopmental process such as myelination using interpeak latencies, our study was aimed to evaluate auditory neural maturation. Most premature infants < 33 weeks GA do not have a complete ABR waveform with all three absolute wave latencies necessary for measuring interpeak latencies, a surrogate marker of myelination. In our study group, more infants with latent iron deficiency had immature ABR waveform compared with infants with normal iron status. Our findings strongly suggest that iron status in the absence of anemia influences auditory neural maturation at both auditory nerve (wave I latency) and brainstem level (wave III and V) and infants with latent iron deficiency have abnormal auditory neural maturation compared with infants with normal iron status.
Some of the perinatal factors such as preeclampsia may be associated with accelerated auditory neural maturation, and hyperbilirubinemia may be associated with transient ABR changes including prolongation of wave latencies.(33, 34) Most studies have reported no significant changes in auditory neural maturation among small for GA infants compared with appropriate for GA infants.(35, 36) Despite the fact that more infants with latent iron deficiency were born to mothers with pre-eclampsia and had lesser degree of hyperbilirubinemia, we found that absolute latencies were prolonged in infants with latent iron deficiency compared with infants with normal iron status.
There is growing evidence from observational studies that latent iron deficiency during the fetal and neonatal period may be associated with acute and long-lasting detrimental effects on neurodevelopment.(1517) Tamura et al reported that late preterm and term infants born with CF < 76 ng/ml had poorer performance in fine motor skills and language development at 5 years of age than those with CF ≥ 76 ng/ml, (17) In another study involving term infants of diabetic mothers, infants with CF ≤ 34 ng/ml had poorer auditory recognition memory as newborns and lower psychomotor developmental scores at 1 year of age than term infants of diabetic mothers with CF > 34 ng/ml.(16) In the only study involving premature infants < 34 weeks GA, serum ferritin concentration < 75 ng/ml was associated with abnormal neurobehavioral status at 37 weeks post-menstrual age.(15) Our findings that in utero iron status strongly influences auditory neural maturation are consistent with the findings of Tamura et al and Sidappa et al.(16, 17) Our study differs from previous studies in two ways. Our study population was different and involved more premature infants. Secondly, we measured concomitant effects of latent iron deficiency on brain maturation using ABR. Further meaningful analysis of our ABR data using a CF < 35 ng/ml as reported by Sidappa et al was not possible as there were only 3 subjects with CF < 35 ng/ml and measurable absolute latencies in our study group.
The major strength of our study is the objective assessment of an ABR outcome after confirming absence of middle ear disease and outer hair cell dysfunction. Moreover, Response Type assignments were done by audiologists without knowledge of the infants’ CF concentrations. Because our study was limited to 27 to 33 weeks GA infants, our findings may not be generalizable to premature infants > 33 weeks GA. Our findings suggest that ABRs may be a surrogate outcome marker that can be used to assess the potential effect of iron status on brain maturation during the critical period of brain development.
In summary, our findings suggest that iron status influences auditory neural maturation in premature infants. The little evidence currently available suggests that the effect of iron deficiency on neurodevelopment may be long-lasting.(16, 17, 3739) Latent iron deficiency is very common among premature infants, and if the subtle neurodevelopmental changes secondary to latent iron deficiency in the neonatal period lay the foundation for abnormal long-term cognitive, motor, language, and behavioral functioning, then a large unrecognized population of premature infants could be at risk as a consequence of an easily treatable nutritional deficiency.(16, 17, 40, 41) Therefore, there is an urgent need to determine if there is a causal relationship between latent iron deficiency and abnormal brain development. To establish a causal relationship, a well designed randomized clinical trial is warranted in high- risk premature infants using an objective test such as the ABR. A similar trial during pregnancy, although feasible, will be technically difficult to conduct without knowledge of at-risk fetuses.
Acknowledgments
We are grateful to Erica Burnell, research coordinator, for data collection.
Supported by NIH K-23 DC 006229-04 and GCRC UL RR 024160 grants. The abstract was presented at the 2009 PAS Meeting in Baltimore. The authors declare no conflicts of interest.
Abbreviations
GAgestational age
ABRauditory brainstem evoked response
NICUneonatal intensive care unit
CFCord Ferritin
URMCUniversity of Rochester Medical Center

Footnotes
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1. Rao R, Georgieff MK. Perinatal aspects of iron metabolism. Acta Paediatr Suppl. 2002;91:124–9. [PubMed]
2. Rao R, Georgieff MK. Neonatal iron nutrition. Semin Neonatol. 2001;6:425–35. [PubMed]
3. Lozoff B. Perinatal iron deficiency and the developing brain. Pediatr Res. 2000;48:137–9. [PubMed]
4. Georgieff MK, Innis SM. Controversial nutrients that potentially affect preterm neurodevelopment: essential fatty acids and iron. Pediatr Res. 2005;57:99R–103R. [PubMed]
5. Georgieff MK. Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr. 2007;85:614S–20S. [PubMed]
6. Chockalingam UM, Murphy E, Ophoven JC, Weisdorf SA, Georgieff MK. Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia. J Pediatr. 1987;111:283–6. [PubMed]
7. Rao R, Georgieff MK. Iron in fetal and neonatal nutrition. Semin Fetal Neonatal Med. 2007;12:54–63. [PMC free article] [PubMed]
8. Georgieff MK, Petry CD, Wobken JD, Oyer CE. Liver and brain iron deficiency in newborn infants with bilateral renal agenesis (Potter’s syndrome) Pediatr Pathol Lab Med. 1996;16:509–19. [PubMed]
9. Georgieff MK, Landon MB, Mills MM, Hedlund BE, Faassen AE, Schmidt RL, et al. Abnormal iron distribution in infants of diabetic mothers: spectrum and maternal antecedents. J Pediatr. 1990;117:455–61. [PubMed]
10. Georgieff MK, MMMI, Gordon K, Wobken JD. Reduced neonatal liver iron concentrations after uteroplacental insufficiency. J Pediatr. 1995;127:308–4. [PubMed]
11. Petry CD, Eaton MA, Wobken JD, Mills MM, Johnson DE, Georgieff MK. Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. J Pediatr. 1992;121:109–14. [PubMed]
12. Chelchowska M, Laskowska-Klita T. Effect of maternal smoking on some markers of iron status in umbilical cord blood. Rocz Akad Med Bialymst. 2002;47:235–40. [PubMed]
13. de Deungria M, Rao R, Wobken JD, Luciana M, Nelson CA, Georgieff MK. Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain. Pediatr Res. 2000;48:169–76. [PubMed]
14. Beard J. Recent evidence from human and animal studies regarding iron status and infant development. J Nutr. 2007;137:524S–30S. [PubMed]
15. Armony-Sivan R, Eidelman AI, Lanir A, Sredni D, Yehuda S. Iron status and neurobehavioral development of premature infants. J Perinatol. 2004;24:757–62. [PubMed]
16. Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, Deregnier RA. Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers. Pediatr Res. 2004;55:1034–41. [PubMed]
17. Tamura T, Goldenberg RL, Hou J, Johnston KE, Cliver SP, Ramey SL, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr. 2002;140:165–70. [PubMed]
18. Amin SB, Merle KS, Orlando MS, Dalzell LE, Guillet R. Brainstem maturation in premature infants as a function of enteral feeding type. Pediatrics. 2000;106:318–22. [PubMed]
19. Amin SB, Orlando MS, Dalzell LE, Merle KS, Guillet R. Morphological changes in serial auditory brain stem responses in 24 to 32 weeks’ gestational age infants during the first week of life. Ear Hear. 1999;20:410–8. [PubMed]
20. Moller AR, Jannetta PJ, Moller MB. Neural generators of brainstem evoked potentials. Results from human intracranial recordings. Ann Otol Rhinol Laryngol. 1981;90:591–6. [PubMed]
21. Moore JK, Perazzo LM, Braun A. Time course of axonal myelination in the human brainstem auditory pathway. Hear Res. 1995;87:21–31. [PubMed]
22. Amin SB, Guillet R. Auditory neural maturation after exposure to multiple courses of antenatal betamethasone in premature infants as evaluated by auditory brainstem response. Pediatrics. 2007;119:502–8. [PubMed]
23. Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr. 1998;68:683–90. [PubMed]
24. Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47:1–29. [PubMed]
25. Tyson JE, Lasky R, Flood D, Mize C, Picone T, Paule CL. Randomized trial of taurine supplementation for infants less than or equal to 1,300-gram birth weight: effect on auditory brainstem-evoked responses. Pediatrics. 1989;83:406–15. [PubMed]
26. Amin SB, Orlando MS, Dalzell LE, Merle KS, Guillet R. Brainstem maturation after antenatal steroids exposure in premature infants as evaluated by auditory brainstem-evoked response. J Perinatol. 2003;23:307–11. [PubMed]
27. Kohelet D, Arbel E, Goldberg M, Arlazzoroff A. Transient neonatal hypothyroxinemia and the auditory brainstem evoked response. Pediatr Res. 1992;32:530–1. [PubMed]
28. Algarin C, Peirano P, Garrido M, Pizarro F, Lozoff B. Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr Res. 2003;53:217–23. [PubMed]
29. Cankaya H, Oner AF, Egeli E, Caksen H, Uner A, Akcay G. Auditory brainstem response in children with iron deficiency anemia. Acta Paediatr Taiwan. 2003;44:21–4. [PubMed]
30. Sarici SU, Serdar MA, Dundaroz MR, Unay B, Akin R, Deda G, et al. Brainstem auditory-evoked potentials in iron-deficiency anemia. Pediatr Neurol. 2001;24:205–8. [PubMed]
31. Shankar N, Tandon OP, Bandhu R, Madan N, Gomber S. Brainstem auditory evoked potential responses in iron-deficient anemic children. Indian J Physiol Pharmacol. 2000;44:297–303. [PubMed]
32. Li YY, Wang HM, Wang WG. The effect of iron deficiency anemia on the auditory brainstem response in infant. Zhonghua Yi Xue Za Zhi. 1994;74:367–9. 92. [PubMed]
33. Amin SB, Ahlfors C, Orlando MS, Dalzell LE, Merle KS, Guillet R. Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics. 2001;107:664–70. [PubMed]
34. Kim CR, Vohr BR, Oh W. Effects of maternal preeclampsia on brain-stem auditory evoked response in very low birth weight infants. J Pediatr. 1995;127:123–7. [PubMed]
35. Jiang ZD, Brosi DM, Wang J, Wilkinson AR. Brainstem auditory-evoked responses to different rates of clicks in small-for-gestational age preterm infants at term. Acta Paediatr. 2004;93:76–81. [PubMed]
36. Mahajan V, Gupta P, Tandon O, Aggarwal A. Brainstem auditory evoked responses in term small for gestational age newborn infants born to undernourished mothers. Eur J Paediatr Neurol. 2003;7:67–72. [PubMed]
37. Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med. 1991;325:687–94. [PubMed]
38. Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics. 2000;105:E51. [PubMed]
39. Felt BT, Beard JL, Schallert T, Shao J, Aldridge JW, Connor JR, et al. Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats. Behav Brain Res. 2006;171:261–70. [PMC free article] [PubMed]
40. Thom R, Parnell W, Broadbent R, Heath AL. Predicting iron status in low birthweight infants. J Paediatr Child Health. 2003;39:173–6. [PubMed]
41. Siddappa AM, Rao R, Long JD, Widness JA, Georgieff MK. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology. 2007;92:73–82. [PMC free article] [PubMed]