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Association between iron status and neurodevelopmental outcomes among VLBW infants
Brain & Development 32 (2010) 849–854 www.elsevier.com/locate/braindev
Original article
Association between iron status and neurodevelopmental outcomes among VLBW infants Noriko Kon, Kyoko Tanaka *, Mariko Sekigawa, Yoshie Negishi, Naomi Yoshikawa, Ken Hisata, Hiromichi Shoji, Toshiaki Shimizu Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan Received 6 July 2009; received in revised form 24 November 2009; accepted 14 December 2009
Abstract Objective: Our purpose was to evaluate iron status and neurodevelopmental outcomes in infants with and without extrauterine growth restriction (EUGR). Methods: This observational study evaluated 38 medically stable premature infants, with birth weights below 1500 g. Iron status was determined by measuring venous levels of Hb, Fe, and serum ferritin. The infants were divided into EUGR and non-EUGR groups. At a corrected age of 18 months, neurodevelopmental outcomes were checked using the Bayley scales, and body weight, body length, and head circumference were measured. Results: Hb levels at corrected ages of 1 and 3 months and iron at a corrected age of 1 and 9 months were significantly lower in the EUGR group compared with those of the non-EUGR group. There was no significant difference in the MDI score between the groups, but the PDI score at a corrected age of 18 months was significantly lower in the EUGR group. We found a positive correlation between the serum level of Fe at 1 month of age and PDI score at 18 months of age. Head circumference at a corrected age of 18 months did not differ between two groups, although body weight and length were lower in the EUGR group. Conclusions: Developmental outcome in preterm infants at a corrected age of 18 months may be influenced by nutritional factors, including iron status, during their early life. Ó 2010 Published by Elsevier B.V. Keywords: Iron supplementation; Extrauterine growth restriction; Neurodevelopment outcome; Low birth weight infants; Preterm infants
1. Introduction It is well known that iron deficiency affects neurodevelopment in infants [1–3]. Neuronal metabolism, neurotransmitter function, and myelination are influenced by iron deficiency, which has greatest impact on the brain during early neurodevelopment [4,5]. A correlation has been reported between iron deficiency and psychomotor disorder in infancy and early childhood [6]. Recently, it was reported that infants with iron deficiency anemia at 6 months of age had less mature auditory brainstem * Corresponding author. Address: Department of Pediatrics, Juntendo University, School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel.: +81 3 3813 3111; fax: +81 3 5800 0216. E-mail address: [email protected] (K. Tanaka).
0387-7604/$ - see front matter Ó 2010 Published by Elsevier B.V. doi:10.1016/j.braindev.2009.12.003
responses, particularly evidenced by longer central conduction times than in control infants; this was suggested to be due to impaired myelination caused by iron deficiency [3]. In addition, after iron therapy in infants with iron deficiency anemia, visual evoked potentials and nerve conduction velocities were improved [7,8]. However, other reports have suggested that iron therapy did not produce improvements [7,9–12]. Therefore, the effects of iron supplementation remain unclear. Based on the guidelines proposed at the Neonatal Nutrition Forum in 2003, newborn preterm infants in Japan are given iron supplementation (Table 1) [13]. These guidelines are intended to increase the level of iron storage in preterm infants, as a group at high risk for iron deficiency, to a level approximating that of full-term infants during the period of hospitalization in the neona-
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tal intensive care unit (NICU). Recently, it was reported that extrauterine growth restriction (EUGR) of low birth weight infants is also associated with delayed mental, motor, and cognitive development in childhood [14]. The objective of the present study was to evaluate the levels of hemoglobin, Fe, and ferritin; the degree of growth after discharge from the hospital; and the neurodevelopment outcomes in EUGR and non-EUGR infants who were given iron supplementation under the guidelines for newborn preterm infants. 2. Subjects and methods
2.3. Assessment of neurodevelopmental status The primary outcome variable was the score at a corrected age of 18 months based on the Bayley Scales of Infant Development, second edition (BSID-II). These scales, considered the gold standard for assessing the global abilities of children aged <42 months old, assess overall mental development, including language and visuomotor problem solving (Mental Development Index, MDI), as well as both fine and gross motor development (Psychomotor Development Index, PDI). The instrument was administered by one of three pediatricians who were trained and experienced in its use.
2.1. Subjects 2.4. Anthropometric measures An observational study was conducted in the NICU of Juntendo University Hospital, Tokyo, Japan. The study subjects were premature infants born between June 2004 and March 2006 with birth weights below 1500 g and no congenital anomalies. The infants were born at and discharged from the same NICU. Institutional review board approval was obtained, and all parents gave informed consent to participation in the study. All of the mothers were married to the infant’s father; both parents were healthy and at least 20 years old. A total of 38 infants, with a mean gestational age of 29.5 weeks (SD = 2.7) and a mean birth weight of 1065 g (SD = 280.5), were included in the study. The iron status was determined in the infants at corrected ages of 1, 3, 6, 9, 12, and 18 months, regardless of discharge from the NICU, by measuring the venous levels of hemoglobin (Hb), Fe, and serum ferritin.
At birth, at a PMA of 40 weeks, at discharge, and when the BSID was administered, the nude weight of each infant was determined with an electronic integrating scale, and body length and head circumference were measured using an infant stadiometer and measuring tape, respectively. 2.5. Statistical analysis The results are expressed as the mean ± standard deviation (SD). Comparisons were made between the EUGR and non-EUGR groups, and the intrauterine growth restriction (IUGR) and non-IUGR groups using a chi-squared test with a continuity correction. Means were compared using a Mann–Whitney U-test for independent samples. Statistical significance was defined as a P-value <0.05.
2.2. Definition of extrauterine growth restriction 3. Results EUGR was defined as growth values less than the 10th percentile of the expected intrauterine growth based on the estimated postmenstrual age (PMA) at the time of discharge from the hospital [14]. We used the gender-specific national standard growth lists, issued by the Ministry of Health, Labor, and Welfare of Japan, for neonates discharged at an estimated gestational age between 36 and 40 weeks. Some of the neonates were discharged later than 40 weeks, and we used the data at a PMA of 40 weeks to estimate whether the infants were EUGR. The infants were divided into EUGR and non-EUGR groups.
The study lasted for 18 months, during which time 38 children (23 males/15 females) with birth weights below 1500 g were recruited into the study. The EUGR and non-EUGR groups included 16 and 22 children, respectively. Table 2 shows the descriptions of the neonates with and without EUGR. There were no significant differences in anthropometric measurements at birth or the proportion of male infants between the two groups, but a significant proportion of infants in the EUGR group (15/16) also showed IUGR at birth (Table 2). In this study, the expression “IUGR” is used instead of “small
Table 1 Guidelines for iron supplementation in newborn preterm infants. 1. 2. 3. 4. 5. 6.
Target: Very low birth weight infant (birth weight < 1500 g) Standard for administration: Iron supplementation starts when the baby’s milk intake increases above 100 ml/kg/day Dose of administration: Maximum 6 mg/kg/day is sufficient Termination: When body weight increases above 2500 g and enteral feeding is sufficient Note: Monitoring will not be needed. Care for symptoms of digestive system Contraindications: None
N. Kon et al. / Brain & Development 32 (2010) 849–854
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Table 2 Descriptions of the neonates with and without EUGR. Characteristic
EUGR group n = 16
Non-EUGR n = 22
P-value
Gestational age (wk) Birth weight (g) Head circumference (cm) Body length (cm) Male/female (n) Maternal age (y) Birth with IUGR (n) Nullipara/parity (n) Single/multiple (n) Necrotizing enterocolitis PVL IVH ROP Bronchopulmonary dysplasiaa Nutrition Day when milk started (d) Duration of intravenous nutrition (d) Day when attained full feed* (d) Breast milk percentage of total fed (%) Weight changeb (g/d) Treatment Days in hospital (d) Duration of iron supplementation (d) Erythropoietin (n) Transfusion (n)
30.9 ± 2.8 1013.3 ± 343.2 26.1 ± 2.4 35.2 ± 3.7 10/6 31.0 ± 4.3 15 13/3 13/3 0 0 0 3 1
28.7 ± 2.3 1103.7 ± 225.7 26.2 ± 2.1 36.2 ± 2.7 13/9 31.9 ± 5.0 5 19/3 19/3 0 0 1 2 1
NS NS NS NS NS NS <0.01 NS NS NS NS NS NS NS
3.2 ± 2.2 7.9 ± 10.3 8.9 ± 7.2 72.3 ± 31.5 22.0 ± 3.7
2.8 ± 1.3 6.6 ± 6.1 8.4 ± 4.1 69.5 ± 34.9 23.8 ± 3.2
NS NS NS NS NS
88.5 ± 56.2 134.3 ± 90.5 13 7
84.2 ± 33.6 101.7 ± 50.1 21 12
NS NS NS NS
Data are means ± SD or number (n). IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity. a Bronchopulmonary dysplasia was defined as oxygen administration at a PMA of 36 weeks. b Weight change was based on weight gain per day [(discharge weight birth weight)/number of days in the hospital]. * Full feed means that total enteral intake reached 100 ml/kg/day.
for gestational age,” to contrast with “EUGR.” As independent factors increasing the risk for EUGR complications, the incidences of periventricular leukomalacia, intracranial hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis; the background of nutritional intervention; and the treatment before discharge from the NICU were compared between the two groups; no significant differences were observed (Table 2). Table 3 compare the levels of Hb, Fe, and ferritin at corrected ages of 1, 3, 6, 9, and 12 months between the EUGR and non-EUGR groups. The level of Hb at corrected ages of 1 and 3 months and that of iron at a corrected age of 1 and 9 months were significantly lower in the EUGR group than in the non-EUGR group: 10.4 (SD = 1.2) vs. 11.1 (1.4), 12.0 (1.2) vs. 12.9 (1.1), and 65.4 (29.6) vs. 80.2 (31.6), respectively (P < 0.05). The MDI score did not differ between the two groups, whereas the PDI score at a corrected age of 18 months was significantly lower in the EUGR group than in the non-EUGR group: 92.6 (SD = 9.9) vs. 99.5 (8.4) (P < 0.05). Ferritin, and neurodevelopment at 18 months of age (Table 4). We found a positive correlation between the serum level of Fe at 1 month of age and PDI score at 18 months of age. However, there were no significant
correlations between ferritin levels at each stage and either MDI or PDI. (Fig. 1). Head circumference at the age of 18 months did not differ between the groups, but body weight and length were significantly lower in the EUGR group (Table 4). 4. Discussion In this study, the EUGR group included infants born with IUGR, which has been reported as a risk factor for EUGR and has been shown to affect the neurodevelopment outcome [15]. Low birth weight and immature gestational age are the most important factors associated with EUGR. Malnutrition, male gender, and exposure to steroids during the period of hospitalization have also been reported as potential risk factors [16,17]. Some studies have suggested that increasing nutritional intake, especially protein, to within the recommended ranges may increase the growth of extremely premature infants, up to or above intrauterine rates. The results of the present study showed no significant differences between the groups with regard to any of these risk factors. This may be attributable to the small number of cases included in this study. Accumulating evidence indicates the presence of defects in both metabolic regulation and physiological
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Table 3 The level of Hb, Fe, ferritin in the group of EUGR and non-EUGR at 1, 3, 6, 9, 12, 18 months. EUGR
Non-EUGR
P-value
Level of Hb (g/dl)
1m 3m 6m 9m 12 m 18 m
10.3 ± 2.4 12.0 ± 1.3 12.8 ± 1.7 13.1 ± 1.6 12.8 ± 2.0 13.0 ± 1.9
11.1 ± 2.0 12.9 ± 1.9 13.0 ± 3.2 13.0 ± 3.0 12.9 ± 2.5 13.2 ± 2.4
P < 0.05 P < 0.05 NS NS NS NS
Level of Fe (lg/dl)
1m 3m 6m 9m 12 m 18 m
32.5 ± 10.2 75.5 ± 15.7 64.7 ± 20.3 65.4 ± 21.2 61.4 ± 20.1 32.2 ± 18.3
53.3 ± 21.2 77.2 ± 35.0 68.3 ± 30.1 80.2 ± 30.2 61.1 ± 30.2 81.5 ± 25.0
P < 0.05 NS NS P < 0.05 NS NS
Level of ferritin (lg/dl)
1m 3m 6m 9m 12 m 18 m
39.8 ± 10.5 112.5 ± 50.5 127.0 ± 49.7 78.7 ± 30.2 78.3 ± 25.0 41.6 ± 18.0
47.3 ± 18.0 26.8 ± 10.1 35.0 ± 12.3 29.5 ± 11.0 29.5 ± 12.0 30.6 ± 12.3
NS NS NS NS NS NS
Data are means ± SD.
Table 4 Anthropometric measures (mean ± SD) and the score of BSID-II in the EUGR non-EUGR group at 18 month and.
MDI PDI BRS orientation Emotional BW (g) BL (cm) HC (cm)
EUGR
Non-EUGR
P-value
92.7 ± 10.5 92.6 ± 11.2 88.5 ± 21.5 63.7 ± 20.3 9192.5 ± 1100.5 78.0 ± 3.4 46.8 ± 0.9
94.1 ± 9.8 99.5 ± 11.2 50.7 ± 21.3 50.7 ± 20.1 9920.0 ± 870.0 80.8 ± 3.0 46.9 ± 1.4
NS P < 0.05 NS NS P < 0.01 P < 0.01 NS
Data are means ± SD.
P=0.01 N=38
Fig. 1. The correlation between the Fe levels at 1 month and the score of PDI.
function in the liver of IUGR neonates [17,18]. Transferrins are iron-binding proteins that are responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Reduced availability of transferrins in the liver of IUGR neonates may result in iron deficiency, thereby impairing numerous iron-dependent pathways [19]. Indeed, IUGR infants show increased risk for anemia, primarily because of impaired iron transport and chronic intra-
uterine hypoxia due to poor placental function. IUGR occurs in pregnancies complicated by severe maternal hypertension or preeclampsia owing to genetic disorders or severe maternal malnutrition. Serum ferritin concentrations are decreased and transferrin levels are increased in IUGR infants [20–22]. However, the level of ferritin in EUGR group was higher than that of non-EUGR group. We attempted to clarify why the ferritin level was lower in the non-EUGR group than the EUGR group. The same trend was also observed in the group divided according to IUGR; the serum ferritin level in the non-IUGR group was lower than that in the IUGR group. We speculated that iron transport is impaired in the IUGR group, resulting in decreased iron concentrations, and ferritin cannot be transported appropriately from the organs to serum in IUGR infants. The findings of the present study suggest that EUGR develops in infants born with IUGR, which is consistent with iron deficiency. However, further evaluations are required including measuring the level of transferrin, total iron binding capacity.
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Iron is an essential micronutrient and plays critical roles in cellular functions in all organ systems. Nutritional intervention, including improving the iron status, is important; as transferrin is an iron-binding protein, early aggressive nutrition with protein may be needed in preterm low birth weight infants. In this study, the PDI score at a corrected age of 18 months was lower in the EUGR group than in the non-EUGR group. And we found the positive association between serum Fe level at 1 month and PDI score at 18 month of age. Iron deficiency is associated with impaired neurodevelopment. The negative effects of iron deficiency on neurodevelopment during early infancy and childhood may be long-lasting or even irreversible, despite treatment for iron deficiency [2,3,9,23–30]. Similarly, iron deficiency during intrauterine development also seems to have long-lasting negative effects on neurodevelopment [31]; decreased umbilical cord serum ferritin levels are associated with poor neurobehavioral status at a PMA of 37 weeks [32] and with impaired mental and psychomotor development at 5 years of age [33]. We had speculated low level of serum iron at early infancy is associated with neurodevelopment in later childhood. IUGR is associated with significant reductions in cognitive and motor skills. Some reports have indicated that in children born to mothers with hypertension during pregnancy, optimal intrauterine growth is linked to the quality of performance on visuospatial, visuomotor, and gross motor tasks [34]. Therefore, both IUGR and EUGR may represent increased risk for developmental disabilities, as PDI may reflect not only fine motor skills but also gross motor skills. In the EUGR group, the physical frame of the infants, including the head circumference and body length at a corrected age of 18 months, remained small, which may contribute to myodynamia and have an impact on PDI. As physical growth is an important factor contributing to muscle power in infancy, we speculated that better physical growth aids in psychomotor development. We also evaluated the DHA status, which is an important nutrient factor for brain development, at each month of age along with Hb, iron, and ferritin status. However, the level of DHA was not different between the EUGR and non-EUGR groups. Further evaluations are necessary to determine what is the factor influence the neurodevelopment in preterm infants, including multivariate analysis to eliminate confounding factors, such as the duration of breast milk feeding, maternal food intake, associations between other nutrient factors and neurodevelopment (e.g., DHA), and socioeconomic status. Long-term followup is also necessary to evaluate the impaired cognitive function at school age. From the present study we recommend that it is necessary to check iron status more carefully, regardless of
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the presence or absence of anemia, especially in cases of IUGR and EUGR. In conclusion, we have shown that the developmental outcome of preterm infants at a corrected age of 18 months may be influenced by nutritional factors, including iron status, during early life. Although significant advances have been made in neonatal intensive care, continuous efforts are needed to determine new strategies for improving the nutritional status of preterm neonates, especially those with IUGR, as the course of postnatal growth affects the later neurodevelopmental outcome. The risk factors for adverse outcomes identified in this study may be useful in future intervention studies. References [1] Lozoff B, Brittenham GM, Viteri FE, Wolf AW, Urrutia JJ. Developmental deficits in iron-deficient infants: effects of age and severity of iron lack. J Pediatr 1982;101:948–52. [2] Hurtado EK, Claussen AH, Scott KG. Early childhood anemia and mild or moderate mental retardation. Am J Clin Nutr 1999;69:115–9. [3] 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. [4] Aggett PJ. Trace elements of the micropremie. Clin Perinatol 2000;27:119–29. [5] Booth IW, Aukett MA. Iron deficiency anaemia in infancy and early childhood. Arch Dis Child 1997;76:549–53, discussion 553–4. [6] Walter T. Effect of iron-deficiency anemia on cognitive skills and neuromaturation in infancy and childhood. Food Nutr Bull 2003;24(4 Suppl):S104–110. [7] Kabakus N, Ayar A, Yoldas TK, Ulvi H, Dogan Y, Yilmaz B, et al. Reversal of iron deficiency anemia-induced peripheral neuropathy by iron treatment in children with iron deficiency anemia. J Trop Pediatr 2002;48:204–9. [8] Sarici SU, Okutan V, Dundaroz MR, Serdar AM, Akin R, Deda G, et al. The effect of iron supplementation on visual-evoked potentials in infants with iron-deficiency anemia. J Trop Pediatr 2001;47:132–5. [9] 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. [10] Lozoff B, Wolf AW, Jimenez E. Iron-deficiency anemia and infant development: effects of extended oral iron therapy. J Pediatr 1996;129:382–9. [11] Oski FA, Honig AS, Helu B, Howanitz P. Effect of iron therapy on behavior performance in nonanemic, iron-deficient infants. Pediatrics 1983;71:877–80. [12] Stevens D. Iron fortified follow on formula from 9 to 18 months improves iron status but not development or growth. Arch Dis Child 2000;82:269–70. [13] Kusuda S, Matsunami S, Kawaguchi C, Takahashi Y, Wada H, Hirano R, et al. Guidelines for iron supplementation to preterm infants (in Japanese). Perinatal Med 2006;36:767–78. [14] Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111:986–90. [15] Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU, Largo RH. Postnatal growth in VLBW infants: significant association with neurodevelopmental outcome. J Pediatr 2003;143:163–70.
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[16] Clark RH, Wagner CL, Merritt RJ, Bloom BT, Neu J, Young TE, et al. Nutrition in the neonatal intensive care unit: how do we reduce the incidence of extrauterine growth restriction? J Perinatol 2003;23:337–44. [17] Peterside IE, Selak MA, Simmons RA. Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats. Am J Physiol Endocrinol Metab 2003;285:E1258–1266. [18] Casimir G. Prevention of asthma in children. Rev Med Brux 1996;17:253–5. [19] Theil EC. Iron, ferritin, and nutrition. Annu Rev Nutr 2004;24:327–43. [20] 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. [21] Siimes AS, Siimes MA. Changes in the concentration of ferritin in the serum during fetal life in singletons and twins. Early Hum Dev 1986;13:47–52. [22] Haga P. Plasma ferritin concentrations in preterm infants in cord blood and during the early anaemia of prematurity. Acta Paediatr Scand 1980;69:637–41. [23] Shafir T, Angulo-Barroso R, Calatroni A, Jimenez E, Lozoff B. Effects of iron deficiency in infancy on patterns of motor development over time. Hum Mov Sci 2006;25:821–38. [24] Lozoff B, Jimenez E, Smith JB. Double burden of iron deficiency in infancy and low socioeconomic status: a longitudinal analysis of cognitive test scores to age 19 years. Arch Pediatr Adolesc Med 2006;160:1108–13. [25] Corapci F, Radan AE, Lozoff B. Iron deficiency in infancy and mother-child interaction at 5 years. J Dev Behav Pediatr 2006;27:371–8.
[26] 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. [27] 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. [28] Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med 1991;325:687–94. [29] Palti H, Meijer A, Adler B. Learning achievement and behavior at school of anemic and non-anemic infants. Early Hum Dev 1985;10:217–23. [30] Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, Franz AR. Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years’ corrected age. Pediatrics 2007;120:538–46. [31] Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol 2006;13:158–65. [32] 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. [33] 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. [34] Kronenberg ME, Raz S, Sander CJ. Neurodevelopmental outcome in children born to mothers with hypertension in pregnancy: the significance of suboptimal intrauterine growth. Dev Med Child Neurol 2006;48:200–6.
Original article
Association between iron status and neurodevelopmental outcomes among VLBW infants Noriko Kon, Kyoko Tanaka *, Mariko Sekigawa, Yoshie Negishi, Naomi Yoshikawa, Ken Hisata, Hiromichi Shoji, Toshiaki Shimizu Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan Received 6 July 2009; received in revised form 24 November 2009; accepted 14 December 2009
Abstract Objective: Our purpose was to evaluate iron status and neurodevelopmental outcomes in infants with and without extrauterine growth restriction (EUGR). Methods: This observational study evaluated 38 medically stable premature infants, with birth weights below 1500 g. Iron status was determined by measuring venous levels of Hb, Fe, and serum ferritin. The infants were divided into EUGR and non-EUGR groups. At a corrected age of 18 months, neurodevelopmental outcomes were checked using the Bayley scales, and body weight, body length, and head circumference were measured. Results: Hb levels at corrected ages of 1 and 3 months and iron at a corrected age of 1 and 9 months were significantly lower in the EUGR group compared with those of the non-EUGR group. There was no significant difference in the MDI score between the groups, but the PDI score at a corrected age of 18 months was significantly lower in the EUGR group. We found a positive correlation between the serum level of Fe at 1 month of age and PDI score at 18 months of age. Head circumference at a corrected age of 18 months did not differ between two groups, although body weight and length were lower in the EUGR group. Conclusions: Developmental outcome in preterm infants at a corrected age of 18 months may be influenced by nutritional factors, including iron status, during their early life. Ó 2010 Published by Elsevier B.V. Keywords: Iron supplementation; Extrauterine growth restriction; Neurodevelopment outcome; Low birth weight infants; Preterm infants
1. Introduction It is well known that iron deficiency affects neurodevelopment in infants [1–3]. Neuronal metabolism, neurotransmitter function, and myelination are influenced by iron deficiency, which has greatest impact on the brain during early neurodevelopment [4,5]. A correlation has been reported between iron deficiency and psychomotor disorder in infancy and early childhood [6]. Recently, it was reported that infants with iron deficiency anemia at 6 months of age had less mature auditory brainstem * Corresponding author. Address: Department of Pediatrics, Juntendo University, School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel.: +81 3 3813 3111; fax: +81 3 5800 0216. E-mail address: [email protected] (K. Tanaka).
0387-7604/$ - see front matter Ó 2010 Published by Elsevier B.V. doi:10.1016/j.braindev.2009.12.003
responses, particularly evidenced by longer central conduction times than in control infants; this was suggested to be due to impaired myelination caused by iron deficiency [3]. In addition, after iron therapy in infants with iron deficiency anemia, visual evoked potentials and nerve conduction velocities were improved [7,8]. However, other reports have suggested that iron therapy did not produce improvements [7,9–12]. Therefore, the effects of iron supplementation remain unclear. Based on the guidelines proposed at the Neonatal Nutrition Forum in 2003, newborn preterm infants in Japan are given iron supplementation (Table 1) [13]. These guidelines are intended to increase the level of iron storage in preterm infants, as a group at high risk for iron deficiency, to a level approximating that of full-term infants during the period of hospitalization in the neona-
850
N. Kon et al. / Brain & Development 32 (2010) 849–854
tal intensive care unit (NICU). Recently, it was reported that extrauterine growth restriction (EUGR) of low birth weight infants is also associated with delayed mental, motor, and cognitive development in childhood [14]. The objective of the present study was to evaluate the levels of hemoglobin, Fe, and ferritin; the degree of growth after discharge from the hospital; and the neurodevelopment outcomes in EUGR and non-EUGR infants who were given iron supplementation under the guidelines for newborn preterm infants. 2. Subjects and methods
2.3. Assessment of neurodevelopmental status The primary outcome variable was the score at a corrected age of 18 months based on the Bayley Scales of Infant Development, second edition (BSID-II). These scales, considered the gold standard for assessing the global abilities of children aged <42 months old, assess overall mental development, including language and visuomotor problem solving (Mental Development Index, MDI), as well as both fine and gross motor development (Psychomotor Development Index, PDI). The instrument was administered by one of three pediatricians who were trained and experienced in its use.
2.1. Subjects 2.4. Anthropometric measures An observational study was conducted in the NICU of Juntendo University Hospital, Tokyo, Japan. The study subjects were premature infants born between June 2004 and March 2006 with birth weights below 1500 g and no congenital anomalies. The infants were born at and discharged from the same NICU. Institutional review board approval was obtained, and all parents gave informed consent to participation in the study. All of the mothers were married to the infant’s father; both parents were healthy and at least 20 years old. A total of 38 infants, with a mean gestational age of 29.5 weeks (SD = 2.7) and a mean birth weight of 1065 g (SD = 280.5), were included in the study. The iron status was determined in the infants at corrected ages of 1, 3, 6, 9, 12, and 18 months, regardless of discharge from the NICU, by measuring the venous levels of hemoglobin (Hb), Fe, and serum ferritin.
At birth, at a PMA of 40 weeks, at discharge, and when the BSID was administered, the nude weight of each infant was determined with an electronic integrating scale, and body length and head circumference were measured using an infant stadiometer and measuring tape, respectively. 2.5. Statistical analysis The results are expressed as the mean ± standard deviation (SD). Comparisons were made between the EUGR and non-EUGR groups, and the intrauterine growth restriction (IUGR) and non-IUGR groups using a chi-squared test with a continuity correction. Means were compared using a Mann–Whitney U-test for independent samples. Statistical significance was defined as a P-value <0.05.
2.2. Definition of extrauterine growth restriction 3. Results EUGR was defined as growth values less than the 10th percentile of the expected intrauterine growth based on the estimated postmenstrual age (PMA) at the time of discharge from the hospital [14]. We used the gender-specific national standard growth lists, issued by the Ministry of Health, Labor, and Welfare of Japan, for neonates discharged at an estimated gestational age between 36 and 40 weeks. Some of the neonates were discharged later than 40 weeks, and we used the data at a PMA of 40 weeks to estimate whether the infants were EUGR. The infants were divided into EUGR and non-EUGR groups.
The study lasted for 18 months, during which time 38 children (23 males/15 females) with birth weights below 1500 g were recruited into the study. The EUGR and non-EUGR groups included 16 and 22 children, respectively. Table 2 shows the descriptions of the neonates with and without EUGR. There were no significant differences in anthropometric measurements at birth or the proportion of male infants between the two groups, but a significant proportion of infants in the EUGR group (15/16) also showed IUGR at birth (Table 2). In this study, the expression “IUGR” is used instead of “small
Table 1 Guidelines for iron supplementation in newborn preterm infants. 1. 2. 3. 4. 5. 6.
Target: Very low birth weight infant (birth weight < 1500 g) Standard for administration: Iron supplementation starts when the baby’s milk intake increases above 100 ml/kg/day Dose of administration: Maximum 6 mg/kg/day is sufficient Termination: When body weight increases above 2500 g and enteral feeding is sufficient Note: Monitoring will not be needed. Care for symptoms of digestive system Contraindications: None
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Table 2 Descriptions of the neonates with and without EUGR. Characteristic
EUGR group n = 16
Non-EUGR n = 22
P-value
Gestational age (wk) Birth weight (g) Head circumference (cm) Body length (cm) Male/female (n) Maternal age (y) Birth with IUGR (n) Nullipara/parity (n) Single/multiple (n) Necrotizing enterocolitis PVL IVH ROP Bronchopulmonary dysplasiaa Nutrition Day when milk started (d) Duration of intravenous nutrition (d) Day when attained full feed* (d) Breast milk percentage of total fed (%) Weight changeb (g/d) Treatment Days in hospital (d) Duration of iron supplementation (d) Erythropoietin (n) Transfusion (n)
30.9 ± 2.8 1013.3 ± 343.2 26.1 ± 2.4 35.2 ± 3.7 10/6 31.0 ± 4.3 15 13/3 13/3 0 0 0 3 1
28.7 ± 2.3 1103.7 ± 225.7 26.2 ± 2.1 36.2 ± 2.7 13/9 31.9 ± 5.0 5 19/3 19/3 0 0 1 2 1
NS NS NS NS NS NS <0.01 NS NS NS NS NS NS NS
3.2 ± 2.2 7.9 ± 10.3 8.9 ± 7.2 72.3 ± 31.5 22.0 ± 3.7
2.8 ± 1.3 6.6 ± 6.1 8.4 ± 4.1 69.5 ± 34.9 23.8 ± 3.2
NS NS NS NS NS
88.5 ± 56.2 134.3 ± 90.5 13 7
84.2 ± 33.6 101.7 ± 50.1 21 12
NS NS NS NS
Data are means ± SD or number (n). IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity. a Bronchopulmonary dysplasia was defined as oxygen administration at a PMA of 36 weeks. b Weight change was based on weight gain per day [(discharge weight birth weight)/number of days in the hospital]. * Full feed means that total enteral intake reached 100 ml/kg/day.
for gestational age,” to contrast with “EUGR.” As independent factors increasing the risk for EUGR complications, the incidences of periventricular leukomalacia, intracranial hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis; the background of nutritional intervention; and the treatment before discharge from the NICU were compared between the two groups; no significant differences were observed (Table 2). Table 3 compare the levels of Hb, Fe, and ferritin at corrected ages of 1, 3, 6, 9, and 12 months between the EUGR and non-EUGR groups. The level of Hb at corrected ages of 1 and 3 months and that of iron at a corrected age of 1 and 9 months were significantly lower in the EUGR group than in the non-EUGR group: 10.4 (SD = 1.2) vs. 11.1 (1.4), 12.0 (1.2) vs. 12.9 (1.1), and 65.4 (29.6) vs. 80.2 (31.6), respectively (P < 0.05). The MDI score did not differ between the two groups, whereas the PDI score at a corrected age of 18 months was significantly lower in the EUGR group than in the non-EUGR group: 92.6 (SD = 9.9) vs. 99.5 (8.4) (P < 0.05). Ferritin, and neurodevelopment at 18 months of age (Table 4). We found a positive correlation between the serum level of Fe at 1 month of age and PDI score at 18 months of age. However, there were no significant
correlations between ferritin levels at each stage and either MDI or PDI. (Fig. 1). Head circumference at the age of 18 months did not differ between the groups, but body weight and length were significantly lower in the EUGR group (Table 4). 4. Discussion In this study, the EUGR group included infants born with IUGR, which has been reported as a risk factor for EUGR and has been shown to affect the neurodevelopment outcome [15]. Low birth weight and immature gestational age are the most important factors associated with EUGR. Malnutrition, male gender, and exposure to steroids during the period of hospitalization have also been reported as potential risk factors [16,17]. Some studies have suggested that increasing nutritional intake, especially protein, to within the recommended ranges may increase the growth of extremely premature infants, up to or above intrauterine rates. The results of the present study showed no significant differences between the groups with regard to any of these risk factors. This may be attributable to the small number of cases included in this study. Accumulating evidence indicates the presence of defects in both metabolic regulation and physiological
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Table 3 The level of Hb, Fe, ferritin in the group of EUGR and non-EUGR at 1, 3, 6, 9, 12, 18 months. EUGR
Non-EUGR
P-value
Level of Hb (g/dl)
1m 3m 6m 9m 12 m 18 m
10.3 ± 2.4 12.0 ± 1.3 12.8 ± 1.7 13.1 ± 1.6 12.8 ± 2.0 13.0 ± 1.9
11.1 ± 2.0 12.9 ± 1.9 13.0 ± 3.2 13.0 ± 3.0 12.9 ± 2.5 13.2 ± 2.4
P < 0.05 P < 0.05 NS NS NS NS
Level of Fe (lg/dl)
1m 3m 6m 9m 12 m 18 m
32.5 ± 10.2 75.5 ± 15.7 64.7 ± 20.3 65.4 ± 21.2 61.4 ± 20.1 32.2 ± 18.3
53.3 ± 21.2 77.2 ± 35.0 68.3 ± 30.1 80.2 ± 30.2 61.1 ± 30.2 81.5 ± 25.0
P < 0.05 NS NS P < 0.05 NS NS
Level of ferritin (lg/dl)
1m 3m 6m 9m 12 m 18 m
39.8 ± 10.5 112.5 ± 50.5 127.0 ± 49.7 78.7 ± 30.2 78.3 ± 25.0 41.6 ± 18.0
47.3 ± 18.0 26.8 ± 10.1 35.0 ± 12.3 29.5 ± 11.0 29.5 ± 12.0 30.6 ± 12.3
NS NS NS NS NS NS
Data are means ± SD.
Table 4 Anthropometric measures (mean ± SD) and the score of BSID-II in the EUGR non-EUGR group at 18 month and.
MDI PDI BRS orientation Emotional BW (g) BL (cm) HC (cm)
EUGR
Non-EUGR
P-value
92.7 ± 10.5 92.6 ± 11.2 88.5 ± 21.5 63.7 ± 20.3 9192.5 ± 1100.5 78.0 ± 3.4 46.8 ± 0.9
94.1 ± 9.8 99.5 ± 11.2 50.7 ± 21.3 50.7 ± 20.1 9920.0 ± 870.0 80.8 ± 3.0 46.9 ± 1.4
NS P < 0.05 NS NS P < 0.01 P < 0.01 NS
Data are means ± SD.
P=0.01 N=38
Fig. 1. The correlation between the Fe levels at 1 month and the score of PDI.
function in the liver of IUGR neonates [17,18]. Transferrins are iron-binding proteins that are responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Reduced availability of transferrins in the liver of IUGR neonates may result in iron deficiency, thereby impairing numerous iron-dependent pathways [19]. Indeed, IUGR infants show increased risk for anemia, primarily because of impaired iron transport and chronic intra-
uterine hypoxia due to poor placental function. IUGR occurs in pregnancies complicated by severe maternal hypertension or preeclampsia owing to genetic disorders or severe maternal malnutrition. Serum ferritin concentrations are decreased and transferrin levels are increased in IUGR infants [20–22]. However, the level of ferritin in EUGR group was higher than that of non-EUGR group. We attempted to clarify why the ferritin level was lower in the non-EUGR group than the EUGR group. The same trend was also observed in the group divided according to IUGR; the serum ferritin level in the non-IUGR group was lower than that in the IUGR group. We speculated that iron transport is impaired in the IUGR group, resulting in decreased iron concentrations, and ferritin cannot be transported appropriately from the organs to serum in IUGR infants. The findings of the present study suggest that EUGR develops in infants born with IUGR, which is consistent with iron deficiency. However, further evaluations are required including measuring the level of transferrin, total iron binding capacity.
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Iron is an essential micronutrient and plays critical roles in cellular functions in all organ systems. Nutritional intervention, including improving the iron status, is important; as transferrin is an iron-binding protein, early aggressive nutrition with protein may be needed in preterm low birth weight infants. In this study, the PDI score at a corrected age of 18 months was lower in the EUGR group than in the non-EUGR group. And we found the positive association between serum Fe level at 1 month and PDI score at 18 month of age. Iron deficiency is associated with impaired neurodevelopment. The negative effects of iron deficiency on neurodevelopment during early infancy and childhood may be long-lasting or even irreversible, despite treatment for iron deficiency [2,3,9,23–30]. Similarly, iron deficiency during intrauterine development also seems to have long-lasting negative effects on neurodevelopment [31]; decreased umbilical cord serum ferritin levels are associated with poor neurobehavioral status at a PMA of 37 weeks [32] and with impaired mental and psychomotor development at 5 years of age [33]. We had speculated low level of serum iron at early infancy is associated with neurodevelopment in later childhood. IUGR is associated with significant reductions in cognitive and motor skills. Some reports have indicated that in children born to mothers with hypertension during pregnancy, optimal intrauterine growth is linked to the quality of performance on visuospatial, visuomotor, and gross motor tasks [34]. Therefore, both IUGR and EUGR may represent increased risk for developmental disabilities, as PDI may reflect not only fine motor skills but also gross motor skills. In the EUGR group, the physical frame of the infants, including the head circumference and body length at a corrected age of 18 months, remained small, which may contribute to myodynamia and have an impact on PDI. As physical growth is an important factor contributing to muscle power in infancy, we speculated that better physical growth aids in psychomotor development. We also evaluated the DHA status, which is an important nutrient factor for brain development, at each month of age along with Hb, iron, and ferritin status. However, the level of DHA was not different between the EUGR and non-EUGR groups. Further evaluations are necessary to determine what is the factor influence the neurodevelopment in preterm infants, including multivariate analysis to eliminate confounding factors, such as the duration of breast milk feeding, maternal food intake, associations between other nutrient factors and neurodevelopment (e.g., DHA), and socioeconomic status. Long-term followup is also necessary to evaluate the impaired cognitive function at school age. From the present study we recommend that it is necessary to check iron status more carefully, regardless of
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the presence or absence of anemia, especially in cases of IUGR and EUGR. In conclusion, we have shown that the developmental outcome of preterm infants at a corrected age of 18 months may be influenced by nutritional factors, including iron status, during early life. Although significant advances have been made in neonatal intensive care, continuous efforts are needed to determine new strategies for improving the nutritional status of preterm neonates, especially those with IUGR, as the course of postnatal growth affects the later neurodevelopmental outcome. The risk factors for adverse outcomes identified in this study may be useful in future intervention studies. References [1] Lozoff B, Brittenham GM, Viteri FE, Wolf AW, Urrutia JJ. Developmental deficits in iron-deficient infants: effects of age and severity of iron lack. J Pediatr 1982;101:948–52. [2] Hurtado EK, Claussen AH, Scott KG. Early childhood anemia and mild or moderate mental retardation. Am J Clin Nutr 1999;69:115–9. [3] 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. [4] Aggett PJ. Trace elements of the micropremie. Clin Perinatol 2000;27:119–29. [5] Booth IW, Aukett MA. Iron deficiency anaemia in infancy and early childhood. Arch Dis Child 1997;76:549–53, discussion 553–4. [6] Walter T. Effect of iron-deficiency anemia on cognitive skills and neuromaturation in infancy and childhood. Food Nutr Bull 2003;24(4 Suppl):S104–110. [7] Kabakus N, Ayar A, Yoldas TK, Ulvi H, Dogan Y, Yilmaz B, et al. Reversal of iron deficiency anemia-induced peripheral neuropathy by iron treatment in children with iron deficiency anemia. J Trop Pediatr 2002;48:204–9. [8] Sarici SU, Okutan V, Dundaroz MR, Serdar AM, Akin R, Deda G, et al. The effect of iron supplementation on visual-evoked potentials in infants with iron-deficiency anemia. J Trop Pediatr 2001;47:132–5. [9] 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. [10] Lozoff B, Wolf AW, Jimenez E. Iron-deficiency anemia and infant development: effects of extended oral iron therapy. J Pediatr 1996;129:382–9. [11] Oski FA, Honig AS, Helu B, Howanitz P. Effect of iron therapy on behavior performance in nonanemic, iron-deficient infants. Pediatrics 1983;71:877–80. [12] Stevens D. Iron fortified follow on formula from 9 to 18 months improves iron status but not development or growth. Arch Dis Child 2000;82:269–70. [13] Kusuda S, Matsunami S, Kawaguchi C, Takahashi Y, Wada H, Hirano R, et al. Guidelines for iron supplementation to preterm infants (in Japanese). Perinatal Med 2006;36:767–78. [14] Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111:986–90. [15] Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU, Largo RH. Postnatal growth in VLBW infants: significant association with neurodevelopmental outcome. J Pediatr 2003;143:163–70.
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