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PEDIATRICS Vol. 111 No. 5 May 2003, pp. 991-995

Nutritional State and Growth and Functional Maturation of the Brain in Extremely Low Birth Weight Infants

Masahiro Hayakawa, MD, PhD*,{ddagger}, Akihisa Okumura, MD, PhD§, Fumio Hayakawa, MD, PhD, Yuuichi Kato, MD*, Makoto Ohshiro, MD*, Nobuo Tauchi, MD, PhD*,{ddagger},§,¶ and Kazuyoshi Watanabe, MD, PhD§

* Department of Pediatric Cardiology and Neonatology, Ogaki Municipal Hospital
{ddagger} Maternity and Perinatal Care Center, Nagoya University Hospital, Nagoya, Japan
§ Department of Pediatrics, Nagoya University Graduate School of Medicine
Department of Pediatrics, Okazaki City Hospital

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Objective. It is well-known that an undernutritional status influences central nervous system development in the fetal and early neonatal period. On the other hand, the maturational delay of the central nervous system is reflected as dysmature pattern (DMP) in the neonatal background electroencephalograph (EEG). Therefore, we hypothesized that the postnatal nutritional status influenced electrophysiologic maturation in extremely low birth weight infants (ELBWIs).

Methods. ELBWIs between 24 and 27 weeks of gestational age who were admitted to Ogaki Municipal Hospital NICU from April 1997 to December 2000 were considered eligible. From the condition of enteral feeding, infants were divided into 2 groups: 1) normal nutritional group (group N), where enteral feeding had been established (100 mL/kg/d) by 3 weeks after birth; 2) undernutritional group (group U), where enteral feeding had not been established by 3 weeks after birth or was discontinued because of clinical problems. Weekly average body weight and head circumference gains were evaluated as nutritional status. EEG records were performed every 2 to 4 weeks until postnatal 15 weeks of age. DMP was defined as the appearance of immature EEG patterns for postconceptional age.

Results. Twenty-one infants had serial EEG recordings; 11 infants belonged to group N and 10 infants to group U. Gestational age, birth weight, and head circumference at birth were not different between the 2 groups. The body weight of group N was significantly heavier than that of group U after 5 postnatal weeks. Similarly, the head circumference of group N was larger than that of group U after 6 weeks of postnatal age. Nine infants demonstrated DMPs. One infant belonged to group N and 8 to group U. DMPs were significantly more frequently found in group U than group N (80% vs 9%). In 6 of the 9 cases, the DMPs lasted until 38 to 40 weeks of postconceptional age. Five of the 6 infants with persistent DMPs suffered from severe undernutritional conditions. The other, who belonged to group N, was treated with corticosteroid for chronic lung disease. In 3 cases, DMPs were observed transiently and their undernutritional status was not so severe.

Conclusions. Our study indicated that a postnatal undernutritional condition was associated with DMPs in ELBWIs. Undernutritional status may affect electrophysiologic maturation.

Key Words: electroencephalographic • undernutrition • dysmature pattern

Abbreviations: EEG, electroencephalograph • ELWBI, extremely low birth weight infant • DMP, dysmature pattern • PDA, patent ductus arteriosus • CLD, chronic lung disease • PCA, postconceptional age • CNS, central nervous system • group N, nutritional group • group U, undernutritional group


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The maintenance of adequate nutrition is crucial in the management of extremely low birth weight infants (ELBWIs). The committee on Nutrition of the American Academy of Pediatrics has recommended that nutrition management of low birth weight infants should mimic postnatally the rate of in utero fetal growth and nutrient accretion.1 However, such nutritional conditions cannot be achieved in most ELBWIs because of intolerance for enteral feeding, necrotizing enterocolitis, and meconium disease.

Undernutrition during fetal and early neonatal period affects the growth of the central nervous system (CNS) and causes several microscopic changes.2,3 Benítez-Bribiesca et al2 suggested that severe protein-calorie malnutrition in early postnatal period produced apical dendrite abnormalities and these pathologic changes might be related to the neurophysiologic deficits. Escobar and Salas3 reported that neonatal undernutrition affected the amygdaloid nucleus. It is likely that undernutrition will disturb functional maturation of the brain during the neonatal period, especially in preterm infants, but this has not been fully understood.

Electroencephalography is useful to evaluate maturational changes of the brain during the neonatal period.4,5 Dysmature patterns (DMP) are a type of chronic-stage electroencephalograph (EEG) abnormalities characterized by the persistence of immature EEG patterns for postconceptional age (PCA).4,6 DMP are associated with poor neurologic outcome such as cognitive impairment.7–9 They are known to be observed in infants suffering from bronchopulmonary dysplasia7 and patent ductus arteriosus (PDA).9

The purpose of this study was to clarify the relation between nutritional state and the growth and functional maturation of the brain in ELBWIs.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
We prospectively studied the relation between nutritional state, and growth and functional maturation of the brain in ELBWIs. Forty-eight preterm infants, having a gestational age between 24 and 28 weeks and weighing <1000 g, were admitted to the neonatal intensive care unit of Ogaki Municipal Hospital from June 1997 to December 2000. Eighteen infants with congenital anomaly, small for gestational age, periventricular leukomalacia, or grade III or IV intraventricular hemorrhage were excluded. Serial EEGs were not recorded in 9 patients. Eventually, 21 infants completed serial EEG recordings. Gestational age was determined on the basis of ultrasound findings during the early stage of pregnancy and last menstrual period. It was confirmed by the New Ballard Score during the first few days of life.10 The result of the New Ballard Score was adopted, when ultrasound findings and/or the mother’s last menstrual period were not available, or when the estimated gestational age was discordant with physical examination.

The following data were collected from the medical records: antenatal corticosteroid use, gestational age, birth weight, 1- and 5-minute Apgar scores, body weight, head circumference, and enteral and parental nutritional intake.

All infants required mechanical ventilation because of respiratory distress. Synthetic surfactant was routinely used when an infant was diagnosed as having respiratory distress syndrome. Chronic lung disease (CLD) was diagnosed when supplementary oxygen was necessary at 36 weeks of PCA accompanied with characteristic radiographic changes. When it was difficult to extubate in infants with CLD, the corticosteroid therapy was considered by attending neonatologists. Our standard corticosteroid therapy for CLD was as follows: dexamethasone was administered intravenously in an initial dose of .50 mg/kg/d for 3 days, followed by .25 mg/kg/d for 3 days, and then .10 mg/kg/d for 3 days.

PDA was diagnosed when there were clinical symptoms such as heart murmur, tachypnea, tachycardia, cardiomegaly, and bounding pulse. We routinely performed prophylactic administration of indomethacine (.1 mg/kg, 1 or 2 doses) even if PDA was asymptomatic. When PDA was symptomatic, recommended doses of indomethacine were administered (.2 mg/kg at initial dose, .1-.25 mg/kg at second and third dose).

Apnea of prematurity was defined as a respitratory pause lasting for longer than 20 seconds or pause within 20 seconds associated with bradycardia (heart rate <100 beats per minute) and/or cyanosis. Intravenous aminophylline was used for infants with apnea. If an infant suffered from severe recurrent apnea, mechanical ventilation was indicated.

Sepsis was defined if an infant had severe deterioration of general condition associated with a positive blood culture.

This study was approved by the Committee of Medical Ethics of the Ogaki Municipal Hospital. Informed consent was obtained from the parents before enrollment.

Nutritional Managements
All infants were administered dextrose and electrolytes during the first 3 days of life. Total parenteral nutrition including amino acids, vitamins, and trace minerals was usually commenced on the fourth day of life. The enteral feeding was started as soon as possible using human milk in principle. The enteral feeding was begun at a dose of .5 to 1.0 mL every 3 hours. Amount of enteral feeding was increased at a rate of 10 to 20 mL/kg/d. When an enteral intake reached 100 to 120 mL/kg/d, parenteral nutrition was discontinued. We usually used human milk fortifier (HMS-1; Morinaga) with human milk after enteral nutrition was established. Human milk, fortified human milk, term formula, and preterm formula were assumed to contain 68 kcal/100 mL, 78 kcal/100 mL, 70 kcal/100 mL, and 80 kcal/100 mL, respectively. The nutritional intake was calculated in every postnatal week according to the composition of the parental and enteral regimen.

Infants were divided into 2 groups by the state of enteral feeding. Normal nutritional group (group N) included those who achieved enteral feeding of 100 mL/kg/d or more at 3 weeks of age. Undernutritional group (group U) included those in whom an amount of enteral feeding did not reach 100 mL/kg/d at 3 weeks of age or enteral feeding was discontinued because of clinical problems.

EEG Recordings
Polygraphic EEG recordings were performed at infant’s bedside using bipolar derivation with 8 surface electrodes (AF3, AF4, C3, C4, O1, O2, T3, and T4), according to the 10–20 international method as previously reported.9,11 Paper speed was 30 mm/s with a time constant of .3 seconds. Amplitudes were set at 10 µV/mm and high frequency filter at 60 Hz. EEGs were recorded for >30 minutes including both active and quiet sleep. The initial EEG was recorded within 72 hours of life and then recorded once every 2 to 4 weeks. All EEGs were evaluated by a well-trained neonatal neurologist (A.O.) who was blind to the clinical course of the infants except for PCA. Background EEG activities were evaluated according to the previously published criteria.6,11 Maturation of background EEG activities was evaluated in terms of the frequency and amplitude of {delta} activities, the incidence of theta waves including immature temporal {theta}, the incidence of brushes, and the continuity assessed by the percentage of discontinuous pattern and the duration of interburst intervals during discontinuous pattern.11,12 DMP were defined as the persistence of EEG patterns 2 weeks or more immature for PCA.

Statistical Analysis
Numerical data are presented as median (range). Statistical analyses between the 2 groups were performed using Mann-Whitney U tests for numerical variables and {chi}2 tests for categorical variables. Statistical significance was considered present at the level of P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Twenty-one infants were studied. Their median birth weight and gestational age were 852 g (558–980 g) and 25.6 weeks (24.1–27.9 weeks), respectively. Clinical characteristics and neonatal clinical events in groups N and U are shown on Table 1. Gestational age, rate of cesarean section, head circumference at birth, Apgar score, and the incidence of sepsis did not differ significantly between the 2 groups. In group U, birth weight was relatively smaller, the use of oxygen and ventilator tended to be longer, CLD was rather frequent, and antenatal corticosteroid tended to be less frequent. However, the differences were not statically significant in these items.


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  		TABLE 1. Patients’ Characteristics and Neonatal Complications

 
The causes of feeding disturbance in group U were as follows: feeding intolerance because of prematurity in 3, necrotizing enterocolitis in 2, water restriction because of PDA in 2, infection in 2, and meconium plug disease in 1. None of the infants in group U suffered from severe central nervous insults and/or severe deterioration of general condition during the study periods.

Weekly nutrient intake is presented on Fig 1. At the third postnatal week, the nutrient intake was significantly larger in group N than in group U (83.1 kcal/kg/d [45.8–88.5] vs 97.6 kcal/kg/d [87.2–107.5], P = .0003). Significant differences of nutrient intake between the 2 groups were constantly observed by the tenth postnatal week.



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  		Fig 1. The comparison of weekly averaged calorie intake in groups N and U. The solid square indicates mean value in group N; the solid circle indicates that in group U. The error bar presented 95% confidence interval. *, P < .05.

 
Weekly gain of body weight and head circumference is shown on Fig 2. Body weight was significantly heavier in group N than in group U at the fifth postnatal weeks (929 g [726–1087] vs 735 g, 464–949 P = .007). Similarly, head circumference was larger in group N than in group U after the sixth postnatal week (27.0 cm [24.5–29.0] vs 25.0 cm [21.7–26.0], P = .01). The differences of body weight and head circumference between the 2 groups were gradually increased by the 15th postnatal week.



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  		Fig 2. The comparison of weekly gain of body weight and head circumference. The solid square indicates mean value in group N; the solid circle indicates that in group U. The error bar presented 95% confidence interval. *, P < .05.

 
DMP were observed in 8 (80%) of 10 infants in group U. In contrast, DMP were seen in 1 (9%) of 11 infants in group N. DMP were more frequently seen in group U than in group N (P = .003). The chronological changes of DMP appearance were shown in Fig 3. DMP was persistent in 6 infants (cases 1–6) and was transient in 3 (cases 7–9). Undernutrition was relatively severe in 6 infants with persistent DMP. In cases 1 to 4, enteral feeding was not established after 6 weeks of age because they suffered from necrotizing enterocolitis, meconium plug syndrome, or severe infection. In case 5, total fluid intake was strictly restricted because of persistent asymptomatic PDA. In case 6, DMP were observed after dexamethazone therapy for CLD. This infant was the only infant in group N. Total calorie intake and head circumference were not different statistically between infants with persistent DMPs and with transient DMPs, although infants with persistent DMPs had less total calorie intake and tended to have a smaller head circumference (Fig 4).



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  		Fig 3. Chronological EEGs changes in infants with DMPs. Upper panel, cases with persistent DMPs; lower panel, cases with transient DMPs. U, group U; N, group N; N, normal EEG record; NEC, necortizing enterocolitis.

 


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  		Fig 4. The comparison of calorie intake and head circumference between infants with persistent DMPs and those with transient DMPs. The solid circle indicates calorie intake and head circumference of infants with persistent DMPs; the solid square indicates those of infants with transient DMPs. The bar represents median value.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Undernutrition can affect the development of CNS. Animal studies demonstrated that the effect of undernutrition is remarkable in cerebral13 and cerebellar cortices,14 and hippocampi,15 where cell proliferation is undergoing.16,17 Dendritic trees of the cerebrum also suffer a reduction of neuronal dendritic spines and branching.18,19 The early postnatal period of very premature infants corresponds with that of development of the CNS.20,21 It is well-known that severe undernutrition inhibits postnatal head growth also in human infants, especially in more premature infants. Brain weight and protein content were found to be reduced proportionately to head circumference in undernutritional infants.22 Winick and Rosso23 demonstrated significant reductions in brain weight, protein, and DNA content in infants who died of severe undernutrition. Our study revealed that head circumference as well as body weight was significantly smaller in group U. Calorie intake was also smaller among them. Thus, we consider that smaller circumference will be related to undernutrition because of insufficient enteral nutrition. Head growth during the early neonatal period is a good predictor of developmental outcome in very low birth weight infants.24 Infants in group U will be at risk for psychomotor retardation.

Most importantly, we demonstrated functional maturation delay in undernutritional infants using serial EEG recordings. Our study is the first 1 that proved undernutrition affects functional maturation of cerebral cortex, although Amin et al25 reported that maturational changes of brain stem auditory response in premature infants was affected by the types of enteral feeding. In this study, DMP were observed in 8 of 10 infants in group U. DMP were persistent in 6 of them. DMP are a type of chronic-stage EEG abnormalities and are characterized by the persistence of EEG patterns immature for PCA.6–8,26 DMP indicate not only a delay in maturational EEG changes but also a risk for later psychomotor retardation. Our previous study displayed that preterm infants with cognitive impairment often showed DMP subsequent to mild but prolonged EEG depression.9 Lombroso26 showed the infants with transient DMP usually had favorable outcomes, but those with persistent DMP had unfavorable prognosis. During the early neonatal period in ELBWI, myelination, growth of dendrites, and the establishment of synaptic connections are prominent.20,21 These processes are possibly disturbed by undernutrition. This can be related to a delay in maturational EEG changes during the neonatal period and later development of cognitive impairment.

Previous studies revealed that DMP were often recognized in infants with bronchopulmonary dysplasia,7 CLD, or PDA.9 Although this may be attributable to chronic hypoxia or unstable circulation, undernutrition may be another factor. Water intake is usually restricted during the management of CLD or PDA. Calorie intake will be inevitably decreased. Thus, nutritional state will tend to be insufficient in infants with CLD or PDA. It is interesting that only 1 infant with DMP with normal nutrition was treated with corticosteroid for CLD. Recently, several authors described that postnatal steroid therapy increased the rate of adverse neurologic outcome.27,28 Murphy et al29 reported postnatal steroid therapy impaired growth of cerebral cortical gray matter. Our study suggested that corticosteroid might also affect maturational EEG changes. Further studies will be necessary to determine the effects of postnatal steroid therapy to functional maturation of the brain in ELBWI.

The strength of this study is that our study is prospective one. Thus, the selection bias of the infants is thought to be very weak, if present. In addition, serial EEGs could be performed regardless of general and nutritional condition of infants. However, there are some limitations in our study. First, the clinical course was various among infants. Infants in group U tended to be smaller and required longer ventilator support. General condition was relatively poor and the incidence of CLD was high. However, treatment strategies were not different between the groups N and U in our institute. We consider that the management against clinical problems, such as acute/chronic respiratory failure, apnea of prematurity, and CLD, was not different between the 2 groups. Antenatal care including corticosteroid use had not been changed during the study period. Therefore, we consider that undernutritional state was a main factor that affected EEG maturation, although growth and maturation of the brain will be affected by the multiple factors. Second limitation is a small number of patients. Severe CNS complications such as intracranial hemorrhage and periventricular leukomalacia are common among very preterm infants. The number of infants without apparent CNS complications in a single hospital is inevitably small. Multicenter studies will be necessary to obtain a more definitive result.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Undernutrition was closely related to a delay in maturational EEG changes in ELBWIs. Although long-term outcome of these infants has not been clarified, they are at risk for neurologic sequelae. Further powerful studies are required to fully understand the relation between nutritional states and their effects to CNS in ELBWIs.


   ACKNOWLEDGMENTS
 
We thank technicians in the division of neurophysiological examination of Ogaki Municipal Hospital for recording neonatal EEGs.


   FOOTNOTES
 
Received for publication May 17, 2002; Accepted Oct 2, 2002.

Reprints requests to (M.H.) Maternity and Perinatal Care Center, Nagoya University Hospital, 65 Tsurumai-cho, Shouwa-ku, Nagoya 46-8550, Japan. E-mail: masahaya{at}med.nagoya-u.ac.jp


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics

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