Published online December 31, 2007
PEDIATRICS Vol. 121 No. 1 January 2008, pp. 148-156 (doi:10.1542/peds.2007-1267)
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ARTICLE

High-Energy and -Protein Diet Increases Brain and Corticospinal Tract Growth in Term and Preterm Infants After Perinatal Brain Injury

Lyvia Dabydeen, MB, BSa, Julian E. Thomas, MDa, Tessa J. Aston, MSca, Hilary Hartley, MSca, Sunil K. Sinha, MD, PhDb and Janet A. Eyre, MBChB, DPhila

a Developmental Neuroscience, School of Clinical Medical Sciences (Child Health), University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom
b Department of Paediatrics and Neonatology, James Cook University Hospital, Middlesbrough, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Our hypothesis was that infants with perinatal brain injury fail to thrive in the first postnatal year because of increased energy and protein requirements from deficits that accumulated during neonatal intensive care. Our aim was to assess whether dietary energy and protein input was a rate-limiting factor in brain and body growth in the first year after birth.

METHODS. We conducted a prospective, double-blind and randomized, 2-stage group sequential study and controlled for gestation, gender, and brain lesion. Neonates with perinatal brain damage were randomly allocated to receive either a high- (120% recommended average intake) or average (100% recommended average intake) energy and protein diet. The study began at term and continued for 12 months. Three-day dietary diaries estimated energy and protein intake. The primary outcome measure was growth of occipitofrontal circumference. Other measures were growth of axonal diameters in the corticospinal tract, which were estimated by using transcranial magnetic stimulation, weight gain, and length.

RESULTS. The study was terminated at the first analysis when the 16 subjects had completed the protocol, because the predetermined stopping criterion of >1 SD difference in occipitofrontal circumference at 12 months’ corrected age in those receiving the higher-energy and -protein diet had been demonstrated. Axonal diameters in the corticospinal tract, length, and weight were also significantly increased.

CONCLUSIONS. These data support our hypothesis that infants with significant perinatal brain damage have increased nutritional requirements in the first postnatal year and suggest that decreased postnatal brain growth may exacerbate their impairment. There are no measures of cognitive ability at 12 months of age, and whether there will be any improvement in the status of these children, therefore, remains to be shown.

Key Words: nutrition • brain growth • corticospinal tract • perinatal brain injury • neonatal encephalopathy • white matter injury • human • randomized • double-blinded

Abbreviations: EAR—estimated average requirement • OFC—occipitofrontal circumference • TMS—transcranial magnetic stimulation • CMCD—central motor conduction delay

Infants with significant brain injury commonly suffer from growth faltering. Although nonnutritional factors related to neurologic pathophysiology will have an impact on growth,1 the pattern of their early growth failure is typical of chronic undernutrition, where body mass is lost before length and brain growth is compromised, suggesting that the early nutritional needs of these infants are not being met.2,3 The growth faltering begins very early, before the development of abnormal neurologic signs; thus, dysphagia is unlikely to be a major factor initially.2,4 It is now appreciated that critically ill neonates accumulate deficits in energy and protein during intensive care, which are not recovered by the time of discharge.5–8 For preterm and term infants, both the accumulated total energy and protein deficits predict the degree of growth faltering during the acute hospital admission.7 Furthermore, it is increasingly appreciated that, to achieve appropriate growth rates after discharge, the dietary intake of these infants must be increased above recommended average requirements9 to meet not only their needs for normal maintenance and growth but also that required to catch up the energy and protein deficits.10 Our hypothesis is that, in infants who suffered significant perinatal brain injury, failure to meet their increased energy and protein requirements acquired during the acute illness contributes significantly to the growth faltering that occurs in the first 6 to 12 months after discharge from hospital. Thus, a component of the early growth faltering arises from relative undernutrition and may be preventable.

It has long been recognized that the most striking consequence of undernutrition during the first 6 to 12 months after birth is permanently reduced brain size,11–17 associated with a thinner cerebral cortex,18 diminished number of neurons,19 reduced myelination,20 poor dendritic arborization, and changes in the microscopic features of dendritic spines, such as a reduction in their width and number.21,22 Numerous studies have documented the relationship between subnormal head growth and such adverse neurodevelopmental outcomes as decreased perceptual motor skills, general cognitive ability, language, academic achievement, adaptive behavior, and higher parental ratings of attention problems. When it has been tested, associations between subnormal head circumference and adverse developmental outcomes remain significant despite controlling for sociodemographic and neonatal risk factors and for major neurosensory impairment.23–33 Early postnatal brain growth seems to be the most sensitive period for later IQ. In children born at term, IQ scores at 8 years are highest in children whose heads grew most during the first year, even after adjusting for confounders.34,35 Head growth after infancy is not associated with later IQ scores and does not compensate for poorer growth in the first year of life.34 Findings from studies of very low birth weight infants also suggest that the critical period for catch-up brain growth, in terms of later intelligence, may be confined to the first year of life.28,32

If our hypothesis is correct, failure in the first year after birth to meet the additional nutritional requirements of children who have suffered acute perinatal brain injury is likely to not only compromise their overall growth but also growth of the brain, thereby compounding their impairment. The aim of our study was to assess whether a high-energy and -protein diet would lead to significantly greater brain and body growth in the first postnatal year for infants who suffered significant perinatal brain injury.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
We undertook a prospective, randomized, and double-blinded comparison of the growth of the brain and overall body growth in the first 12 months after term in infants with acute perinatal brain injury fed either a diet that met recommended estimated average requirements (EARs) for energy (average-energy group) or a high-energy diet with a target energy input of 120% EAR (high-energy group).9 For both groups, the target for their protein/energy ratio was 2.5 g/420 kJ (100 kcal) to 3.6 g/420 kJ (100 kcal), as recommended by the expert panel for the American Society for Nutritional Sciences.36 Ethical approval was obtained according to the Declaration of Helsinki from the ethical committees of the participating centers, as was written informed consent from the parent(s). To achieve double-blinding, only the pediatric nutritional team composed of a consultant specializing in gastroenterology and childhood nutrition (Dr Thomas) and pediatric dieticians (Ms Aston and Ms Hartley) was aware of subject allocation. The remainder of the research team and the families were blinded to subject allocations, which were not revealed to the investigators until after the principal data analyses were performed.

Subject Recruitment
Subjects were recruited by the research associate (Dr Dabydeen) while inpatients in 1 of the 4 level 3 neonatal intensive care nurseries in north east England. Subjects were allocated to treatment groups by minimization, a method of ensuring excellent balance between groups for several prognostic factors, even in small samples. With minimization, the group allocated to the next enrolled participant depends on the characteristics of those participants already enrolled. The aim is that each allocation should minimize the imbalance across multiple factors.37 If the parent(s) gave consent for inclusion, the infants were allocated to be fed to a target nutritional input of either 100% or 120% of the estimated average energy requirement for age and birth weight centile.9 Dr Thomas was responsible for minimization, which was computer generated and controlled for 3 prognostic factors: gestation (≤32 or >32 weeks), gender, and brain lesion.

There were 2 inclusion criteria: severe neonatal encephalopathy38 and/or gestation of ≤32 weeks with white matter disease.39 Subjects were excluded if they had congenital malformations, chromosomal abnormalities, or significant chronic illnesses (ie, pulmonary, cardiac, renal, or gastrointestinal) or had taken medication affecting growth and, therefore, would be expected to have atypical postdischarge growth.

Children with severe neonatal encephalopathy were identified clinically based on their history, electroencephalogram findings, and clinical signs.38 To identify subjects with white matter disease, all of the infants born at ≤32 weeks of gestation had ultrasound scans performed by a consultant radiologist using a 7.5-MHz transducer at postnatal days 1 to 3 and 7 to 10 and at ≥3 weeks after birth. White matter disease was defined as evidence of multiple, bilateral echolucencies, characteristic of cystic periventricular leukomalacia and/or intraventricular hemorrhage with parenchyma echodensities or lucencies consistent with parenchymal infarction and/or nonprogressive ventricular enlargement, defined as ≥1 lateral ventricle greater than the 99th percentile, without an increased rate of head growth.39

Nutrition
The target nutritional energy and protein inputs were computed throughout the 12 months according to the infant's age and birth weight percentile.9 For weight reference standards, the revised United Kingdom 1990 reference data (version 1996/1) were used.40 The parents and the dietician agreed on individualized feeding plans based on the child's target energy and protein input and ensuring a balanced intake of vitamins and minerals. A dietician (Ms Aston or Ms Hartley) contacted the family weekly and visited the family in the home as required to ensure that these targets were being achieved. The strategies used to achieve the targets included increasing feed volumes, altering food texture and thickness, increasing parental feeding skill, and correcting the feeding position of the infant. If these measures failed, energy and protein supplementation of feeds was introduced. Ethical approval did not allow for invasive interventions, such as gastrostomy feeding, and such interventions remained the decision of the clinical team involved with each child's care. The difference between target and intake was monitored weekly, using parental 24-hour dietary recall. On the basis of these data, feeding plans were continuously adjusted. A formal 3-day, prospectively collected food diary was used to estimate nutritional intake near term and at 3-monthly intervals. Immediately before each diary, a dietician visited the home to provide training in the estimation of the volumes and the description of the food and fluids consumed and wasted. During the visit the dietician observed a feed to confirm the accuracy of the estimations. The parents were provided with record sheets and chose 3 days when the children were eating their usual diet. For children fed infant formula, the volume consumed was recorded. Two infants (1 in each intervention group; Table 1) were partially breastfed, but breastfeeds were not included in the target intake or in the food diary. For those taking a mixed diet, the parents also gave a full description of the foods offered, including keeping food labels. For home-prepared food, parents provided recipes and described the cooking methods. Immediately after completion of each diary, the dietician revisited the home to review and clarify the record. The forms were then coded by the dieticians, and the daily intakes of energy, protein, and nutrients were computed using a food database (Microdiet, Downlee Systems Limited, High Peak, United Kingdom [www.microdiet.co.uk]).


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  		TABLE 1 Characteristics of Subjects

 
Deprivation
To look for possible socioeconomic differences between the groups that might confound the findings, the deprivation rating of the subjects was determined using the Townsend Deprivation Scale and the ward in which they were resident. The Townsend Deprivation Scale is particularly suitable for our study, because it is based on data from the north of England and provides an index of material deprivation for all 678 wards in which are subjects could have been resident, derived from 4 variables: unemployment, car ownership, housing tenure, and household overcrowding.41

Outcome Measures
All of the outcome measurements were made by Dr Dabydeen and Dr Thomas, who were blind to subject allocation. Measurements were made at baseline (term) and final measurements at 12 months; intermediate measurements were also made to provide information on the pattern of growth in the first 12 months. Head circumference and weight were, therefore, also measured at 3 monthly intervals (Fig 3 A and B), corticospinal tract axonal diameter was also estimated at 4 and 8 months (Fig 3C), and length was also measured at 6 months. SD (z) scores for anthropometric measures, derived from the British 1990 growth reference, which was revised in September 1996, were used so that age and gender data could be combined.40


Figure 3
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  		FIGURE 3 OFC (A), weight (B), and maximum axonal diameter in the corticospinal projection to the motoneurons of biceps (C) in the 2 intervention groups. Filled circles indicate the high-energy group; filled squares, average-energy group; open triangles, no-consent group. The numbers above each graph are the P values for the comparison between the 2 intervention groups at each time point. Weight and OFC are expressed as z scores corrected for baseline at term. Data are graphed as mean and 95% CLs for the mean except for the axonal diameters for the no-consent group, which are individual values for the 3 subjects joined by a dotted line. The hashed line indicates the mean values for axon diameter obtained in our previous studies of normal subjects by using TMS. The stars represent data obtained by direct postmortem measurement obtained at the level of the pyramid in a neurologically normal subject at term and at 4 and 8 months (reported by Verhaart77).

 
Weight was measured to the nearest 10 g, with the child unclothed, by using a portable digital electronic scale. Length was measured using a horizontal stadiometer accurate to 1 cm. For both weight and length, 3 measurements were made, and the mean was calculated.

Brain Growth
Two measures for brain growth were used. The first was occipitofrontal circumference (OFC), because it is a validated indicator of brain volume, weight, and DNA content in newborns, children, and adults.17,42–45 The second was axon diameter growth in the corticospinal tract. This was chosen because it can be measured noninvasively with transcranial magnetic stimulation (TMS),46 and axon diameter growth is a marker for growth of the pyramidal neuron as a whole, because there is a positive linear correlation between axonal diameter and soma size and the horizontal spread of the dendritic tree in layer 5 pyramidal neurons of the motor cortex.47–50

Occipitofrontal Circumference
OFC was measured by using a flexible, nonstretchable tape scaled to 1 mm. The tape was placed superior to the supraorbital ridge and adjusted around the occiput until a maximum circumference was obtained from ≥3 measurements.

Corticospinal Axonal Diameter
TMS (MagStim Company Ltd, Whitland, Wales) was used to estimate the conduction delay within the corticospinal tract following previously published methods.46 A figure-8 coil, with each circle having a diameter of 55 mm (SPC-ENG 8618; MagStim Company Ltd), was used to excite corticospinal neurons. TMS was applied during the spontaneous contraction of biceps. Electromyogram was recorded bilaterally from biceps using miniaturized, skin-mounted differential amplifiers. A –3-dB bandpass of 5 to 1500 Hz was applied, and the signals were sampled at 5 KHz and stored on computer. The onset latency of the motor-evoked potentials in biceps was defined as when the electromyogram of biceps clearly deviated by eye from background activity. Total motor conduction delay was estimated from the shortest onset latency of 20 motor-evoked potentials at a stimulation intensity of 1.2 times the threshold or at the maximum stimulator output. Magnetic stimulation over the C5 vertebra excited spinal motor roots. The longest onset latency of 20 responses in biceps estimated peripheral motor conduction delays. Subtraction of peripheral from total motor conduction delays estimated central motor conduction delays (CMCDs).

The corticospinal pathway length to C5 was estimated from the distance from the vertex to vertebra prominens, which we have demonstrated previously to be 1.3 times the corticospinal pathway length.51 The maximum conduction velocity of corticospinal axons projecting to C5 was calculated by dividing this distance by the conduction delay of corticospinal axons projecting to bicep spinal motoneurons (CMCD for biceps minus 1 millisecond for spinal transsynaptic delay).46 The maximum diameter was then determined using the ratio between the conduction velocity of myelinated corticospinal axons and their diameters of 5.2 m · seconds–1 · µm–1, derived by using invasive measurements in subhuman primates, including developing primates.52

Statistical Analysis
The study was designed to test the 1-sided hypothesis that brain growth for those fed the higher-energy diet would be greater than that of those fed the average-energy diet.53 We decided a clinically significant effect would be a 0.5-SD increase in OFC. There was evidence, however, that there might be a more substantial effect, because additional nutrition given early in development to preterm infants increased the OFC by >1 SD and reduced the incidence of cerebral palsy at the age of 7 to 8 years by ninefold.54,55 Therefore, for ethical considerations, a 2-stage, 1-sided, group-sequential design was adopted with a prespecified stopping criterion of a ≥1 SD increase in head circumference.53 The first-stage analysis was specified to occur when 8 subjects had been recruited to each group, giving an 80% power at the .05 level of detecting a 1-SD increase in OFC at 12 months’ corrected age. If the study then continued, the final analysis was specified to take place when 32 subjects had been recruited into each group, giving an 80% power of detecting a 0.5-SD increase at the .05 level. The study design allowed for the possibility that our first-stage analysis may produce significant results; thus, minimization was chosen as the most suitable tool to achieve a balance of critical prognostic variables between small groups. The only statistical comparisons made were based on the a priori hypotheses. The 2 groups were compared by analysis of covariance, examining baseline corrected data, with birth weight z score included as a covariant to control for the effect of extreme outliers.56 Data from children who were eligible to participate but whose parents refused consent have been included for comparison in the graphs but were not included in the statistical analyses.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The study was stopped at the first-stage analysis because the prespecified stopping criterion of a >1-SD increase in OFC at 12 months of age had been demonstrated in the high-energy group compared with the average-energy group (Fig 3A).

Characteristics of the Subjects
Forty-three infants were considered for inclusion. Eight were excluded because of chronic lung disease. The parents of 35 infants were approached for consent, of whom 16 gave consent; 5 were term infants (birth weight z score: mean: –0.07; median: –0.08; range: –1.52 to + 1.67) and 11 were preterm infants (gestation: mean: 28 weeks; median: 28 weeks; range: 23–31 weeks; birth weight z score: mean: –0.27; median: –0.04; range: –1.37 to 0.91). The parents of 19 declined, and these infants formed the no-consent group. Six were term (birth weight z score: mean: –0.38; median: –0.5; range: –1.59 to + 1.57) and 13 were preterm (gestation: mean: 28 weeks; median: 27 weeks; range: 24–31 weeks; birth weight z score: mean: 0.52; median: 0.50; range: –1.59 to 1.57). Mortality in the first year was 6%, representing 2 infants, both from the no-consent group.

All 16 of the subjects recruited completed the study protocol, and all were included in the analysis. The 19 who declined consent agreed to weight and OFC data being collected, and 3 also consented to TMS studies.

The characteristics of recruited subjects by group allocation (high-energy group and average-energy group) and those whose parents declined consent (no-consent group) are summarized in Table 1 and Fig 1A. There was no significant difference between the groups on the level of deprivation (Table 1; P = .64). There were no significant differences in gestational age at birth (Fig 1A; P = .53), the number of days the infants received assisted ventilation while in intensive care (mean ± 95% confidence limits: high-energy group: 13.6 ± 3.5; average-energy group: 9.12 ± 1.70; P = .62), or in baseline entry anthropometric measures between the groups (Table 1; Fig 1A; birth weight: P = .98; baseline weight: P = .85; birth OFC: P = .33; baseline OFC: P = .27). The weight z scores were significantly lower at discharge from the hospital compared with that at birth for both groups (Fig 1B; paired t test: high-energy group: P = .047; average-energy group: P = .01).


Figure 1
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  		FIGURE 1 A, Gestational age, weight, and OFC at birth and at baseline for the 2 intervention groups. The data are graphed as mean and 95% CLs for the mean. B, Comparison of the weight z scores at birth and at baseline for the 2 intervention groups. Circles indicate the high-energy group; squares, average-energy group; Triangles, no-consent group.

 
Estimated Nutritional Intake
All of the children were fed orally, and none had a gastrostomy inserted during the period of the study. Figure 2 shows the estimated energy intake and the protein/energy ratios achieved. The mean energy intake for the average-energy group remained close to the target of 100% EAR. The mean energy intake of the high-energy group was also close to the target (mean: 119%) for the first 6 months. It then fell progressively to a mean of 101% EAR by 12 months’ corrected age (Fig 2A). The mean protein/energy ratios remained within our target range of 2.5 g/420 kJ (100 kcal) to 3.6 g/420 kJ (100 kcal) throughout the first 12 months (Fig 2B).


Figure 2
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  		FIGURE 2 Estimated energy (A) and protein intake (B) (1 kcal = 4.2 kJ) for the 2 study groups. Intake is expressed as the percentage of the EARs for age and birth weight centile of the subject. Data are graphed as mean and 95% CLs for the mean. Filled circles indicate the high-energy group; filled squares, average-energy group.

 
Occipitofrontal Circumference
The high-energy group had significantly greater head circumference z scores at 12 months (Fig 3A). All 3 of the groups showed an initial drop in the OFC z scores in the first 6 months. Thereafter, the high-energy group showed an increase in OFC z scores, whereas the average-energy group showed a continuing decline. The no-consent group showed the most rapid decline in OFC z scores.

Weight
The z scores for weight for the high-energy group were greater throughout the study than those of the average-energy group (Fig 3A). The differences were significant at 3 months and 6 months. The no-consent group had the lowest-weight z scores throughout the study (Fig 3B).

Length
The high-energy group maintained a normal length (mean z score ± 95% confidence limits: 6 months: –0.15 ± 0.55; 12 months: 0.31 ± 0.58), whereas the average-energy group showed faltering in linear growth (mean z score ± 95% confidence limits: 6 months: –1.34 ± 0.52; 12 months: –0.98 ± 0.0.60). The differences between the high-energy group and the average-energy group were significant (6 months: P = .019; 12 months: P = .04). No measures of length were made in the no-consent group.

Corticospinal Axonal Diameter
All 3 of the groups had similar maximum axonal diameters near term (Fig 3C). The high-energy group showed the greatest rate of growth so that at 7.5 and 12 months’ corrected age, their axonal diameters are significantly larger than those in the average-energy group. The 3 children studied in the no-consent group showed little increase in axonal diameter.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This is the first double-blinded, randomized, and prospective study to assess the effect of dietary supplementation on the growth of human infants who have been critically ill in the neonatal period and suffered parenchymal brain injury. A previous study of supplemental nutrition in unselected premature infants54,55 and animal experiments had suggested that the effect might be large, and indeed it was, with a >1-SD increase in head size and corticospinal axonal diameter at age 1 year with significantly greater weight and length gains also observed in the group fed a high-energy and -protein diet compared with those fed an average-energy and -protein diet.

Both groups had significantly lower weight z scores on discharge from the hospital than at birth and so had a real need for catch-up growth in the first year. Despite the estimated mean energy intake being maintained at or greater than their estimated average energy requirements for age and birth weight percentile, rather than showing catch-up growth, the children in both experimental groups showed progressive weight faltering when their energy intake was close to 100% EAR (Figs 2 and 3; from birth in the average-energy group and from 6 months in the high-energy group). This supports our hypothesis that these children required a greater-than-average energy and protein intake just to achieve appropriate growth rates, let alone catch-up growth in the first year.

It is possible that energy and protein intake were significantly overestimated by parents; however, we believe this is unlikely, because before weaning, the parents were simply required to record the volume of feed consumed. In the later 6 months, after the introduction of solid food, we minimized the possibility of overestimation by careful training and by observing feeds to confirm parental estimates at the start of each 3-day diary.

For both groups, weight z scores were significantly lower at discharge from the hospital compared with at birth, providing strong evidence for significant energy and protein deficits accumulated during their acute illnesses (Fig 1B).7 It is conceivable also that repair of acute brain injury requires additional energy over and above that needed for normal brain growth. As far as we are aware, there have been no studies either in humans or in animal models that have addressed this issue. Finally, the infants recovering from acute brain injury may have dysregulation of central energy homeostasis. There is some evidence to support this in that both term and preterm infants without brain damage, when offered calorically dense feeds, consume lower volumes than those offered less energy-dense feeds. Thus, there is little difference in the overall energy intake, implying that the neuroendocrine control of energy intake is mature before term.57–60 In contrast, the infants in our high-energy group maintained an increased energy input for the first 6 months despite being fed calorically dense feeds (Fig 2A), suggesting they had impairment of, or delay in, the maturation of energy homeostasis.

The observed growth benefit in those fed the high-energy and -protein diet may have resulted from either increased energy or protein intakes (Fig 2).61,62 It is academic to try and argue for or against either, because protein and energy needs are reciprocally limiting. If energy intake is insufficient, protein is used as an energy source, and the nitrogen balance becomes less positive. Increasing the caloric intake will spare the protein loss and improve nitrogen retention, but with limited protein intake, the protein retention reaches a plateau, and the energy excess is used for only fat deposition.8,36 It was for these reasons that our target protein/energy ratio in both our experimental groups was between 2.5 g/420 kJ (100 kcal) and 3.6 g/420 kJ (100 kcal), as recommended by the expert panel of the American Society for Nutritional Sciences.36 Increased intakes of other dietary constituents, such as zinc, calcium, phosphorus, and vitamins, may also have contributed.8,63 However, the intakes of vitamins, minerals, and essential fatty acids for those in both intervention groups far exceeded reference nutrient intake norms. These factors are unlikely, therefore, to be rate limiting when comparing growth between the 2 intervention groups but may well have been important factors when considering the failure to thrive observed in the no-consent group when compared with both intervention groups.

It is likely that the support and education provided to the family by a dietary therapist going regularly into the home also has a beneficial effect. This does not, however, explain the difference between the 2 intervention groups, because there were no significant differences between the groups in the hours of therapy time (median [range]: contacts: high-energy group: 38 h [14–80 h]; average-energy group: 28 h [10–78 h]; duration of each home visit: high-energy group: 0.97 h [0.72]1.23 h]; average-energy group: 1.01 h [0.84–1.22 h).

The growth of both our average- and high-energy groups was better than that described in 2 previous studies of the early growth of similar children with perinatal brain injury. In contrast, the pattern of growth of the 19 infants in our no-consent group was very similar, with mean weight z scores falling to –2 by 12 months of age (Fig 3).2,64 It is noteworthy that, despite severe failure to thrive, none of the children in the no-consent group were referred by their clinicians to a specialist nutritional service during the period of the study or had gastrostomies placed. We hypothesize that the progressive onset of feeding difficulties compromised the intake of the children in the no-consent group and that their intake increasingly did not even meet the average recommended energy intake, as has been described by Sullivan et al65 in older children with cerebral palsy.

There was a striking difference in the rate of head circumference growth between the 2 study groups, with the high-energy group having significantly greater head circumferences at 12 months than the average-energy group. The no-consent group showed the greatest faltering of head circumference growth. None of the 3 groups maintained their birth or enrollment z score for OFC; this is not surprising, because all either had ultrasound evidence of white matter loss or had suffered a very severe encephalopathy, likely to lead to neuronal loss. Head circumference is an excellent predictor of brain volume, weight, and DNA content.17,42–45 Children without brain damage who die during the first year of life with severe undernutrition have significantly reduced OFCs, total brain weight, and RNA and DNA content.14–17 Postnatal catch-up growth in OFC in small-for-gestational-age infants only occurs if adequate nutrition is achieved during the first year.29,66,67 The children in the average-energy group and the no-consent group are likely, therefore, to have permanent reductions in brain volume, weight, and cell number in comparison with the high-energy group.

TMS revealed nearly normal growth of corticospinal axonal diameters in the high-energy group (Fig3C), whereas it was significantly reduced in the average-energy group. Disturbingly, the 3 children studied from the no-consent group demonstrated almost no growth in maximum axonal diameter. Prolonged CMCDs have been reported previously in undernourished children, consistent with decreased axonal conduction velocities and diameters,68 and, as in the present study, the degree of prolongation was related to the severity of growth faltering. Undernourishment during early development in the rat leads to permanent reductions in corticospinal tract axonal diameters, implying that the reduced axonal diameters observed in our study at 12 months of age may persist into adulthood.69,70 Because axonal diameter growth is a marker for growth of the neuron as a whole, these data imply decreased neuronal growth in the average-energy group and the no-consent group relative to the high-energy group.47–50 Consistent with our findings, decreased soma size, dendritic arborization of cortical pyramidal neurons, dendritic spine number, and synapse/neuron ratio have been found after undernourishment during development in animals.71 Similar changes are observed in histopathological studies of the pyramidal neurons of the motor cortex in children who die after undernutrition in the first year after birth.21,22 Thus, we propose that the reduced axonal diameters of the subjects in the average-energy group and the no-consent group are markers for decreased pyramidal neuron soma size, dendritic arborization, and synapse number and indicate that undernutrition during the first 12 months leads to exacerbation of the original neurologic deficit.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
An implicit assumption by many clinical caregivers is that abnormalities in growth and body composition in infants with significant brain injury are because of unalterable aspects of the disease process and, thus, even very severe failure to thrive is tolerated, as is clearly demonstrated in our no-consent group. Our randomized and double-blinded study establishes that a component of their growth failure in the first year is preventable with early intervention by a skilled nutritional team. The long-term benefits of increased nutrition and increased brain and body growth for children with significant perinatal brain injury are unknown, because previous studies of postnatal nutrition and neurodevelopmental outcome have predominantly excluded such infants. However, randomized intervention studies investigating the benefits of nutritional supplementation for children who are undernourished or at risk of undernourishment have demonstrated long-term benefits for both motor development and academic achievement if the intervention begins before 12 months of age.72–75 All of the infants in our study had very significant brain damage, and the majority are likely to have significant neurologic sequelae.61,76 Neurodevelopmental tests are not sensitive enough to distinguish between degrees of severity of impairment in infancy and early childhood. We have, therefore, elected to wait and perform detailed reassessments of the children at the age of 8 years when we can perform MRI scans without the need for a general anesthetic and can assess their motor and cognitive outcomes in detail with appropriately sensitive tests. Nonetheless, the benefits of supplemental nutrition in terms of body and brain growth indicate that additional studies are required, directly measuring the energy and protein balance of high-risk infants with parenchymal brain injury to define an optimal diet that meets their nutritional needs during this critical period of brain growth.


   ACKNOWLEDGMENTS
 
Funding for this study was obtained from the Newcastle Health Care Charity and the Wellcome Trust.

We thank the parents who willingly consented to their child's involvement in the study and the consultants at the NICUs who agreed for their patients to be included in the study.


   FOOTNOTES
 
Accepted Jul 3, 2007.

Address correspondence to Janet A. Eyre, MBChB, DPhil, Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Queen Victoria Road, Newcastle Upon Tyne NE1 4LP, United Kingdom. E-mail: j.a.eyre{at}ncl.ac.uk

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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