Characteristics of the Follow-up Cohort
Infants were examined from February 2003 through June 2007. The number of infants eligible for the study and follow-up is shown in Figure 1. Of the 22 infants in the standard AA, 19 (86%) completed at least 4 visits and of the 21 infants in the early and high AA, 17 (81%) completed at least 4 visits. The demographics and clinical outcomes of those who failed to return or complete the follow-up at 18 to 24 months were comparable to those who did (Table 1). There was a trend toward lower GA on those infants lost to follow-up from the early and high AA group. In the group that completed the 18- to 24-month follow-up, there was a tendency of higher incidence of BPD in the early and high AA group (Table 1). The total number of days of mechanical ventilation was 15 ± 15 in the standard group versus 22 ± 19 in the early and high AA group (P = 0.2).
General Health and Growth Outcomes
The weight, length, and head circumference measures at each visit were converted to sex-standardized z scores. As expected for ELBW infants, all of the z scores were below the mean. The early and high AA infants had z score means for weight that were significantly lower than the standard AA group at 6, 12, and 18 months CGA as well as at 24 months chronological age (Fig. 2). In addition, the z scores for length/height and head circumferences were significantly lower for the early and high AA group at most visits (Fig. 2). The differences in weight and fronto-occipital circumference (FOC) were found mostly in boys at 6-, 12-, 18-, and 24-month visits (P < 0.05 for male differences between groups at each visit). Postdischarge outcomes, including hospital readmissions, use of pulmonary and seizure medications, blindness, and breast-feeding rates, were similar in both groups up to 12 months CGA (Table 2).
The Bayley II Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) scores at 6, 12, 18, and 24 months are detailed in Table 2. The MDI and PDI scores were similar between groups at each age tested, with the exception of a lower MDI score at 18 months CGA in the early and high AA group. This difference was not found at 24 months of age. No differences in the rate of cerebral palsy and blindness were seen between groups (Table 2). A total of 3 infants were blind: 1 had bilateral retinal detachment, 1 had bilateral optic nerve atrophy, and 1 had bilateral decreased vision caused by retinopathy of prematurity and laser therapy that qualified for legal blindness. There was no difference in the percentage of infants who received early childhood intervention services between groups at any GA (Table 2) or the number of visits with speech-language, physical pathologytherapy, or occupational therapy (data not shown).
Single and cumulative concentrations of 18 plasma AAs have been published (7). The cumulative concentrations of AAs negatively correlated with MDI at 18 months CGA (Fig. 3). Similarly, cumulative concentrations of essential and nonessential AA had a negative correlation with MDI at 18 months CGA (data not shown). The cumulative AA concentrations showed a negative correlation with FOC and weight z scores at 18 CGA and 24 months of age (Fig. 3).
Four AAs, phenylalanine, isoleucine, valine, and leucine, were associated with poor growth and low MDI and/or PDI scores. Levels of these AAs were divided into quartiles. Those with the highest phenylalanine concentrations had significantly lower MDI score (67 ± 14 high vs 82 ± 12 low phenylalanine, P < 0.05) and lower FOC z score at 12, 18, and 24 months CGA (P < 0.05 at each visit). Infants with the highest isoleucine and valine levels had lower MDI score at 12 and 18 months CGA (high isoleucine 67 ± 16 vs low isoleucine 81 ± 13, P < 0.05; high valine 68 ± 16 vs low valine 81 ± 13, P < 0.05) and lower weight and FOC z scores at 12, 18, and 24 months CGA (P < 0.05 at each visit). High plasma leucine was also associated with lower weight z scores at 6, 12, 18, and 24 months CGA (P < 0.05 at each visit). There were no differences in BW, GA, length of stay, Clinical Risk Index for Babies score, BPD, or IVH between those infants with high cumulative or single AA concentrations (upper quartile) versus those with lower concentrations (lower quartiles) with the exception of isoleucine. Infants with the highest isoleucine concentrations were smaller (BW 706 ± 174 g high quartile vs 846 ± 113 g, P < 0.05) and had a higher incidence of IVH (67% high isoproterenol vs 12% low isoproterenol group). All of the infants in the high quartiles of phenylalanine, isoleucine, valine, and leucine received early and high AA, whereas only 37% of infants in the lower quartiles were from the early and high AA group.
ELBW infants who received early and high IV AA during the first week of life had comparable MDI and PDI scores to infants who received the standard IV AA therapy at 2 years of age; however, those allocated to early and high IV AA were associated with impaired overall growth at 2 years. IV AA are widely used in premature infants and many advocate its administration of up to 4 g · kg−1 · day−1 during the first week of life to mimic fetal protein accretion rates (10); however, there are no prospective data on the long-term effects of this nutritional approach.
The short-term benefits of early provision of AA up to 3 g · kg−1 · day−1 in ELBW infants during the first few days of life have been demonstrated in several studies (2–5). There are reports of an association of early protein and energy intake with improved growth and neurodevelopment in ELBW infants (3,11). In a retrospective review of energy and protein intake during the first week of life, every 10 kcal · kg−1 · day−1 of energy intake was associated with a 4.6-point increase with the MDI and each gram per kilogram per day in protein intake was associated with an 8.2-point increase in the MDI. Their nursery protocol at the time started with parenteral nutrition on DOL 1 with 3.4 kcal/g carbohydrate infused, 1.0 g · kg−1 · day−1 of protein, and advanced by 0.5 g · kg−1 · day−1 up to 2.5 to 3.5 g · kg−1 · day−1(11). This standard protein regimen is similar to our control population. Therefore, the long-term effects of early and high IV AA supplementation (up to 4 g · kg−1 · day−1, reached as early as 48 hours of life) in ELBW infants remain relatively unstudied.
The primary outcome measure for the present study was incidence of hyperkalemia; early and high AA supplementation had no effect on the incidence of hyperkalemia in ELBW infants (8). The majority of ELBW infants with the exception of the most immature neonates appeared to tolerate both regimens. From birth to discharge, growth was similar between groups; however, infants in the early and high AA group had significantly reduced global growth after 3 months CGA, and these differences were maintained up to 2 years of age. Interestingly, those differences were more pronounced in boys; sex differences have been reported in other trials (3).
Several possibilities may explain the differences in growth at 2 years. Disproportional branched-chain AA concentrations have been linked to impaired growth and development in human and animal studies with possible mechanisms related to insulin release, tissue protein synthesis/degradation, catabolism of other branched-chain AAs, and transport of large neutral AAs into tissues, particularly the brain (12). Infants with metabolic disorders involving single high AA concentrations such as phenylketonuria have poor neurodevelopment and growth (13,14). ELBW infants face severe nutritional compromises during critical growth and development that may have lasting consequences (15).
Alternatively, early postnatal diet may have contributed to the differences in growth at 2 years, but enteral intake in the first week of life, time to reach full feeds, and days of TPN were similar between groups. Postdischarge diet would be another factor for the differences in growth at 2 years. The follow-up clinic devotes meticulous attention to caloric intake and calculations up to 12 months, which may be reliable when the infant remains on a predominantly milk diet. Afterwards, tracking the food intake of these infants has been difficult and is based upon parental recall. In the present study, there were no differences in the rates of continued breast-feeding and/or other socioeconomic factors between the 2 groups.
Our data showed a trend of a higher incidence in BPD in the early and high AA group. BPD, known to be associated with poor neurodevelopment and growth, could explain the growth differences (16–18). Our definition of BPD was based on continued oxygen supplementation at 36 weeks CGA. Our unit policy is to wean babies to maintain oxygen saturations in the low 90s. Ten of the 14 infants were weaned off oxygen shortly after the 36th week CGA, and the total days on mechanical ventilation were not different between groups. In addition, the clinical status of the infants at 40 weeks CGA (discharged off oxygen), the rehospitalization rates, and subsequent respiratory medications were similar between groups (Tables 1 and 2). Thus, chronic respiratory compromise does not appear to be the sole explanation for the growth differences between groups. Furthermore, those infants lost to follow-up from the early and high AA group tended to be of a lower GA, which theoretically could contribute to even more growth discrepancies.
We recently reported the plasma AA concentrations from this trial (7). There were major differences in AA concentrations when higher amounts of AA were provided. In the present study, we only found significant differences in MDI scores at 18 months. A larger sample size will be helpful to determine whether the lower MDI scores are truly significant and whether those differences persist beyond 18 months CGA. Of most concern are the negative correlations found between plasma AA concentrations and MDI scores and growth regardless of randomization.
In addition, infants who received early and higher parenteral AA had particularly higher concentrations of isoleucine, leucine, valine, phenylalanine, Lysine, Methionine, and proline (7). These between-group differences resolved by DOL 7 except for leucine, and therefore infants may tolerate this regimen after the first week of life. High leucine increases branched-chain α-keto acid dehydrogenase leading to diminished valine and isoleucine for protein synthesis (19). It is important to note that infants with the highest concentrations from 4 of these 7 AAs were associated with significantly lower MDI scores and worse growth outcomes up to 2 years of age. Demographic characteristics were similar to those with lower AA concentrations with the exception of group allocation and BUN levels. Interestingly, infants with higher isoleucine concentrations were smaller and had higher incidence of IVH, but our numbers are too small to consider any causal relation.
A weakness of the present study is the small sample size, and although follow-up was planned, growth and developmental parameters were not planned outcome measures. It is important to emphasize the strength that most infants had serial, detailed evaluations set a priori during the first 2 years of life by the premature infant development premiere program. This program has reported that infants younger than 27 weeks had decreased weight and FOC that started at 12 months CGA, reached a nadir at 24 months, and persisted. The MDI and PDI scores of those infants paralleled their growth z scores (20). The mean GA for both groups in the present study was <27 weeks gestation, and therefore differences found at 2 years of age may persist.
Because many premature infants have impaired neurological development, long-term follow-up is of utmost importance to evaluate effects of therapies used in the first few weeks of life. Although our study was not powered for long-term follow-up assessments, reporting the 2-year outcome from the present study will provide the basis for power calculations and hypothesis framework for future studies.
In summary, ELBW infants who received early and higher IV AA during the first week of life up to 4 g · kg−1 · day−1 did not have improved global growth at 2 years. Before this therapy becomes standard of care, further larger trials are needed to assess the best strategy of IV AA advancement and dosage to provide the most benefit and long-term safety.
We thank the personnel from the premature infant development premiere program in San Antonio, TX, for their dedication to the children and thorough evaluations.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
Bayley II; blood urea nitrogen; mental developmental index; protein; psychomotor developmental index