Postnatal growth restriction (PNGR) is a common finding during neonatal hospitalization in very low birth weight (VLBW) infants who are frequently described small-for-gestational age (SGA) at discharge (1–3). Insufficient nutritional support is the primary etiology of PNGR in VLBW infants (4,5), and both have been associated with impaired neurodevelopmental outcomes (6–8), metabolic disorders (9–11), and persistent short stature (9,12,13). Early “aggressive” nutrition has been proposed for VLBW infants as more optimal nutrition (14–16). This concept has been translated in the recent recommendations (17–19). A minimum of 40 kcal/kg/day and 2.0 g/kg/day of protein is advocated from the first day of life and should be increased to 120 kcal/kg/day with 3.8 g/kg/day of protein by the end of the first week (17–22).
A significant variation has been observed regarding nutritional practices among neonatal intensive care units (NICUs) (15,23–26). The aim of this study was to evaluate postnatal growth during the early postnatal, intermediary, and stable growth periods until discharge in VLBW infants after implementing optimized nutritional policies, which are based on the most recent recommendations.
PATIENTS AND METHODS
This study is a prospective, observational, noninterventional, and single-center cohort study in infants with a birth weight (BW) of <1250 g. Exclusion criteria were admission after 24 hours of life or hospitalization in the NICU shorter than 3 weeks. Severely ill infants and infants with congenital anomalies were not excluded. Final evaluation was completed at either discharge from the NICU or 40 weeks’ postmenstrual age (PMA).
A standard ready-to-use parenteral nutrition (PN) solution was prepared by the hospital pharmacy containing per 100 mL:2.7 g amino acids (Primene 10%, Baxter, Clintec Benelux, Brussels, Belgium), 12 g dextrose, electrolytes, and minerals (Table 1). PN was initiated during the first hours of life. To supply a minimum of 40 kcal/kg/day with 2.0 g/kg/day of protein on the first day of life, additional amino acids were added to the standard PN solution during the first 3 days of life. An intravenous lipid emulsion (Clinoleic 20%, Baxter) also was administered from the first day of life. Nutritional supplies were increased progressively according to our revised nutritional protocol to reach recommended intakes (Table 2). The use of insulin was limited to treat glucose intolerance only when serum glucose was >1.8 g/L. PN could be discontinued if enteral feeds were well tolerated once 120 mL/kg/day had been achieved and tolerated.
Minimal enteral feeds of human milk (HM), own mother's milk, or bank pooled donor's HM were initiated when infants were clinically stable. Enteral feeds were increased by 10 to 20 mL/kg/day until 160 to 180 mL/kg/day according to tolerance. Upon achieving 50 mL/kg/day enteral feeding, human milk fortifier (HMF) (Enfamil Human Milk Fortifier, Mead Johnson, Evansville, IN) was gradually introduced up to full fortification (4 packs/100 mL) when more than 100 mL/kg/day was well tolerated. During the study period, 12 infants on full enteral feeding received an individualized fortification of HM for a period of 1 to 6 weeks. HM composition was determined daily by Milcoscan and enriched with medium-chain fatty acids (Liquigen, Nutricia, Bornem, Belgium) to reach a HM fat content of 4 g/100 mL and with HMF to reach a protein supply of 4.1 g/kg/day (27). Preterm infant formulas (PTFs), 80 kcal/100 mL and 2.9 to 3.2 g protein/100 kcal, were substituted for HM in infants with appropriate feeding tolerance when HM was not available.
Nutritional intakes from PN, HM, PTFs, and supplements were calculated from patients’ medical charts daily during the first 14 days of life and weekly thereafter. Energy intake is expressed in kilocalories (1 kcal = 4.18 kJ). The manufacturer's label provided detail of the commercial products’ nutritional content. HM nutrient content was derived from HM analysis performed in our nutrition laboratory and estimated to be 64 kcal, 1.4 g of protein, 3.2 g of fat, and 7 g of carbohydrate per 100 mL, which is consistent with previously published literature (28).
Growth parameters collected included daily body weight measurements (±5 g, Seca 727, Seca Corp, Hamburg, Germany), crown-heel length, and head circumference measurements (±1 mm, Seca 231 and Seca 212). The latter were measured at birth, controlled after 1 to 2 days, and measured weekly afterward. Weight gain (WG) was calculated by the formula:
Equation (Uncited)Image Tools
This formula was used to assess weekly WG and WG from 3 days of age to discharge. Growth parameters were converted to standard deviation (SD; z) score using the Usher reference growth chart (29). SGA infants were defined as BW z score under 2 SD according to PMA. The proportion of SGA infants also was evaluated at discharge. Catch-up growth was defined as an increase in weight z score. Perinatal and postnatal parameters also were collected.
Data were analyzed separately in appropriate-for-gestational age (AGA, N = 82) and SGA (N = 20) infants in 6 groups according to age at discharge, group A: AGA infants discharged after 3 to 5 weeks (n = 7); group B: AGA infants discharged after 6 to 8 weeks (n = 27); group C: AGA infants discharged after 9 to 11 weeks (n = 23); group D: AGA infants discharged after 12 to 15 weeks (n = 25); group E: SGA infants discharged after 3 to 7 weeks (n = 10); and group F: SGA infants discharged after 8 to 11 weeks (n = 10). All of the analyses were performed using Statistica version 8.0 (Statsoft Inc, Tulsa, OK).
Normally distributed data are presented as mean values with SD, and groups are compared by a t test. Non-normally distributed data are presented as median value with range and groups were compared by Mann-Whitney test. Categorical data are presented as actual numbers or percentages, and groups were compared by the χ2 test.
Univariate and stepwise multivariate analysis were used to evaluate the influence of clinical characteristics and nutritional intakes (fluid, energy, protein, and protein:energy ratio) on growth expressed as body weight z score changes from birth to discharge, from birth to 3 days, from 3 days to 3 weeks, and from 3 weeks to discharge. The relation was presented by Pearson correlation coefficient (r or r2). Results were considered significant at P < 0.05.
From January 2006 to December 2007, 117 infants with a BW <1250 g were admitted and consecutively enrolled in the study. During the study period, of the 117 infants, 14 died, 1 remained <3 weeks, and the remaining 102 infants were analyzed, BW 1005 ± 157 g and gestational age (GA) 28.5 ± 1.9 weeks. The cohort declined progressively after 3 weeks and discharge occurred at a mean PMA of 37.3 ± 2.3 weeks after 62.0 ± 21.5 days. Clinical characteristics of the study population are described in Table 3.
Nutritional intakes during the study were similar between the AGA and SGA groups. On the first day of life, 38 ± 6 and 40 ± 6 kcal/kg/day (P = 0.23) with 2.4 ± 0.4 and 2.5 ± 0.2 g/kg/day of protein (P = 0.26) were administered in the AGA and SGA groups, respectively. Mean intake during the first week was 79 ± 14 and 85 ± 14 kcal/kg/day (P = 0.07) with 3.1 ± 0.5 and 3.3 ± 0.4 g/kg/day of protein (P = 0.27), respectively.
At 1 week of age, 113 ± 20 and 118 ± 19 kcal/kg/day (P = 0.30) with 3.8 ± 0.6 and 3.8 ± 0.6 g/kg/day of protein (P = 0.92) were administered in the AGA and SGA groups, respectively. Mean enteral intake was 41 ± 34 and 56 ± 42 mL/kg/day (P = 0.09) representing 24% ± 21% and 33% ± 26% of total energy (P = 0.12), respectively. Twenty infants solely received PN, 78 received HM, 3 received PTF, and 1 received both HM and PTF.
At 2 weeks of age, 127 ± 20 and 123 ± 24 kcal/kg/day (P = 0.43) with 4.0 ± 0.6 and 3.9 ± 0.6 g/kg/day of protein (P = 0.27) were administered in the AGA and SGA groups, respectively. Mean enteral intake was 92 ± 64 and 101 ± 73 mL/kg/day (P = 0.56) representing 54% ± 38% and 61% ± 44% of total energy (P = 0.49), respectively. Seventeen infants solely received PN, 65 received HM, 15 received PTF, and 5 received both HM and PTF.
At 3 weeks of age, 126 ± 22 and 130 ± 17 kcal/kg/day (P = 0.43) with 3.9 ± 0.5 and 3.8 ± 0.5 g/kg/day of protein (P = 0.76) were administered in the AGA and SGA groups, respectively. Mean enteral intake was 114 ± 66 and 127 ± 55 mL/kg/day (P = 0.43) representing 68% ± 38% and 75% ± 32% of total energy (P = 0.41). Seven infants solely received PN, 67 received HM, 22 received PTF, and 6 received both HM and PTF.
Afterward, energy and protein intakes slightly decreased with the introduction of term infant formulas in the enteral diet. At the end of the study, mean enteral intake was 165 ± 22 mL/kg/day representing 99% ± 10% of total energy. Eighty-five infants received exclusive enteral feeding. One infant solely received PN, 9 received HM, 84 received a formula, and 8 received both HM and formula.
From birth to discharge, mean intake was 122 ± 10 and 122 ± 10 kcal/kg/day (P = 0.99) with 3.7 ± 0.2 and 3.7 ± 0.2 g/kg/day of protein (P = 0.95) in the AGA and SGA groups, respectively. Enteral feeding was introduced at a mean age of 3.9 ± 4.2 and 2.9 ± 4.2 days (P = 0.35), and PN was discontinued at a mean age of 28.6 ± 18.8 and 21.3 ± 15.1 days (P = 0.11), respectively. No metabolic perturbations were related to the higher nutritional intakes (data not shown).
Discharge occurred at the same PMA in the AGA and SGA groups, 37.2 ± 2.4 and 37.8 ± 1.7 weeks (P = 0.33) but weight z score change from birth was significantly different, −0.37 ± 0.57 and 0.18 ± 0.52, respectively (P < 0.01). Length z score change from birth also was different, −1.56 ± 0.80 and −1.11 ± 0.65 (P < 0.05) in the AGA and SGA groups, respectively, but head circumference z score change was not, −0.12 ± 0.90 and −0.07 ± 0.69 (P = 0.81). The same proportion of infants was SGA according to PMA at birth (N = 20) and at discharge (N = 21, P = 0.74) (Fig. 1).
Initial weight loss in the AGA and SGA groups occurred during 2.8 ± 1.6 and 2.8 ± 1.5 days (P = 0.91), respectively, with a maximal loss of 8.2% ± 4.6% and 8.0% ± 4.1% of BW (P = 0.86), respectively, and BW was regained at 6.8 ± 3.4 and 6.7 ± 2.9 days (P = 0.85).
WG during the second week of life was significantly lower in the AGA group, 11.6 ± 9.2 g/kg/day, compared to 17.5 ± 7.4 g/kg/day in the SGA group (P < 0.01). Afterward, WG was not significantly different in the AGA and SGA groups, 15.5 ± 7.6 and 18.0 ± 8.3 g/kg/day during the third week (P = 0.20), 17.7 ± 2.0 and 18.1 ± 1.9 g/kg/day between 3 and 7 weeks (N = 79, P = 0.56), and 13.9 ± 3.4 and 15.6 ± 1.7 g/kg/day between 7 and 10 weeks (N = 47, P = 0.22) (Fig. 2). At discharge, WG from 3 days of life was significantly lower in the AGA group, 14.4 ± 2.1 g/kg/day, compared to 16.6 ± 1.6 g/kg/day in the SGA group (P < 0.01).
Weight z score decreased during first 3 days of life, −0.70 ± 0.47 and −0.55 ± 0.25 (P = 0.18) in the AGA and SGA groups, respectively. Then, in AGA infants from groups A, B, and C, weight z score stabilized until 2 weeks of life (0.02 ± 0.59, P = 0.77) and increased thereafter 0.06 ± 0.09 per week until discharge. In AGA infants from group D, weight z score decreased up to 3 weeks of life to −0.93 ± 0.56, then increased 0.06 ± 0.04 per week up to discharge, similarly to other AGA groups. In SGA group, weight z score increased from 3 days to 2 weeks of life of 0.21 ± 0.29 (P < 0.01), then increased to discharge of 0.11 ± 0.08 per week, a value significantly higher than in the AGA groups (P < 0.01) (Fig. 3).
Stepwise multivariate analysis showed that the weight z score change from birth to discharge could be explained by BW z score (∼43%), GA (∼8%) and mean protein:energy ratio during study (∼5%). From birth to 3 days of life, the weight z score change could be explained by BW z score (∼15%) and mean fluid intake during the first 3 days (∼9%). From 3 days to 3 weeks of life, the weight z score change could be explained by mean protein intake during the first week of life (∼32%), weight z score at 3 days of life (∼12%), mechanical ventilation duration (9%), GA (∼4%), and mean fluid intakes during the first 3 weeks (∼3%). From this analysis, it may be suggested in our population that an increase of 1 g/kg/day of protein intake during the first week of life had increased the weight z score at 3 weeks of 0.61. After 3 weeks of life, the weight z score change could be explained by mean energy intake (∼11%) and mechanical ventilation duration (∼8%).
Mortality for VLBW infants has decreased during the last decade, especially in extremely low BW infants (30). Additionally, postnatal growth also has improved, with 40% to 50% of infants described as SGA at discharge (31–33). To our knowledge, this is the first study in VLBW infants that reports limited PNGR with a similar proportion (20%) of SGA infants at birth and at discharge (Fig. 1).
The clinical interpretation of growth rate in the NICU is influenced frequently by many factors and the role of each independent factor is frequently difficult to isolate from others because most of them are correlated together. Water homeostasis after birth implies a contraction of extracellular fluid and results in the well-known postnatal weight lost that usually represents in VLBW infants 7% to 20% of BW during the 3 to 5 first days (19,34). In previous studies, BW was observed to be regained after 11 to 18 days of life, and afterward, the WG was observed at 12 to 17 g/kg/day without significant catch-up at the age of discharge (19,34).
In our study, most of the observed benefits in growth concerns the first weeks of life. On average, the maximal weight loss was 8% of BW after 3 days of life and time to regain BW was observed at 7 days of life. The initial weight loss after 3 days of life corresponded to a decrease in weight z score of ∼0.70 from birth and may be considered as obligatory water loss. The major weight z score change during hospitalization occurred during these first 3 days and was inversely related to BW z score, which may be explained by differences in water content and body composition.
Body weight and weight z score at birth usually are used as baseline data to evaluate postnatal growth and adequacy of nutritional intakes before delivery. This study suggests that a baseline at 3 days of age could be more adequate to evaluate fetal growth, postnatal nutrition, and subsequent growth.
A significant part of PNGR in VLBW infants has been linked to insufficient nutrition, which is mainly caused by fears of metabolic intolerance of PN or fears of necrotizing enterocolitis (NEC) (4,5). Wilson et al (14) introduced the concept of early “aggressive” nutrition that has been demonstrated to safely support protein accretion and growth (14–16). Recent recommendations have included this policy for VLBW infants (16–22). Knowledge regarding nutritional requirements has increased among NICUs (35), but a wide variability in nutritional practices still existed with frequent insufficient intakes, especially during the first weeks of life (5,25,26,36).
In our study, early PN support resulted in intakes of 120 kcal/kg/day and 3.8 g/kg/day of protein at 7.8 ± 4.5 and 5.7 ± 3.5 days of age, respectively, and a significant reduction in cumulative nutritional deficit occurred compared with previous studies (data not shown). Further decrease in weight z score was not observed after the third day of life on average, except in the youngest and sickest VLBW infants characterized in group D. In those infants, energy intake during the first 3 weeks of life was significantly lower than in the other groups of AGA infants (102 ± 11 vs 111 ± 10, P < 0.01).
Higher protein intakes during the first week of life have been associated with better cognitive function at 18 months (37). Additionally, improved growth also has been associated with improved long-term outcomes (6,7). High protein intake from birth allows a positive nitrogen balance (15). Stable isotope studies also have been used to demonstrate beneficial effects on albumin synthesis and glutathione availability (38,39). High protein intake also improves glucose tolerance (40), anabolism (41), and growth (42). It has been shown that high protein intakes from birth are well tolerated without indications of protein overload such as hyperaminoacidemia, hyperuremia, and/or metabolic acidosis (14–16,19).
Clark et al (43) have evaluated 2 doses of intravenous protein administration in preterm infants and they did not observe a significant difference in WG after 28 days; however, there was a clear tendency, even if not significant, in favor of the high protein intake group, 12.9 versus 11.4 g/kg per day. Furthermore, there also was a high variability of WG between the 2 parenteral regimen, and the enteral intakes were insufficiently provided to interpret intakes and related growth correctly.
In our study, postnatal growth is related to early nutritional support and our study emphasizes the importance of initial optimal nutritional supply, especially for proteins. In VLBW infants, PN is essential for initial nutritional supply. Our study confirmed that the use of a well-balanced standard PN solution in VLBW infants allows to provide PN immediately after birth, optimizes nutritional intakes, and improves growth (44,45).
Enteral nutrition also is important in VLBW infants. Early minimal enteral feeding has been demonstrated to stimulate intestinal function and development, improve growth, decrease incidence of sepsis and osteopenia, and reduce hospitalization, without increased risk of NEC (21). HM is preferred for enteral nutrition because it stimulates gastrointestinal development, host defenses, and neurodevelopment (46). Moreover, HM also has been associated with a reduced incidence of sepsis and NEC (46); however, exclusive HM feeding has been associated with poor growth and nutritional deficits in VLBW infants, and HMF has been developed to improve growth with a positive impact on WG, length, head circumference, and bone mineral content (27,46).
A high variability in expressed breast milk composition exists and individual fortification allows compensating for this variability, especially for protein and fat content. De Halleux et al (27) have suggested that an individualized daily fortification of HM in VLBW infants increases intakes and results in better growth at a rate similar to that in PTF-fed infants. When HM is not available, enriched PTFs have been developed to meet preterm infants’ high nutritional requirements, and the use of high protein:energy content PTF increases WG in VLBW infants (40,47,48).
In our study, catch-up growth occurred in every subgroup after 1 to 3 weeks of life and persisted throughout the study in most infants (Fig. 3). SGA infants demonstrated an earlier and higher WG compared to AGA infants. SGA infants tended to receive higher nutritional intakes during the first weeks of life (P = 0.07) and had higher WG (P < 0.01). According to postnatal age, their WG profile was similar to that of AGA infants (Fig. 2). Among the 9 SGA infants born ≤30 weeks’ gestation, 4 (44%) became AGA according to PMA at the time of discharge (BW 791 ± 60 g, GA 28.0 ± 1.3 weeks, BW z score −2.30 ± 0.18).
Different methods for WG calculation exist. Frequently, WG calculation is based on the mean body weight during the study period, but Patel et al (49) reported an exponential formulation that is more accurate. With this exponential formulation (49), WG from 3 days of age to discharge corresponds to 15.5 ± 2.1 and 17.7 ± 1.3 g/kg/day in the AGA and SGA groups, respectively (P < 0.01), values slightly higher than the 14.4 ± 2.1 and 16.6 ± 1.6 g/kg/day reported above.
This study had some limitations. It is not a randomized controlled trial; however, it is not ethical to voluntary limit nutritional support in some infants. A retrospective control group was not easily available because nutritional support was progressively improved in our NICU. We reported in 56 VLBW infants that a period of 10 days was necessary to reach 120 kcal/kg/day and 3.2 g/kg/day of protein. In that study, targeted nutritional intakes were rarely maintained during the stable growing period because of various clinical conditions, and 60% of VLBW infants were SGA at discharge (50). Another limitation was the accurate estimation of nutritional intakes in infants receiving HM caused by the high variability in the macronutrient composition of expressed breast milk (27). The strength of this study is that the entire population of <1250 g infants was consecutively included, even those with abdominal surgical malformations (n = 3) or with severe prematurity-related diseases.
Early nutritional support is important to consider in VLBW infants because insufficient nutrition and postnatal growth have long-term effects on neurodevelopment outcomes. This study confirmed that the first week of life is a critical period to promote growth. Postnatal weight loss and PNGR may be limited to the first 3 days of life in most VLBW infants. Subsequent growth also may be optimized, with catch-up growth allowing a reduction of SGA infants at discharge compared to previous studies. Optimizing nutritional supply to reflect more recent recommendations improves growth in VLBW infants and dramatically reduces PNGR. Long-term improvements in health and development need to be evaluated in further studies.
We thank Fakher Habibi, MD, for help in the collection of data and Monica Marlowe, MD, for the English revision.
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