INTRODUCTION

As survival of extremely premature infants has increased, nutritional support has become a more prominent component of patient care. Many studies have reported postnatal growth that significantly lags behind intrauterine patterns throughout hospitalization and leads to extrauterine growth retardation (EUGR).^1,2,3,4,5,6 Outcomes from a number of studies show that very very low birth weight (VVLBW) (<1000 g) and extremely low birth weight (ELBW) (<750 g) infants often remain physically smaller than term-born peers during infancy and well into childhood^7,8,9,10 and that poor neurodevelopmental outcomes are more common in infants with subnormal postnatal head growth.^8,9,10

The goal in this study was to identify predictors of EUGR in infants <1000 g and to evaluate their nutritional intake and subsequent growth.

METHODS

This was a retrospective medical chart review of infants born between 1/1/1997 and 12/31/2000, approved by the Human Studies Committees at the University of Louisville. Eligible infants, were 1000 g and 29 weeks gestation at birth, were admitted to the neonatal intensive care unit (NICU) at Kosair Children's Hospital, Louisville, KY, within 24 hours of birth, survived for at least 7 days and were free of major congenital anomalies. Demographic data, birth events, daily weights, head circumference (HC), and nutrient intakes were gathered from nursing notes and medical charts. Gestational age (GA) was determined from maternal dates or physical examinaton.¹¹ Clinical complications, events and medications were tracked throughout hospitalization. Late-onset sepsis was defined by a positive blood culture; bronchopulmonary dysplasia (BPD) was defined as a requirement for supplemental oxygen at a postconceptional age (PCA) of 36 weeks. Small for gestational age (SGA) was defined as weight or HC <10th percentile by Lubchenco intrauterine growth grids.¹² Weight and HC percentiles were recoded into 5 categories: 0 (<10th), 1 (10th to 25th), 2 (25th to 50th), 3 (50th to 75th), 4 (75th to 90th), and 5 (>90th).

Weight was measured daily on an electronic scale (5 g); weight changes (g/kg/day) were calculated weekly and are reported from day of life (DOL) 21 through DOL 84 or hospital discharge/transfer. HC (cm) was measured over the largest occipital-frontal area with a paper tape. Energy (kcal/kg/day) and protein intakes (g/kg/day) from parenteral and enteral sources were calculated daily and averaged weekly. Total parenteral nutrition (TPN) was started within the first days of life. The initiation of enteral feeding was at the discretion of the attending physician, resident, or neonatal nurse practitioner. Expressed maternal milk (HM) was the feeding of choice. When HM was not available, premature infant formula (PTF: Similac Special Care 24^® Ross Products Division, Abbott Laboratories, Columbus, OH) was used. HM fortification began once the infant reached full enteral feeding volumes (140 to 150 cc/kg/day). During the years 1997 to 1999, when HM was fortified, Mead Johnson Human Milk Fortifier^® (Mead Johnson Nutritionals, Evansville, IN) or Similac Natural Care^® (Ross Products Division) was used. Beginning in 2000, Similac Human Milk Fortifier^® (Ross Products Division) was used. Energy and protein contents of fortified milk were calculated according to the manufacturer's label. When fluid restriction was necessary, hypercaloric formulas (HM or PTF-based) at 27 or 30 kcal/oz were used. There was occasional use of elemental or hydrolyzed formulas, such as Pregestimil,^® Portagen,^® (Mead Johnson Nutritionals) or NeoCate^® (SHS North America). Formula-fed infants were transitioned to a nutrient-enriched formula (NeoSure,^® Ross Products Division) a few days prior to discharge. Human milk-fed infants were transitioned to unfortified HM and/or NeoSure^®. Infants were classified as EUGR (<10th percentile) or non-EUGR based on weight for gestation at hospital discharge.

Fisher's exact test was used to compare the EUGR and non-EUGR groups in terms of dichotomous predictors. The two-sample t-test was used for continuous variables and the Mann–Whitney–Wilcoxon test was used for ordinal variables. Variables that were significant at the 0.05 level were entered into a stepwise logistic regression analysis to determine the net effect for each predictor while controlling for the others. This procedure was performed only on those observations that had complete data for all of the significant predictors. Only those predictors that were significant at the 0.05 level after controlling for the other retained variables were retained in the final model. Once the variable selection process was completed, the logistic regression model was re-estimated using all subjects with complete data for the retained variables. The methods of Hosmer and Lemeshow¹³ were used to verify the accuracy of the final logistic regression model. The area under the receiver operating characteristic (ROC) curve was used to determine the model's accuracy in discriminating between EUGR and non-EUGR infants.

Since birth weight was the predictor of primary interest, it was evaluated as a predictor in its raw form (BW), after converting to a percentile score (BW percentile), and dichotomized (SGA_weight). Separate logistic regression analyses were performed to see which other predictors had an independent effect in predicting EUGR when considered in combination with each of these BW variables.

Statistical analysis was performed using the SAS System for Windows (Release 8.02). Statistical significance was set at p< 0.05.

RESULTS

There were 220 infants who met inclusion criteria: 18 infants died after DOL 7 and 3 infants were transferred to their hospital of birth prior to 36 weeks PCA. These infants were included in the data set until the time of death/transfer. Two infants had post-hemorrhagic hydrocephalus and were excluded from HC measures. One infant remained in the hospital beyond 200 days and was excluded from analysis of discharge data.

Clinical characteristics and significant medical events/medications are listed in Table 1. Infants who developed EUGR had significantly lower birth weights (46% were <750 g at birth) and were more likely to be SGA at birth (p=0.015). Hypotension, sepsis and BPD were more commonly found in EUGR infants; however, surfactant usage was less frequent than in non-EUGR infants (69 vs 82.5%, p=0.035).

Table 1 - Significant Predictors of EUGR.

Full table

Several characteristics were significant predictors of EUGR. The stepwise logistic regression analyses indicated that BW percentile had the greatest predictive accuracy for EUGR, and that only "days of TPN" and "HC percentile at RTBW" were independent predictors of EUGR when considered along with BW percentile (Table 2). That is, of the predictors in Table 1, only days of TPN and HC percentile at RTBW contributed significantly to the prediction of EUGR once the BW percentile of the infant was taken into account. The area under the ROC curve for the logistic regression model containing BW percentile, days of TPN, and HC at RTBW percentile was 0.847.

Table 2 - Logistic Regression Model for EUGR.

Full table

Figure 1 shows energy intake by week of life in the two groups of infants, including a reference line representing the minimal presumed requirement of 120 kcal/kg/day. At no time during hospitalization did the mean energy intake of either group reach 120 kcal/kg/day. EUGR infants consistently received less energy than non-EUGR infants. Statistically significant differences occurred at weeks 5, 6, and 9–11.

Figure 1.

Energy intake (kcal/kg/day) by week of life in infants that develop EUGR compared to those who do not. *p range 0.000 to 0.027. Reference line represents 120 kcal/kg/day (presumed requirement).¹⁵

Full figure and legend (77K)

Figure 2 displays protein intake by week of life in the two groups of infants, including a reference line representing the minimal presumed requirement of 3.0 g/kg/day. Again, EUGR infants consistently received lower amounts of protein at the same time they were receiving less energy. Statistically significant differences occurred at weeks 5 and 9 to 11.

Figure 2.

Protein intake (g/kg/day) by week of life in infants that develop EUGR compared to those who do not. *p ranges 0.025 to 0.046. Reference line represents 3.0 g/kg/day (presumed requirement).¹⁶

Full figure and legend (71K)

Figure 3 displays weekly changes in weight for the two groups with a reference line for approximate intrauterine growth of 15 g/kg/day. Non-EUGR infants had consistently higher weight gains than EUGR infants (except week 3) and actually exceeded a mean of 15 g/kg/day in 4 of 12 weeks. The highest mean weight gain in EUGR infants (14.4 g/kg/day) occurred in week 6.

Figure 3.

Weight change (g/kg/day) by week of life in infants that develop EUGR compared to those who do not. *p ranges 0.004 to 0.026. Reference line represents fetal growth rate of 15 g/kg/day.¹⁴

Full figure and legend (61K)

DISCUSSION

EUGR is common in VVLBW and ELBW infants, regardless of growth status at birth.^6,14 In our study, 86% of infants demonstrating EUGR at discharge were appropriately grown at birth; 60% of EUGR infants had evidence of growth retardation by return to birth weight (RTBW). Although not retained in the logistic regression model, EUGR infants required significantly more days of assisted ventilation, oxygen, and TPN, indicating a higher degree of illness. They were also more likely to be hypotensive or septic but, interestingly, were less likely to have received artificial surfactant. Later introduction of enteral feedings and slower advancement (i.e. more days needed to achieve 100 or 120 kcal/kg/day) could be factors in the slower growth experienced by these infants.

EUGR infants appear to be chronically undernourished, based on the presumed requirements of 120 kcal/kg/day¹⁵ (energy) and 3.0 g/kg/day¹⁶ (protein), neither of which was consistently achieved by either group. This supports the premise of a recent article by Embleton et al.⁵ in which their infants, especially those <30 weeks gestation, showed significant cumulative deficits in both energy and protein at discharge. The authors suggest that, rather than looking at intake on a daily basis, it may be more helpful to assess nutrient deficits in both a cumulative fashion and in terms of nutrient intake needed to offset early shortfalls. Our study supports this concept because it focuses on our failure to consistently provide minimal recommended intakes and the resulting development of growth retardation in a large proportion of our NICU graduates. The weight gap between the groups, only 90 g at birth, grew to over 400 g at 36 weeks GA and the proportion of growth-retarded infants quadrupled from 14% at birth to 59% at discharge. Postnatal growth rates are related to a variety of factors, only one of which is nutrient intake. In their study, Embleton et al.⁵ reported that nutrient intake explained 45% of the variation in growth performance, the effects of birth weight explained 7%, and the rest was attributable to non-nutritional factors (criticality of illness, local feeding practices, etc.).

If a return to prenatal growth trajectories is a goal, infants must receive sufficient calories and protein to support weight gains that exceed in utero rates (>15 g/kg/day), an uncommon event in our study groups. Ziegler²⁰ suggests that fixed protein intakes, such as those provided by commercial formulas and fortified human milk (especially beyond the early weeks), are inadequate for addressing growth needs of the premature infant. He speculates that selectively providing increased protein for the small premature infant may better meet their needs.

It has been hypothesized that improved nutrition in the early postnatal period could ameliorate common morbidities that negatively impact growth in this population of infants.^17,18,19 BPD and late-onset sepsis affected a significant proportion of our EUGR infants and probably contributed to nutritional inadequacy and growth faltering. Therefore, exploring a strategy to improve nutritional support early in an infant's hospital course may, in and of itself, decrease morbidities that impair growth and outcome.

Poor growth in VVLBW infants is common; its inevitability remains unknown. While supporting an infant's return to her/his in utero growth trajectory prior to discharge is a desirable goal, it is difficult to achieve.

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