PEDIATRICS Vol. 114 No. 6 December 2004, pp. 1597-1600 (doi:10.1542/peds.2004-1232)
Randomized, Controlled Trial of Slow Versus Rapid Feeding Volume Advancement in Preterm Infants
From the Department of Pediatrics, University of Texas–Houston Medical School, Houston, Texas
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objectives. To determine whether infants who are fed initially and advanced at 30 mL/kg per day (intervention) take fewer days to get to full feedings than those who are fed initially and advanced at 20 mL/kg per day (control), without increasing their incidence of feeding complications and necrotizing enterocolitis (NEC). We also examined whether these infants regain birth weight earlier, have fewer days of intravenous fluids, and a have shorter hospital stay.
Methods. A randomized, controlled, single-center trial was conducted in a Neonatal Intensive Care Unit of a community-based county hospital in Houston, Texas. Infants between 1000 and 2000 g at birth, gestational age 
35 weeks, and weight appropriate for gestational age were allocated randomly to feedings of expressed human milk or Enfamil formula starting and advanced at either 30 mL/kg per day or 20 mL/kg per day. Infants remained in the study until discharge or development of stage 
IIA NEC.
Results. A total of 155 infants were enrolled: 72 infants in the intervention group and 83 in the control group. Infants in the intervention group achieved full-volume feedings sooner (7 vs 10 days, median), regained birth weight faster (11 vs 13 days, median), and had fewer days of intravenous fluids (6 vs 8 days, median). Three infants in the intervention group and 2 control infants developed NEC for an overall incidence of 3.2% (relative risk: 1.73; 95% confidence interval: 0.30–10.06).
Conclusion. Among infants between 1000 and 2000 g at birth, starting and advancing feedings at 30 mL/kg per day seems to be a safe practice and results in fewer days to reach full-volume feedings than using 20 mL/kg per day. This intervention also leads to faster weight gain and fewer days of intravenous fluids.
Key Words: enteral feedings • newborn • necrotizing enterocolitis
Abbreviations: NEC, necrotizing enterocolitis • EHM, expressed human milk • NPO, nothing by mouth
Optimal enteral feeding methods in preterm infants have not been well defined.1 Controversy exists regarding when feedings should be started, whether minimal enteral feedings should be used routinely in small preterm infants, and how fast to advance enteral feedings.2–5 Preterm infants can exhibit delayed gastric emptying and often have feeding residuals, although what constitutes a clinically significant gastric residual remains unclear.6 However, recent evidence suggests that very low birth weight infants who develop necrotizing enterocolitis (NEC) have more gastric residuals than those who do not.7 On the basis of these and other factors, enteral feedings are frequently advanced slowly in these neonates. This practice may compromise the precarious nutritional status of some of these infants and prolong the use of intravenous fluids.
Increments of enteral feeding of 10 to 20 mL/kg per day have been reported as safe in a prospective study,4 but several retrospective studies have suggested that advancing feedings rapidly is associated with an increased risk for NEC.8,9 In 1 of these studies, feeding increments were as high as 40 to 50 mL/kg per day.8 Conversely, a relatively more rapid advancement of enteral feedings in preterm infants may improve their growth and nutritional status, decrease the need for and hazards of intravenous infusion solutions, and potentially shorten the length of hospitalization. Rayyis et al5 reported no difference in the incidence of feeding intolerance or NEC in infants who received 35-mL versus 15-mL feeding advancements. Intermediate rates of advancement have not been studied. Therefore, we examined whether infants who were fed initially and advanced at 30 mL/kg per day take fewer days to get to full feedings than those who were fed initially and advanced at 20 mL/kg per day, without increases in their incidence of feeding complications and NEC. Also, we studied whether infants who were fed the higher volume regain birth weight earlier, have fewer days of intravenous fluids, and have a shorter hospital stay than those who were advanced at the slower rate.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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All eligible infants were cared for in either the level 2 or 3 neonatal intensive care unit of a large community-based county hospital in Houston, Texas, during 1994–1995. Entry criteria included birth weight of 1000 to 2000 g, gestational age of 35 weeks or less determined by the modified Ballard examination,10 and weight and length appropriate for gestational age. We chose not to include infants who weighed <1000 g because their feedings are often started many days after birth as a result of their degree of sickness; feedings are frequently stopped for various reasons; and given our low number of admissions of infants <1000 g, it would not have been feasible to study enough infants in such a group in a single-center trial. Exclusion criteria were the presence of major congenital anomalies or congenital abnormalities of the gastrointestinal tract, antenatal exposure to controlled substances, and extramural birth. Informed parental consent was obtained before enrollment. Infants were continued in the study until discharged from the hospital or the development of stage IIA or greater NEC using Bell’s staging criteria.11 Infants were allocated into the intervention and control groups by blinded, random-draw, numerical assignment. People who were not involved in the study drew the numbers from an envelope that was kept in a locked drawer. Infants were assigned to both groups on the date of enrollment into the study. Before the initiation of feedings, attending physicians and caregivers were unaware of group assignment.
The attending physicians determined the timing of the initiation of feedings and of the infants’ discharge to home. When an infant had a venous or arterial umbilical catheter, feedings were begun 24 hours after its removal. Infants who were given indomethacin for closure of a patent ductus arteriosus were not fed while receiving the drug and for 24 hours after the last dose was given. Waiting 24 hours after indomethacin therapy and removal of umbilical lines was considered standard of care at our facility during that period.
Expressed human milk (EHM) or standard formula of 20 kcal/30 mL (Enfamil; Mead-Johnson Nutritionals, Evansville, IN) was used for initiating feedings on the basis of recommendations of the formula company at the time.12 In the intervention group, feedings were initiated with 30 mL/kg per day of either Enfamil 20 cal/oz formula or EHM and advanced by 30 mL/kg per day until 150 mL/kg per day was reached. Feedings in the control group were initiated with 20 mL/kg per day of either Enfamil 20 cal/oz formula or EHM and advanced by 20 mL/kg per day until 140 mL/kg per day was reached. The last day of advancement in the control group was 10 mL/kg per day for a total of 150 mL/kg per day. All feedings were given as a bolus. Infants received intravenous fluids for the usual clinical indications until the enteral intake was 120 mL/kg per day. After a volume of 150 mL/kg per day was reached, both groups were switched to 24 cal/oz Enfamil premature formula or EHM fortified with Human Milk Fortifier, 4 packages per 100 mL of EHM to make 24 cal/oz (Mead Johnson Nutritionals). Infants were returned to 20 cal/oz Enfamil or nonfortified human milk when they weighed 
1800 to 1900 g. They were discharged from the hospital when they weighed 2000 g and were medically stable.
The following conditions, defined a priori, were cause for discontinuation of feedings: residual gastric contents of more than one third of the volume of the previous feeding, vomiting >3 times in a 24-hour period not associated with eructation, bile-stained vomitus or residuals, distended abdomen, guaiac-positive stools not associated with a rectal fissure or trauma, or abnormal findings on abdominal radiographs. Pediatric radiologists without knowledge of group assignment interpreted all abdominal radiographs.
Infants who were ordered to have nothing by mouth (NPO) for <24 hours had feedings resumed at the volume that they were receiving before they were order to receive NPO and were subsequently advanced according to initial group assignment. Infants who were ordered to receive NPO for >24 hours had feedings resumed at their initial feeding volume (20 or 30 mL/kg per day) and then were advanced at those same volumes.
The primary outcome measure was days to get to full feedings. Sample size calculations were done using an 
= .05 and ß = .8, medium effect size, 2-sided hypothesis. Using these criteria, the minimum sample size needed to evaluate the effect of feeding advancement volume was 64 per group.13 Recruitment was continued to include 25% more infants in both groups to allow for attrition as a result of removal from the protocol by the parents or attendings, transfer to another institution, and lack of compliance. Secondary outcomes were days to regain birth weight, days of intravenous fluids, length of hospital stay, and the incidence of feeding complications and NEC. Analysis of the data was done using Minitab version 12 and Epistat 5.3. The t test was used to compare continuous variables with a normal distribution, whereas the Mann-Whitney test was used to analyze continuous variables that were not normally distributed. Categorical variables were compared using Fisher exact test.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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A total of 160 preterm infants were initially enrolled, but 5 infants were withdrawn from the study. Two infants were found to meet exclusion criteria after enrollment; 1 had fetal alcohol syndrome and the second an in utero intestinal perforation and peritoneal calcifications diagnosed by radiograph. One infant who weighed 1920 g and was assigned to the lower feeding volume was withdrawn from the study by the attending after only a few feeds. Another infant who was born to a human immunodeficiency virus–positive mother was advanced at 50 mL/kg per day and developed NEC on day 12. The remaining 155 infants were analyzed on an intention-to-treat basis. Their characteristics are shown in Table 1. The groups were comparable for gestational age, birth weight, and day of life when feedings were begun. Both groups had a preponderance of Hispanic infants. There were similar numbers of boys and girls and of infants who were fed EHM (partial or full volume) in both groups. None of the other demographic variables was significantly different.
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Infants who were fed and advanced at 30 mL/kg per day achieved full-volume feedings of 150 mL/kg per day and 120 kcal/kg per day before the control group (Table 2). The time to regain birth weight and to reach a weight of 2000 g was significantly shorter in the intervention group. Also, infants in the intervention group had significantly fewer days of intravenous fluids. The median length of stay in the intervention group was 5 days shorter than the control group, but this difference only approached statistical significance (P = .15).
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Three of the 72 infants in the intervention group and 2 of the 83 infants in the control group developed NEC, for an overall incidence of 3.2% (relative risk for NEC: 1.73; 95% confidence interval: 0.30–10.06; P = .66). The gestational age of the 3 infants who developed NEC in the intervention group was between 30 and 33 weeks, and the age of onset of NEC was between 5 and 8 days after birth. Two of them were receiving feedings of EHM before receiving a diagnosis of NEC. Both control infants who developed NEC were of 29 weeks’ gestation, and NEC was diagnosed at 11 and 41 days after birth, after several days of full feedings with formula. At our institution, the incidence of NEC in preterm infants who weighed between 1000 and 2000 g and were not enrolled in the study during the same period was 4.1%.
The reasons for discontinuation of feedings during the study are shown in Table 3. Indomethacin use was the most common cause for stopping feeds. Other complications were less frequent, and no differences between groups were detected.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Defining the best method for feeding preterm infants remains a challenging goal. These infants often have feeding difficulties primarily because of immaturity of their gastrointestinal system.1,3,6,14 It has been well established that inadequate provision of adequate nutrition in very low birth weight neonates often leads to suboptimal growth at discharge.15 Despite the importance of this subject, many of the published studies regarding feeding practices have been based on retrospective data or have had a small sample size.2,4,8,9,16,17 Several studies have indicated that early enteral feeding may stimulate the premature intestinal tract and improve feeding tolerance, but systematic reviews examining the use of minimal enteral feedings or comparing early versus delayed initiation of progressive enteral feedings have been inconclusive.3,16–19 One of the major concerns related to feeding premature infants is the occurrence of NEC. Although prematurity per se is the primary risk factor for NEC, a relationship of the rate of advancement of enteral feeding with NEC has been suggested, but causality has not been proved.4,8,9,20
In our study, the second largest controlled trial of feeding advancement in preterm infants, we showed that advancing feedings at a rate of 30 mL/kg per day is as safe as advancing at the rate of 20 mL/kg per day. Infants in the intervention group reached full volume of feedings (150 mL/kg per day) and regained birth weight before control infants. In addition, the low incidence of NEC in our study was comparable in both groups. Data from our study, that of the small trial of Book et al4 and the largest trial to date reported by Rayyis et al, which included 185 infants,5 were included in a systematic review by Kennedy et al.21 These authors concluded that more rapid rates of advancing feeding volume result in a reduction in days to attain full enteral feedings and to regain birth weight but expressed concern about adopting this practice widely given the limited information regarding safety, particularly with regard to NEC. A recent study by Berserth et al20 that included infants <32 weeks’ gestation, compared feeding 20 mL/kg per day for 10 days and then advancing the feeding volume, to starting at 20 mL/kg per day and advancing daily by 20 mL/kg per day until a volume of 150 mL/kg per day was attained. The trial was stopped prematurely because the data safety committee found an increased risk of NEC in infants who were advanced daily (10%) compared with those who had a period of minimal enteral feedings (1.4%). However, the mean gestational age and birth weight of infants in this trial was much less than in our study. Moreover, these authors reported that the incidence of proven NEC in their neonatal intensive care unit was 12%, which is higher than reports from other centers, including this report.20,22
The reasons for stopping feedings were uncommon in both groups from our study, as has been reported by others.6,7,20 We chose to give all feedings as a bolus, which has also been shown to lead to full feedings earlier than administering them continuously using infusion pumps.23,24 We showed that infants who were advanced more rapidly had significantly fewer days of intravenous fluids and went home 5 days before the control infants. Although our study was not powered to determine significant differences in length of stay, both of these findings suggest that overall costs of neonatal care may be reduced by advancing feedings more rapidly in infants between 1000 and 2000 g.
Finding the best method to feed premature infants while minimizing complications is of utmost importance. Most of the studies to date that have addressed this critical aspect of neonatal care have taken place at a single institution. Thus, many questions remain unanswered. Only a large, multicenter, prospective trial with a large enough sample size would be able to test adequately better ways of optimizing enteral nutrition without increasing morbidity like NEC.
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FOOTNOTES |
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Accepted Jun 17, 2004.
Reprint requests to (J.C.) Department of Pediatrics, University of Texas–Houston Medical School, 6431 Fannin St, MSB 3.218, Houston, TX 77030. E-mail: judith.caple{at}uth.tmc.edu
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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