To gather information regarding the efficacy of early minimal enteral nutrition on overall feeding tolerance in extremely low birth weight infants.
Prospective randomized controlled trial comparing the early use of minimal enteral nutrition in extremely low birth weight infants from day 2 to day 7 vs control infants. On day 8, feeding volume in both groups were advanced by 10 ml kg−1 day−1 until full enteral feedings were reached. Time to full feeds, number of intolerance episodes, anthropometric measurements, peak total bilirubin levels, incidence of necrotizing enterocolitis and incidence of sepsis were compared between the two groups with t-test and χ2 test.
Eighty-four infants were enrolled in the study but only 61 infants completed the feeding protocol. No statistically significant differences were found between the groups with regards to growth patterns, feeding tolerance, mortality, length of hospital stay and incidence of sepsis and necrotizing enterocolitis.
Early minimal enteral nutrition use in extremely low birth weight infants did not improve feeding tolerance.
Many issues regarding the optimal nutritional management of premature infants remain controversial. Among these is the initiation of enteral nutrition in very low birth weight (VLBW, ⩽1500 g) and extremely low birth weight (ELBW, ⩽1000 g) premature infants. It is often feared that starting full enteral feedings very early may predispose these infants to necrotizing enterocolitis (NEC). Thus, many neonatologists delay the initiation of enteral feedings in favor of prolonged total parenteral nutrition.1
Several researchers have investigated the use of minimal enteral nutrition (MEN) in preterm infants to stimulate the developing gastrointestinal tract and enhance feeding tolerance. This involves the introduction of hypocaloric, low-volume enteral nutrition that does not contain sufficient calories to sustain somatic growth.2 Typical volumes used for MEN range from 12 to 24 ml kg−1 day−1.3 The benefits of MEN on gut function are clear; infants who receive MEN have rapid whole gut transit time4 and more normal patterns of gastroduodenal motility.5, 6, 7 These translate clinically to improved tolerance of enteral feedings, earlier full enteral feedings and later, more rapid achievement of full nipple feedings.2, 5, 8
Although several trials on MEN use intentionally studied high-risk infants with multiple risk factors, none showed an increased incidence of NEC.8, 9, 10, 11, 12, 13 Infants enrolled in these preliminary studies, however, were mainly VLBW; no study looked specifically at ELBW infants. It is our belief that ELBW infants would benefit the most from the advantages of MEN. The purpose of this study was to gather pilot data regarding the effects of early MEN use on overall feeding tolerance in ELBW infants.
This was a prospective, randomized, controlled trial conducted between January 2001 and August 2003 at the Neonatal Intensive Care Unit of Loyola University Medical Center. This study was reviewed and approved by the Loyola University Medical Center Institutional Review Board. Infants were eligible for the study if they were within 24 h of age with a birth weight of equal to or less than 1000 g and an informed parental consent was obtained. Infants were excluded from the study if they had any of the following criteria: (1) complex congenital anomalies; (2) cyanotic congenital heart disease; (3) required dopamine ⩾15 μg kg−1 min−1 or more than one inotrope; (4) persistent metabolic acidosis (pH<7.25 or base deficit of ⩾10 mmol l−1 for greater than 4 h) or (5) were undergoing exchange transfusion. The presence of umbilical artery catheter (UAC) or hemodynamically stable patent ductus arteriosus (PDA) treated with indomethacin were not among the exclusion criteria. On enrollment, infants were randomly assigned using sealed envelopes to receive either intravenous alimentation alone (none per orem group; NPO) or small boluses of nasogastric or orogastric feedings in addition to intravenous alimentation (MEN group) to be initiated on day 2. Standard intravenous fluids consisting of dextrose and/or electrolyte solution were used for the first day. On day 2, infants in the NPO group were started on intravenous alimentation consisting of dextrose, amino acids and lipids. This was gradually advanced to full parenteral nutrition as per the protocol. Infants in this group remained on intravenous alimentation alone through day 7. Infants assigned to the MEN group received early enteral nutrition consisting of unfortified breast milk or 20 kcal oz−1 Similac Special Care Formula at 12 ml kg−1 day−1 divided into six feedings, in addition to intravenous alimentation that was similar in fluid, energy and protein value to that in the NPO group. It is the usual practice in our unit to initiate minimal enteral feedings with full strength breast milk or premature formula, as earlier studies have shown that functional maturation of the preterm intestine is enhanced by the early introduction of enteral nutrients, an effect that is not seen if sterile water or diluted formula is used.5 Breast milk, if available, was always the first choice for enteral nutrition. These infants remained on this regimen through day 7. This volume was not included in the calculation for the total daily fluid requirement of these infants. MEN was withheld if the infant met the exclusion criteria, developed NEC, frank blood in the stools or bilious emesis.
On day 8, both groups received bolus feedings of 20 ml kg−1 day−1 total of breast milk or 20 kcal oz−1 Similac Special Care Formula divided every 2 h. If this was tolerated, feedings were advanced by 10 ml kg−1 day−1 until full volume (150 ml kg−1 day−1) was reached. Total parenteral nutrition volume was decreased accordingly as enteral nutrition was advanced. When feeding volume was at 100 ml kg−1 day−1, fortification to 24 kcal oz−1 was done by either adding Similac Human Milk Fortifier to breast milk or switching to 24 kcal oz−1 Similac Special Care Formula. Once full volume enteral feedings were achieved, infants were monitored for one additional week. A feeding schedule was maintained at each infant's bedside, and monitored daily by the nutrition support team so that milk advancement and use of parenteral nutrition was consistent for all study infants. Once feeding intolerance developed, feedings were withheld until the problem was resolved. Reasons for discontinuing feedings were recorded. Feedings were then restarted at the previously tolerated volume and were continually advanced by 10 ml kg−1 day−1 until full volume was achieved.
Feeding intolerance was defined as: (a) abdominal tenderness or discoloration; (b) frequent emesis (>2 episodes per 8 h shift); (c) gastric residuals of more than 50% of the previous feeding volume; (d) bilious gastric residuals with radiologic evidence of proper nasogastric/orogastric tube position; (e) grossly bloody stools and/or (f) radiographic or clinical evidence suggestive of NEC. NEC was defined as clinical signs with radiographic evidence of pneumatosis intestinalis or portal venous gas, or by intraoperative or autopsy diagnosis.
Data collected on study entry included birth weight, crown–heel length, head circumference, gestational age, gender, mode of delivery, ethnicity, exposure to antenatal steroids and Apgar score. Clinical measures of feeding tolerance included the number of days to reach full feedings, the number of days feedings were withheld, the number of episodes of feeding intolerance and the number of days on parenteral nutrition. Daily weight, weekly length and head circumference were recorded. Other clinical outcome variables of interest included serum total and direct bilirubin levels, serum alkaline phosphatase levels, days under phototherapy and days with central arterial or venous lines in place. Adverse outcome variables included incidence of NEC, intraventricular hemorrhage (IVH) and sepsis.
Continuous variables with normal distribution were compared using the two-tailed unpaired Student's t-test whereas the Mann–Whitney test was used to analyze continuous variables that were not normally distributed. Categorical differences were compared using the χ2 test. P<0.05 was needed for significance.
A total of 157 infants were available for enrollment during the study-period and consent was obtained for 84 infants. Forty-one were randomized to the MEN group and 43 to the NPO group. As shown in Table 1, initial clinical characteristics were similar in both groups on enrollment. The mean gestational age in both groups was 26 weeks with an average birth weight of 760±131 g (weight in grams±s.d.) in the MEN group and 759±151 g in the NPO group. Five infants were excluded after enrollment, one from the MEN group and four from the NPO group. Four of these infants had complex congenital anomalies detected after randomization. These included diaphragmatic hernia, jejunal atresia, large ventricular septal defect in congestive heart failure and tetralogy of Fallot. Consent was withdrawn from one infant in the NPO group. Only 61 infants completed the feeding protocol and were available for comparison: 33 in the MEN group and 28 in the NPO group (Figure 1). Infants in both the groups did not differ in birth weight, gestational age, sex, ethnicity, Apgar scores and anthropometric measurements (Table 2). Of the 33 infants in the MEN group who completed the feeding protocol, 31 infants actually received minimal enteral feedings started on day 2. Two of the 33 infants had a PDA with significant metabolic acidosis, thus MEN feedings were held initially. The mean volume of minimal enteral feedings during the intervention was 1.5 ml every 6 h. Eighty-two percent of infants in the MEN group had an UAC placed for a median duration of 7 days (range 1 to 13 days) compared to 93% in the NPO group for a median duration of 8 days (range 1 to 13 days). Although not statistically significant, more infants in the NPO group received antenatal steroids (61 vs 79%; P=0.13) whereas a higher percentage of infants in the MEN group received postnatal steroids (61 vs 46%; P=0.27). Three quarters of the infants in the NPO group were delivered by cesarean section compared to only 48% in the MEN group (P=0.03).
The NPO group regained birth weight at a median of 12 days (range 5 to 17 days), which was comparable to 13 days (range 7 to 20 days) for the MEN group. Breast milk was used solely for 52% of infants in the MEN group compared to 68% in the NPO group (P=0.20; Table 3). Weight, length and head circumference were similar in both groups at the beginning of the study and at 32 weeks corrected gestational age. The average weight gain per day was comparable in the MEN group at 12.2±3.1 g per day compared to the NPO group at 13.2±3.6 g per day (P=0.24). There was no significant difference between groups in episodes of feeding intolerance, days feedings were held, days on parenteral alimentation, days with a central line in place and days to full enteral feedings (Table 4). The peak total serum bilirubin was higher in the NPO group compared to the MEN group and approached statistical significance (P=0.07). However, this did not lead to a reduction in number of days under phototherapy for the MEN group. Conjugated bilirubin and alkaline phosphatase levels were not significantly different between both the groups.
The incidence of a PDA did not differ between both groups. Eighteen of the 20 infants in the MEN group who had a PDA continued to receive minimal enteral feedings while on indomethacin treatment. Two infants in the NPO group had enteral feedings continued while receiving indomethacin for a PDA. Most of the infants in the NPO group who were diagnosed with a clinically significant PDA in the first week of life did not have enteral feedings as per protocol.
Mortality was 17% (7) in the MEN group and 26% (11) in the NPO group (P=0.34). The cause of mortality was not different between the groups. None of the infants who expired completed the feeding protocol and were excluded from the analysis. Three infants in the MEN group (9%) developed NEC compared to four infants in the NPO group (14%). The incidence of sepsis (defined as a systemic bacterial infection documented by a positive blood culture) was similar in both the groups (39 vs 32%; Table 5). The median length of hospital stay did not differ significantly between both groups.
The incidence of grade 3 or 4 IVH was significantly higher in the NPO group compared to the MEN group (39 vs 15%; P=0.03). When stratified by delivery method, the rate of grade 3 or 4 IVH was 42.9% for the NPO group compared to 18.8% for the MEN group (P=0.12) in infants delivered by cesarean section and 28.6% for the NPO group compared to 12.5% for the MEN group (P=0.35) in infants delivered vaginally. Generally, lesser rates of severe IVH were seen in infants delivered vaginally, but an interaction between feeding method and delivery method was not demonstrated.
This study is the first to look at the effect of early MEN specifically in ELBW infants. Since ELBW infants are at an increased risk of feeding intolerance, a feeding strategy that would enhance gastrointestinal maturation would greatly benefit this particular subset of high-risk premature neonates. In our study, the early initiation of MEN in ELBW infants did not show a difference in the adverse outcomes between infant groups. This observation is in agreement with the previous studies involving more mature VLBW infants. Unlike earlier studies, however, our study was unable to demonstrate a significant beneficial effect of MEN on feeding tolerance, growth velocity, need for phototherapy and incidence of total-parenteral-nutrition-related complications.
It is still a relatively common practice to withhold feedings when a UAC is in place or when an infant is receiving indomethacin for PDA treatment because of the concerns about the risk of NEC. A recent survey by Tiffany et al.14 reported that newborns with UACs in place received trophic enteral nutrition most of the time (30%), some of the time (49%) or none of the time (22%). Davey et al.10 and Wilson et al.15 found no difference in feeding tolerance and incidence of NEC among infants started on enteral feedings with a low or high UAC in place. In our study, 82% of infants in the MEN group received minimal enteral feedings with a UAC in place, whereas 90% of infants in this group also continued to receive minimal enteral feedings while receiving indomethacin to treat a PDA. Despite these presumed risk factors, we did not observe an increased incidence of NEC in the MEN group.
A lower incidence of grade 3 to 4 IVH was noted in the MEN infants who completed the feeding protocol. This occurred despite the higher percentage of antenatal steroid exposure, higher percentage of cesarean section delivery and lower incidence of PDA and PDA ligation in the NPO group. This, however, has not been previously reported in the English literature as a beneficial effect of MEN and is likely just a chance association, hence should be interpreted with caution. The incidence of grade 3 to 4 IVH and the rate of cesarean-section delivery were significantly higher in the NPO group compared to the MEN group. When stratified by delivery method, generally lower rates of severe IVH were seen in infants delivered vaginally, but a statistically significant interaction between delivery method and feeding method was not demonstrated.
Studies on feeding advancement in premature neonates have looked mainly at VLBW infants. Prospective randomized controlled trials comparing a ‘fast’ vs ‘slow’ rate of feeding advancement in preterm infants done by Rayyis et al.16 and Caple et al.17 did not show an increased incidence of NEC or NEC with intestinal perforation. On the other hand, a recent study by Berseth et al.18 comparing the use of minimal feedings for 10 days against daily advancing feedings started on the first day was stopped prematurely after an increased rate of NEC was found in the infants who were advanced daily, suggesting that minimal feedings in the first few days have a protective effect against NEC. Since our study was done at a time when there was a significant concern about early initiation of enteral feedings in ELBW infants in our Neonatal Intensive Care Unit, it was the group consensus that feeding advancements should be done cautiously. Although there was no difference in feeding tolerance between groups using a slow rate of feeding advancement (10 ml kg−1 day−1), there might have been a significant difference if feedings were advanced at a larger volume daily (20 to 30 ml kg−1 day−1).
It seems that early initiation of enteral feedings in VLBW infants is the currently accepted norm. However, a recent retrospective chart review showed sizable variations in perceived practices compared to actual practices.19 Seventy-four percent of clinicians surveyed, perceived the initiation of enteral feedings to be started by day 4 compared to the actual average of day 10. In our study, ELBW infants in the MEN group had feedings initiated by day 2. We speculate that a feeding regimen involving early initiation of MEN for a few days followed by a feeding advancement of 20 to 30 ml kg−1 day−1 may lead to a better tolerance of enteral feedings and earlier attainment of full enteral feedings in ELBW infants. This may lead to a reduction in the total-parenteral-nutrition-related complications and potentially shorten the length of hospital stay.
A limitation of this study is its relatively small sample size and single-center origin. Since feeding practices vary among different centers, a large multi-centered trial with a uniform feeding protocol should be undertaken to clearly demonstrate the safety as well as beneficial effects of MEN on feeding tolerance in ELBW infants. Based on the incidence of mortality or NEC in this pilot data, a sample size of 191 infants per group would be needed for an appropriately powered (β=0.20, α=0.05) study.
This pilot study is the first to investigate the effect of early initiation of MEN specifically in ELBW infants. In agreement with prior studies, our data did not show a difference in adverse outcomes like mortality, NEC or sepsis between groups. In contrast to prior studies, however, the early initiation of MEN in this particular subset of high-risk infants did not lead to a significant improvement in the feeding tolerance. Further larger studies are needed to clearly show the safety and efficacy of early MEN use in ELBW infants.
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We acknowledge Dr Richard Martin and Dr Monika Bhola for their thoughtful review of the manuscript. We thank Julie Di Fiore and Mary Ann O'Riordan for providing help with the statistical analysis. We also thank Linda Juretschke NNP, Zeynep Salih MD, and Mathew Co for their assistance in data collection and manuscript preparation.
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Mosqueda, E., Sapiegiene, L., Glynn, L. et al. The early use of minimal enteral nutrition in extremely low birth weight newborns. J Perinatol 28, 264–269 (2008). https://doi.org/10.1038/sj.jp.7211926
- minimal enteral nutrition
- extremely low birth weight infants
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