Early Human Development 90 (2014) 227–230
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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Early enteral feeding in very low birth weight infants Emily Hamilton ⁎, Cynthia Massey, Julie Ross, Sarah Taylor Division of Neonatology, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States
a r t i c l e
i n f o
Article history: Received 8 June 2013 Received in revised form 7 February 2014 Accepted 11 February 2014 Keywords: Early enteral feeding Very low birth weight infants Necrotizing enterocolitis Parenteral nutrition Prematurity
a b s t r a c t Background/aim: Debate exists about when to initiate enteral feeding (EF) in very low birth weight (VLBW) preterm infants. This retrospective study compared the effectiveness of an education-based quality improvement project and the relationship of time of the first EF to necrotizing enterocolitis (NEC) or death incidence and parenteral nutrition (PN) days in VLBW infants. Study design/subjects: VLBW infants born in 2 epochs were compared for hour of the first feed, PN days, NEC or death incidence, and feeding type. The 2 epochs were temporally divided by a quality improvement initiative to standardize initiation of EF in postnatal hours 6–24. Results: 603 VLBW infants were included. Median time of feed initiation decreased from 33 (Epoch 1) to 14 h (Epoch 2) (p b 0.0001). Median PN days were 14 vs. 12, respectively (p = 0.07). The incidence of NEC or death was 13.4% vs. 9.5%, respectively (p = 0.14). When controlling for birth weight, gestational age, race, gender, and time period, earlier feed initiation was associated with decreased NEC or death (p = 0.003). Evaluation of the relationship of early EF (defined as within the first 24 h) in Epoch 2 alone showed that early EF was significantly associated with decreased NEC or death (6.3 vs 15.1%) (RR, 95% CI = 0.28, 0.13–0.58) and less PN days (p b 0.0001). Conclusions: In a VLBW infant cohort, an education-based process improvement initiative decreased time of EF initiation to a median of 14 h with no associated increase in NEC or death. In fact, results suggest that earlier feeding is associated with decreased NEC or death. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Debate continues regarding early postnatal readiness for enteral feeding in very low birth weight (VLBW) (b 1500 g) infants [1]. Much has been published about the potential benefits of early feeds. Early enteral nutrition is known to decrease gut atrophy and intestinal permeability [2] and has been associated with improved postnatal growth and decreased incidence of sepsis [3]. However, concern for an association with necrotizing enterocolitis (NEC) has propagated delaying enteral nutrition in this population [4]. Recent data suggest that implementation of a feeding protocol not only is safe but also may decrease the incidence of NEC [5,6]. At our institution, despite a feeding order to initiate minimal enteral nutrition at 6–24 postnatal hours, this clinical plan was not widely accepted by the nursing staff and required an education-based quality improvement initiative to improve the process. This education consisted of a presentation on the purpose of the feeding plan and the evidence supporting early enteral feeding. We hypothesized that there would be a significant decrease in time to the first enteral feed following the ⁎ Corresponding author at: Division of Neonatology, MUSC Children's Hospital, 165 Ashley Avenue, MSC 917, Charleston, SC 29425, United States. Tel.: +1 843 792 2112; fax: +1 843 792 8801. E-mail address: [email protected] (E. Hamilton).
http://dx.doi.org/10.1016/j.earlhumdev.2014.02.005 0378-3782/© 2014 Elsevier Ireland Ltd. All rights reserved.
educational initiative and that this would result in fewer total parenteral nutrition days, as infants would reach full feeds faster. With the longstanding concern that early feeding increases the risk for NEC, we also followed this outcome as a safety measure. 2. Patients and methods After IRB approval, this retrospective study was performed at a single university-based tertiary care neonatal intensive care unit (Medical University of South Carolina). In 2005, neonatal service admission orders were revised to have the default feeding plan include initiation of feeds between 6 and 24 postnatal hours. In July 2008, general clinician subjective experience concluded that this feed initiation order was not consistently followed by nursing staff. At that time, a process improvement plan was initiated to educate staff in regard to this order and the scientific evidence supporting the importance and safety of early enteral nutrition. Additionally, staff received education and instructions to initiate maternal breast pumping within 6 h of infant delivery and to request maternal assent for donor human milk at infant delivery. This education occurred over a 6-month period. The university hospital perinatal information database was queried to identify and collect demographics for VLBW infants admitted January 1, 2007–June 30, 2008 (Epoch 1) and January 1, 2009–June 30, 2010
228
E. Hamilton et al. / Early Human Development 90 (2014) 227–230
(Epoch 2). Infants were excluded if they had congenital gastrointestinal or cardiac anomalies, were transferred in after 24 postnatal hours, or died in the first 24 postnatal hours prior to initiation of feeding protocol. Infant demographics including the incidence of small-for-gestationalage (SGA) status defined by Fenton growth chart [7], the hour of the first feed, age at initiation and total days of parenteral nutrition, NEC or death incidence, and type of feed given during the first 24 postnatal hours were obtained. Additionally, central line days, central line associated blood stream infections, feeding intolerance (defined as documentation of diagnosis by clinical provider), bronchopulmonary dysplasia (defined as requiring oxygen at 36 weeks gestation), retinopathy of prematurity (Stages 3–4), weight gain velocity from birth to hospital discharge, and length of stay was compared between the two groups. In further evaluation of growth, the infants in each epoch who were discharged at 35–37 weeks post-menstrual age (PMA) and had weight, length, and head circumference measurements at hospital discharge had comparison of these growth parameters. During both time periods, infants were fed by the same feed advancement protocol. This protocol standardizes both duration of trophic feeds and feed volume advancement until 160 ml/kg/day volume is reached. The protocol includes a statement to not initiate feeds for infants with a surgical abdomen, hypotension requiring inotropic or vasopressor support, or FiO2 ≥ 0.6. Upon initiation of feeds, infants were preferentially fed mother's milk unless contraindicated. When mother's milk was not available, donor human milk was substituted for infants born b 30 weeks gestation, and 24 kcal/oz preterm infant formula was substituted for more mature infants. Once feeds were initiated, feed advancement was performed by standardized orders stratified by birth weight, and details are as follows: (1) trophic feeds (12 ml/kg/day) for 1–5 days; (2) feed volume advancement by 15–30 ml/kg/day; (3) human milk fortification to 24 kcal/oz at 100 ml/kg/day; (4) goal feed volume of 160 ml/kg/day; and (5) human milk fortification with whey protein to 26 kcal/oz at 160 ml/kg/day. Additionally, parenteral nutrition was initiated on postnatal day 1 and discontinued when the infant was receiving at least 120 ml/kg/day enteral feeds. 3. Statistical analyses The patient sample was defined by date of birth based on the time of the quality improvement initiative. Therefore, no power analysis was performed. The first outcome measurement was to determine whether the process improvement plan was associated with feed initiation per protocol (6–24 postnatal hours) and whether feed initiation was significantly earlier in Epoch 2 than in Epoch 1. Following these assessments, if a significant clinical difference was observed, then evaluation of factors associated with this change was to be investigated. The studied factors were days of parenteral nutrition, incidence of NEC or death, and type of enteral nutrition received in the first 24 postnatal hours, central line days, central line associated blood stream infections, feeding intolerance, hospital weight growth velocity, retinopathy of prematurity, bronchopulmonary dysplasia, and length of hospital stay. Outcomes for days of parenteral nutrition, incidence of NEC or death, and type of enteral nutrition in the first 24 postnatal hours were also compared by postnatal hour of the first feed. To further evaluate growth between
the two epochs, for infants with hospital discharge at 35–37 weeks PMA, hospital discharge weight, length, and head circumference were compared. Results were tested for normality followed by the appropriate test (Student's t-test or Wilcoxon Rank Sum) for comparison. Chisquare, Fisher's exact, linear regression, and logistic regression were also performed. Significance was defined a priori as p b 0.05. In the secondary analysis, the outcome factors were evaluated in relationship to early feeding, defined as feeding before 24 postnatal hours, and postnatal hour of the first feed in Epoch 2 only. This epoch was chosen due to standardization of feed initiation practice. In Epoch 1, the practitioner choice to delay feeds may have biased the association of feed initiation and outcome.
4. Results A total of 603 VLBW infants (Epoch 1 = 277, Epoch 2 = 326) met the inclusion criteria. Their characteristics are shown in Table 1. The groups were comparable for race, gender, and incidence of SGA status but statistically different for median gestational age and birth weight, with infants in Epoch 1 having lower gestational age at birth and smaller size than infants in Epoch 2. As shown in Fig. 1, compared to Epoch 1, a significantly larger proportion of infants in Epoch 2 was receiving enteral nutrition by postnatal hour 24 (75.5 vs. 36.5%, p b 0.0001). The hour of enteral feed initiation significantly decreased from Epoch 1 to Epoch 2 (median of 33 vs. 14 h, p b 0.0001) (Table 2). As shown in Table 2, no significant difference in median total parenteral nutrition days was observed (p = 0.07), but the decrease in median days may be considered clinically important. Also of note, due to a concomitant improvement initiative, compared to Epoch 1, significantly more infants in Epoch 2 had initiation of parenteral nutrition on the first day (85.9% versus 96% respectively, p b 0.001). Additionally, the percent of infants diagnosed by a clinician as having feeding intolerance was significantly higher in Epoch 1, and hospital growth velocity was significantly higher in Epoch 2 without a significant difference in length of hospital stay. In evaluation of NEC and NEC or death, no significant difference existed between epochs. However, death alone was significantly higher in Epoch 1, and the associated morbidity of central line associated blood stream infections was also significantly higher in Epoch 1. Since the lower gestational age and birth weight observed in Epoch 1 are risk factors for NEC and death, a logistic regression was performed to account for these factors. When controlling for birth weight, gestational age, race, gender, and time period, the postnatal hour of feed initiation was associated with NEC or death (p = 0.003). Meaning the earlier feeding was initiated, the less likely NEC or death were to occur. In further appraisal of growth between epochs, infants with hospital discharge at 35–37 weeks PMA had comparison of growth parameters (Table 3). For these infants, weight at discharge was significantly higher in Epoch 2, but no difference was found for length or head circumference at discharge. The higher weight at discharge was congruent with the significantly higher growth velocity also observed during Epoch 2.
Table 1 Patient characteristics.
Birth weight median (grams) (range) Gestational age (PMA) median (weeks) (range) Male (%) Black (%) White (%) Hispanic (%) Asian (%) SGA (%)
Epoch 1 (n = 277)
Epoch 2 (n = 326)
p-Value
1030 (385–1496) 28 (22–35) 44.4 57.8 32.9 8.3 1.1 16.3
1135 (385–1495) 29 (23–35) 46.6 52.5 39.6 6.8 1.2 12.3
0.002 0.04 NS NS NS NS NS NS
E. Hamilton et al. / Early Human Development 90 (2014) 227–230
0.4
229
Epoch 1 Epoch 2
0.35
Fraction of infants
0.3 0.25 0.2 0.15 0.1 0.05 0
Hour of first feed Fig. 1. Postnatal hour of the first enteral feed compared between epochs.
4.1. Type of feeding The type of the first feeding is presented in Table 3. Of the 347 (Epoch 1 = 101, Epoch 2 = 246), VLBW infants fed in the first 24 h, the type of feeding of the first feed is presented in Table 4. In Epoch 2, significantly more infants received human milk when compared to formula and significantly more infants received mother's milk when compared to donor milk or formula as the first feed. In the evaluation of cumulative feed intake in the first 24 h, of the 347 infants receiving early enteral feeding, 19.3% received only mother's milk. As shown in Table 5, there was a significant difference between epochs in infants who received no human milk. Evaluation of whether early exposure to formula increases the risk for NEC was hindered by the clinical practice to provide donor human milk for infants born b30 weeks gestation. Therefore, 133 infants received formula in the first postnatal day, and, of these, only 1 developed NEC. Of note, the infant who received formula and developed NEC was not fed by standard clinical practice, as she was b30 weeks PMA (29 weeks), but received formula instead of donor human milk. 4.2. Evaluation of outcomes with standard feed initiation practice To evaluate early enteral feeding with standardized clinical feeding practice, early enteral feeding was evaluated in Epoch 2 specifically. During this time period, VLBW infants fed within the first 24 h when compared to infants with later initiation of feeds demonstrated significantly less NEC incidence (4.6 vs 14%)(RR, 95% CI = 0.3, 0.13–0.71)
and significantly less NEC/death (6.3 vs 15.1%)(RR, 95% CI = 0.28, 0.13–0.58), respectively. In Epoch 2, feeding within the first 24 h was associated with less days of PN when compared to infants fed later [median (interquartile range) 10 (7–18) versus 18 (10–27) days (p b 0.0001)]. Also, when controlling for birth weight, gestational age, race, and gender, earlier postnatal hour of feed initiation was associated with decreased NEC or death (p = 0.004) (OR, 95% CI = 1.013, 1.004–1.021). 5. Discussion An education-based process improvement initiative decreased time to initiation of enteral feeds to a median of 14 h for VLBW infants with no associated increase in NEC or death. Additionally, results suggest that earlier feeding is associated with decreased NEC or death in this population. In Epoch 2, having initiation of enteral feeds by postnatal hour 24 was associated with significantly less total parenteral nutrition days. The primary goal with this retrospective study was to determine how well enteral feeding guidelines for VLBW infants were being followed. Based on the statistically significant reduction in the hour of the first enteral feed between the time periods, the educational initiative was successful. This study is unique since it evaluated outcomes of VLBW infants based on an enteral feeding protocol that begins within the first 24 postnatal hours. We also wanted to ensure that utilization of the early enteral feed initiation guideline did not introduce additional risks to this fragile infant population. The absence of an increase in the
Table 2 Comparison of outcomes by epoch.
First EF median (hours) (interquartile range) PN median (days) (interquartile range) NEC, n (%) Death, n (%) NEC or death, n (%) Central line days, median (interquartile range) Central line associated blood stream infection, n (%) Feeding intolerance, n (%) Bronchopulmonary dysplasia Retinopathy of prematurity Growth velocity, g/day median (IQ) Length of hospital stay, median days (interquartile range)
Epoch 1 (n = 277)
Epoch 2 (n = 326)
p-Value
33 (17–52) 14 (8–22) 18 (6.5) 25 (9) 37 (13.4) 12 (7–18) 7 (2.5) 43 (15.5) 63 (22.7) 8 (2.9) 17.9 (15.2–20.4) 42 (24–66)
14 (8–24) 12 (7–20) 23 (7.1) 12 (3.7) 31 (9.5) 11 (7–15) 0 21 (6.4) 80 (24.5) 14 (4.3) 21.6 (18.8–25.5) 46 (27–68)
b0.0001 NS NS 0.006 NS NS 0.004 0.0003 NS NS b0.0001 NS
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E. Hamilton et al. / Early Human Development 90 (2014) 227–230
Table 3 Growth parameters [median (interquartile range)] for infants discharged at 35–37 weeks PCA. Parameter
Epoch 1, n = 109
Epoch 2, n = 130
p-Value
Weight, g Length, cm Head circumference, cm
1935 (1720–2171) 43 (41–45) 31 (30–32.5)
2176 (1847–2450) 43 (41.5–45) 31.5 (30.5–32.5)
b0.0001 NS NS
Table 4 Type of the first enteral feed (of babies fed within 24 h). Type of feed
Epoch 1, n = 101 (%)
Epoch 2, n = 246 (%)
p-Value
Mother's milk Mother's milk or donor human milk Formula
22 (21.8) 58 (57.4)
88 (35.8) 177 (72.0)
0.011 0.009
43 (42.6)
69 (28.0)
0.009
hand, the fact that early feeding was associated with less NEC and death in Epoch 2 with protocol-driven feed initiation supports the potential benefit of early feeding. Evaluation of early enteral feeding has been limited by the concern that early feeding leads to NEC. However, as early enteral feeding has been shown to decrease gut atrophy and intestinal permeability, physiology supports that it may be protective against NEC. In the future, it will be important to determine if the incidence of feeding intolerance and/or NEC following feeding early with formula is similar to that following early feeding with mother's milk or whether early feedings should be delayed until the mother's milk is available. Also, further evaluation of specific gestational age groups will be useful in determining whether our findings of the benefits of early enteral feeds are similar in both degrees of prematurity. Likewise, since it has been shown that SGA infants are at a greater risk for NEC and death, a subpopulation analysis of this group of infants will be beneficial. 6. Conclusion
Table 5 Type of enteral feed given in the first 24 h. Type of feed in the first 24 h
Epoch 1, n = 101 (%)
Epoch 2, n = 246 (%)
p-Value
100% mother's milk 100% mother's milk or donor human milk No mother's milk or donor human milk
20 (19.8) 56 (55.4)
47 (19.1) 158 (64.2)
NS NS
35 (34.7)
47 (19.1)
0.002
incidence of NEC or death in the group of infants fed earlier suggests that feeding early is safe. In fact, we propose that feed initiation in the first 24 h may be protective because when controlling for gestational age, birth weight, gender, and race, infants receiving feeds in the first 24 h demonstrated significantly less NEC or death. Our finding of less NEC or death is in contrast to a Cochrane review which concluded that early enteral feeding did not confer any substantial clinical benefits for VLBW infants [1]. The majority of studies included in this review had initiation of trophic enteral feeds at postnatal day 3 or later and delayed advancement of the feeding volume for at least 5 days, making it difficult to compare to our feeding practice. An observational study suggested that delayed enteral feeding and slower advancement of feeding volume may be associated with a lower risk of NEC [8]. However, a recent Cochrane review looking at the effect of timing of enteral feeds and the development of NEC concluded that there is insufficient evidence that delaying enteral feeds reduces the risk of NEC [9]. Our data suggest that early enteral feeding may actually decrease the risk of NEC in VLBW infants. In our study, infants in Epoch 2 also demonstrated significantly higher growth velocity during hospitalization. Full enteral nutrition has been shown to decrease the rate of protein breakdown [10], but the volume of feed required to achieve this effect is not known. Instead, the improvement in growth in Epoch 2 is likely associated with concurrent changes in other nutritional practices such as earlier introduction of parenteral nutrition, lipid infusion, and standardization of higher enteral protein. Our study is limited by the retrospective design. Additionally, since the study was designed to compare two time periods encompassing a quality improvement initiative, no power analysis was performed. Therefore, our results showing an association between feeding early and less NEC and death in VLBW infants must be interpreted with caution. In particular, a concomitant factor may both influence the delay of enteral feeding and be associated with NEC and death. On the other
A process improvement initiative decreased the time of enteral feed initiation to a median of 14 h for VLBW infants with no associated increase in NEC or death. In fact, the results suggest that earlier enteral feeding is associated with decreased NEC or death. As expected, total parenteral nutrition days were significantly less for infants fed by postnatal hour 24 when compared to infants with feeds initiated later. This retrospective study suggests that initiating enteral feeds within the first 24 postnatal hours in VLBW infants is safe, well-tolerated, and may be associated with decreased NEC or death. Conflict of interest Dr. Taylor has received an honorarium for webinar development and presentation from Ameda. The other authors have no conflicts of interest relevant to this article to disclose. Acknowledgments Myla Ebeling was responsible for data analysis. References [1] Bombell S, McGuire W. Early trophic feeding for very low birth weight infants. Cochrane Database Syst Rev 2009;8(3):CD000504. [2] Rouwet EV, Heineman E, Buurman WA, ter Riet G, Ramsay G, Blaco CE. Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period. Pediatr Res 2002;51(1):64–70. [3] Flidel-Ramon O, Friedman S, Lev E, Juster-Reicher A, Amitay M, Shinwell ES. Early enteral feeding and nosocomial sepsis in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2004;89(4):F289–92. [4] Cakmak Celik F, Aygun C, Cetinoglu E. Does early enteral feeding of very low birth weight infants increase the risk of necrotizing enterocolitis? Eur J Clin Nutr 2009;63(4):580–4. [5] McCallie KR, Lee HC, Mayer O, Cohen RS, Hintz SR, Rhine WD. Improved outcomes with a standardized feeding protocol for very low birth weight infants. J Perinatol 2011;31(Suppl. 1):S61–7. [6] Patole SK, de Klerk N. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal Ed 2005;90(2):F147–51. [7] Fenton TR. A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format. BMC Pediatr 2003;3:13. [8] Henderson G, Craig S, Brocklehurst P, McGuire W. Enteral feeding regimens and necrotising enterocolitis in preterm infants: a multicentre case–control study. Arch Dis Child Fetal Neonatal Ed 2009;94(2):F120–3. [9] Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2011;16(3):CD001970. [10] Denne SC. Regulation of proteolysis and optimal protein accretion in extremely premature newborns. Am J Clin Nutr 2007;85:621S–4S (Suppl.).
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Early enteral feeding in very low birth weight infants Emily Hamilton ⁎, Cynthia Massey, Julie Ross, Sarah Taylor Division of Neonatology, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States
a r t i c l e
i n f o
Article history: Received 8 June 2013 Received in revised form 7 February 2014 Accepted 11 February 2014 Keywords: Early enteral feeding Very low birth weight infants Necrotizing enterocolitis Parenteral nutrition Prematurity
a b s t r a c t Background/aim: Debate exists about when to initiate enteral feeding (EF) in very low birth weight (VLBW) preterm infants. This retrospective study compared the effectiveness of an education-based quality improvement project and the relationship of time of the first EF to necrotizing enterocolitis (NEC) or death incidence and parenteral nutrition (PN) days in VLBW infants. Study design/subjects: VLBW infants born in 2 epochs were compared for hour of the first feed, PN days, NEC or death incidence, and feeding type. The 2 epochs were temporally divided by a quality improvement initiative to standardize initiation of EF in postnatal hours 6–24. Results: 603 VLBW infants were included. Median time of feed initiation decreased from 33 (Epoch 1) to 14 h (Epoch 2) (p b 0.0001). Median PN days were 14 vs. 12, respectively (p = 0.07). The incidence of NEC or death was 13.4% vs. 9.5%, respectively (p = 0.14). When controlling for birth weight, gestational age, race, gender, and time period, earlier feed initiation was associated with decreased NEC or death (p = 0.003). Evaluation of the relationship of early EF (defined as within the first 24 h) in Epoch 2 alone showed that early EF was significantly associated with decreased NEC or death (6.3 vs 15.1%) (RR, 95% CI = 0.28, 0.13–0.58) and less PN days (p b 0.0001). Conclusions: In a VLBW infant cohort, an education-based process improvement initiative decreased time of EF initiation to a median of 14 h with no associated increase in NEC or death. In fact, results suggest that earlier feeding is associated with decreased NEC or death. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Debate continues regarding early postnatal readiness for enteral feeding in very low birth weight (VLBW) (b 1500 g) infants [1]. Much has been published about the potential benefits of early feeds. Early enteral nutrition is known to decrease gut atrophy and intestinal permeability [2] and has been associated with improved postnatal growth and decreased incidence of sepsis [3]. However, concern for an association with necrotizing enterocolitis (NEC) has propagated delaying enteral nutrition in this population [4]. Recent data suggest that implementation of a feeding protocol not only is safe but also may decrease the incidence of NEC [5,6]. At our institution, despite a feeding order to initiate minimal enteral nutrition at 6–24 postnatal hours, this clinical plan was not widely accepted by the nursing staff and required an education-based quality improvement initiative to improve the process. This education consisted of a presentation on the purpose of the feeding plan and the evidence supporting early enteral feeding. We hypothesized that there would be a significant decrease in time to the first enteral feed following the ⁎ Corresponding author at: Division of Neonatology, MUSC Children's Hospital, 165 Ashley Avenue, MSC 917, Charleston, SC 29425, United States. Tel.: +1 843 792 2112; fax: +1 843 792 8801. E-mail address: [email protected] (E. Hamilton).
http://dx.doi.org/10.1016/j.earlhumdev.2014.02.005 0378-3782/© 2014 Elsevier Ireland Ltd. All rights reserved.
educational initiative and that this would result in fewer total parenteral nutrition days, as infants would reach full feeds faster. With the longstanding concern that early feeding increases the risk for NEC, we also followed this outcome as a safety measure. 2. Patients and methods After IRB approval, this retrospective study was performed at a single university-based tertiary care neonatal intensive care unit (Medical University of South Carolina). In 2005, neonatal service admission orders were revised to have the default feeding plan include initiation of feeds between 6 and 24 postnatal hours. In July 2008, general clinician subjective experience concluded that this feed initiation order was not consistently followed by nursing staff. At that time, a process improvement plan was initiated to educate staff in regard to this order and the scientific evidence supporting the importance and safety of early enteral nutrition. Additionally, staff received education and instructions to initiate maternal breast pumping within 6 h of infant delivery and to request maternal assent for donor human milk at infant delivery. This education occurred over a 6-month period. The university hospital perinatal information database was queried to identify and collect demographics for VLBW infants admitted January 1, 2007–June 30, 2008 (Epoch 1) and January 1, 2009–June 30, 2010
228
E. Hamilton et al. / Early Human Development 90 (2014) 227–230
(Epoch 2). Infants were excluded if they had congenital gastrointestinal or cardiac anomalies, were transferred in after 24 postnatal hours, or died in the first 24 postnatal hours prior to initiation of feeding protocol. Infant demographics including the incidence of small-for-gestationalage (SGA) status defined by Fenton growth chart [7], the hour of the first feed, age at initiation and total days of parenteral nutrition, NEC or death incidence, and type of feed given during the first 24 postnatal hours were obtained. Additionally, central line days, central line associated blood stream infections, feeding intolerance (defined as documentation of diagnosis by clinical provider), bronchopulmonary dysplasia (defined as requiring oxygen at 36 weeks gestation), retinopathy of prematurity (Stages 3–4), weight gain velocity from birth to hospital discharge, and length of stay was compared between the two groups. In further evaluation of growth, the infants in each epoch who were discharged at 35–37 weeks post-menstrual age (PMA) and had weight, length, and head circumference measurements at hospital discharge had comparison of these growth parameters. During both time periods, infants were fed by the same feed advancement protocol. This protocol standardizes both duration of trophic feeds and feed volume advancement until 160 ml/kg/day volume is reached. The protocol includes a statement to not initiate feeds for infants with a surgical abdomen, hypotension requiring inotropic or vasopressor support, or FiO2 ≥ 0.6. Upon initiation of feeds, infants were preferentially fed mother's milk unless contraindicated. When mother's milk was not available, donor human milk was substituted for infants born b 30 weeks gestation, and 24 kcal/oz preterm infant formula was substituted for more mature infants. Once feeds were initiated, feed advancement was performed by standardized orders stratified by birth weight, and details are as follows: (1) trophic feeds (12 ml/kg/day) for 1–5 days; (2) feed volume advancement by 15–30 ml/kg/day; (3) human milk fortification to 24 kcal/oz at 100 ml/kg/day; (4) goal feed volume of 160 ml/kg/day; and (5) human milk fortification with whey protein to 26 kcal/oz at 160 ml/kg/day. Additionally, parenteral nutrition was initiated on postnatal day 1 and discontinued when the infant was receiving at least 120 ml/kg/day enteral feeds. 3. Statistical analyses The patient sample was defined by date of birth based on the time of the quality improvement initiative. Therefore, no power analysis was performed. The first outcome measurement was to determine whether the process improvement plan was associated with feed initiation per protocol (6–24 postnatal hours) and whether feed initiation was significantly earlier in Epoch 2 than in Epoch 1. Following these assessments, if a significant clinical difference was observed, then evaluation of factors associated with this change was to be investigated. The studied factors were days of parenteral nutrition, incidence of NEC or death, and type of enteral nutrition received in the first 24 postnatal hours, central line days, central line associated blood stream infections, feeding intolerance, hospital weight growth velocity, retinopathy of prematurity, bronchopulmonary dysplasia, and length of hospital stay. Outcomes for days of parenteral nutrition, incidence of NEC or death, and type of enteral nutrition in the first 24 postnatal hours were also compared by postnatal hour of the first feed. To further evaluate growth between
the two epochs, for infants with hospital discharge at 35–37 weeks PMA, hospital discharge weight, length, and head circumference were compared. Results were tested for normality followed by the appropriate test (Student's t-test or Wilcoxon Rank Sum) for comparison. Chisquare, Fisher's exact, linear regression, and logistic regression were also performed. Significance was defined a priori as p b 0.05. In the secondary analysis, the outcome factors were evaluated in relationship to early feeding, defined as feeding before 24 postnatal hours, and postnatal hour of the first feed in Epoch 2 only. This epoch was chosen due to standardization of feed initiation practice. In Epoch 1, the practitioner choice to delay feeds may have biased the association of feed initiation and outcome.
4. Results A total of 603 VLBW infants (Epoch 1 = 277, Epoch 2 = 326) met the inclusion criteria. Their characteristics are shown in Table 1. The groups were comparable for race, gender, and incidence of SGA status but statistically different for median gestational age and birth weight, with infants in Epoch 1 having lower gestational age at birth and smaller size than infants in Epoch 2. As shown in Fig. 1, compared to Epoch 1, a significantly larger proportion of infants in Epoch 2 was receiving enteral nutrition by postnatal hour 24 (75.5 vs. 36.5%, p b 0.0001). The hour of enteral feed initiation significantly decreased from Epoch 1 to Epoch 2 (median of 33 vs. 14 h, p b 0.0001) (Table 2). As shown in Table 2, no significant difference in median total parenteral nutrition days was observed (p = 0.07), but the decrease in median days may be considered clinically important. Also of note, due to a concomitant improvement initiative, compared to Epoch 1, significantly more infants in Epoch 2 had initiation of parenteral nutrition on the first day (85.9% versus 96% respectively, p b 0.001). Additionally, the percent of infants diagnosed by a clinician as having feeding intolerance was significantly higher in Epoch 1, and hospital growth velocity was significantly higher in Epoch 2 without a significant difference in length of hospital stay. In evaluation of NEC and NEC or death, no significant difference existed between epochs. However, death alone was significantly higher in Epoch 1, and the associated morbidity of central line associated blood stream infections was also significantly higher in Epoch 1. Since the lower gestational age and birth weight observed in Epoch 1 are risk factors for NEC and death, a logistic regression was performed to account for these factors. When controlling for birth weight, gestational age, race, gender, and time period, the postnatal hour of feed initiation was associated with NEC or death (p = 0.003). Meaning the earlier feeding was initiated, the less likely NEC or death were to occur. In further appraisal of growth between epochs, infants with hospital discharge at 35–37 weeks PMA had comparison of growth parameters (Table 3). For these infants, weight at discharge was significantly higher in Epoch 2, but no difference was found for length or head circumference at discharge. The higher weight at discharge was congruent with the significantly higher growth velocity also observed during Epoch 2.
Table 1 Patient characteristics.
Birth weight median (grams) (range) Gestational age (PMA) median (weeks) (range) Male (%) Black (%) White (%) Hispanic (%) Asian (%) SGA (%)
Epoch 1 (n = 277)
Epoch 2 (n = 326)
p-Value
1030 (385–1496) 28 (22–35) 44.4 57.8 32.9 8.3 1.1 16.3
1135 (385–1495) 29 (23–35) 46.6 52.5 39.6 6.8 1.2 12.3
0.002 0.04 NS NS NS NS NS NS
E. Hamilton et al. / Early Human Development 90 (2014) 227–230
0.4
229
Epoch 1 Epoch 2
0.35
Fraction of infants
0.3 0.25 0.2 0.15 0.1 0.05 0
Hour of first feed Fig. 1. Postnatal hour of the first enteral feed compared between epochs.
4.1. Type of feeding The type of the first feeding is presented in Table 3. Of the 347 (Epoch 1 = 101, Epoch 2 = 246), VLBW infants fed in the first 24 h, the type of feeding of the first feed is presented in Table 4. In Epoch 2, significantly more infants received human milk when compared to formula and significantly more infants received mother's milk when compared to donor milk or formula as the first feed. In the evaluation of cumulative feed intake in the first 24 h, of the 347 infants receiving early enteral feeding, 19.3% received only mother's milk. As shown in Table 5, there was a significant difference between epochs in infants who received no human milk. Evaluation of whether early exposure to formula increases the risk for NEC was hindered by the clinical practice to provide donor human milk for infants born b30 weeks gestation. Therefore, 133 infants received formula in the first postnatal day, and, of these, only 1 developed NEC. Of note, the infant who received formula and developed NEC was not fed by standard clinical practice, as she was b30 weeks PMA (29 weeks), but received formula instead of donor human milk. 4.2. Evaluation of outcomes with standard feed initiation practice To evaluate early enteral feeding with standardized clinical feeding practice, early enteral feeding was evaluated in Epoch 2 specifically. During this time period, VLBW infants fed within the first 24 h when compared to infants with later initiation of feeds demonstrated significantly less NEC incidence (4.6 vs 14%)(RR, 95% CI = 0.3, 0.13–0.71)
and significantly less NEC/death (6.3 vs 15.1%)(RR, 95% CI = 0.28, 0.13–0.58), respectively. In Epoch 2, feeding within the first 24 h was associated with less days of PN when compared to infants fed later [median (interquartile range) 10 (7–18) versus 18 (10–27) days (p b 0.0001)]. Also, when controlling for birth weight, gestational age, race, and gender, earlier postnatal hour of feed initiation was associated with decreased NEC or death (p = 0.004) (OR, 95% CI = 1.013, 1.004–1.021). 5. Discussion An education-based process improvement initiative decreased time to initiation of enteral feeds to a median of 14 h for VLBW infants with no associated increase in NEC or death. Additionally, results suggest that earlier feeding is associated with decreased NEC or death in this population. In Epoch 2, having initiation of enteral feeds by postnatal hour 24 was associated with significantly less total parenteral nutrition days. The primary goal with this retrospective study was to determine how well enteral feeding guidelines for VLBW infants were being followed. Based on the statistically significant reduction in the hour of the first enteral feed between the time periods, the educational initiative was successful. This study is unique since it evaluated outcomes of VLBW infants based on an enteral feeding protocol that begins within the first 24 postnatal hours. We also wanted to ensure that utilization of the early enteral feed initiation guideline did not introduce additional risks to this fragile infant population. The absence of an increase in the
Table 2 Comparison of outcomes by epoch.
First EF median (hours) (interquartile range) PN median (days) (interquartile range) NEC, n (%) Death, n (%) NEC or death, n (%) Central line days, median (interquartile range) Central line associated blood stream infection, n (%) Feeding intolerance, n (%) Bronchopulmonary dysplasia Retinopathy of prematurity Growth velocity, g/day median (IQ) Length of hospital stay, median days (interquartile range)
Epoch 1 (n = 277)
Epoch 2 (n = 326)
p-Value
33 (17–52) 14 (8–22) 18 (6.5) 25 (9) 37 (13.4) 12 (7–18) 7 (2.5) 43 (15.5) 63 (22.7) 8 (2.9) 17.9 (15.2–20.4) 42 (24–66)
14 (8–24) 12 (7–20) 23 (7.1) 12 (3.7) 31 (9.5) 11 (7–15) 0 21 (6.4) 80 (24.5) 14 (4.3) 21.6 (18.8–25.5) 46 (27–68)
b0.0001 NS NS 0.006 NS NS 0.004 0.0003 NS NS b0.0001 NS
230
E. Hamilton et al. / Early Human Development 90 (2014) 227–230
Table 3 Growth parameters [median (interquartile range)] for infants discharged at 35–37 weeks PCA. Parameter
Epoch 1, n = 109
Epoch 2, n = 130
p-Value
Weight, g Length, cm Head circumference, cm
1935 (1720–2171) 43 (41–45) 31 (30–32.5)
2176 (1847–2450) 43 (41.5–45) 31.5 (30.5–32.5)
b0.0001 NS NS
Table 4 Type of the first enteral feed (of babies fed within 24 h). Type of feed
Epoch 1, n = 101 (%)
Epoch 2, n = 246 (%)
p-Value
Mother's milk Mother's milk or donor human milk Formula
22 (21.8) 58 (57.4)
88 (35.8) 177 (72.0)
0.011 0.009
43 (42.6)
69 (28.0)
0.009
hand, the fact that early feeding was associated with less NEC and death in Epoch 2 with protocol-driven feed initiation supports the potential benefit of early feeding. Evaluation of early enteral feeding has been limited by the concern that early feeding leads to NEC. However, as early enteral feeding has been shown to decrease gut atrophy and intestinal permeability, physiology supports that it may be protective against NEC. In the future, it will be important to determine if the incidence of feeding intolerance and/or NEC following feeding early with formula is similar to that following early feeding with mother's milk or whether early feedings should be delayed until the mother's milk is available. Also, further evaluation of specific gestational age groups will be useful in determining whether our findings of the benefits of early enteral feeds are similar in both degrees of prematurity. Likewise, since it has been shown that SGA infants are at a greater risk for NEC and death, a subpopulation analysis of this group of infants will be beneficial. 6. Conclusion
Table 5 Type of enteral feed given in the first 24 h. Type of feed in the first 24 h
Epoch 1, n = 101 (%)
Epoch 2, n = 246 (%)
p-Value
100% mother's milk 100% mother's milk or donor human milk No mother's milk or donor human milk
20 (19.8) 56 (55.4)
47 (19.1) 158 (64.2)
NS NS
35 (34.7)
47 (19.1)
0.002
incidence of NEC or death in the group of infants fed earlier suggests that feeding early is safe. In fact, we propose that feed initiation in the first 24 h may be protective because when controlling for gestational age, birth weight, gender, and race, infants receiving feeds in the first 24 h demonstrated significantly less NEC or death. Our finding of less NEC or death is in contrast to a Cochrane review which concluded that early enteral feeding did not confer any substantial clinical benefits for VLBW infants [1]. The majority of studies included in this review had initiation of trophic enteral feeds at postnatal day 3 or later and delayed advancement of the feeding volume for at least 5 days, making it difficult to compare to our feeding practice. An observational study suggested that delayed enteral feeding and slower advancement of feeding volume may be associated with a lower risk of NEC [8]. However, a recent Cochrane review looking at the effect of timing of enteral feeds and the development of NEC concluded that there is insufficient evidence that delaying enteral feeds reduces the risk of NEC [9]. Our data suggest that early enteral feeding may actually decrease the risk of NEC in VLBW infants. In our study, infants in Epoch 2 also demonstrated significantly higher growth velocity during hospitalization. Full enteral nutrition has been shown to decrease the rate of protein breakdown [10], but the volume of feed required to achieve this effect is not known. Instead, the improvement in growth in Epoch 2 is likely associated with concurrent changes in other nutritional practices such as earlier introduction of parenteral nutrition, lipid infusion, and standardization of higher enteral protein. Our study is limited by the retrospective design. Additionally, since the study was designed to compare two time periods encompassing a quality improvement initiative, no power analysis was performed. Therefore, our results showing an association between feeding early and less NEC and death in VLBW infants must be interpreted with caution. In particular, a concomitant factor may both influence the delay of enteral feeding and be associated with NEC and death. On the other
A process improvement initiative decreased the time of enteral feed initiation to a median of 14 h for VLBW infants with no associated increase in NEC or death. In fact, the results suggest that earlier enteral feeding is associated with decreased NEC or death. As expected, total parenteral nutrition days were significantly less for infants fed by postnatal hour 24 when compared to infants with feeds initiated later. This retrospective study suggests that initiating enteral feeds within the first 24 postnatal hours in VLBW infants is safe, well-tolerated, and may be associated with decreased NEC or death. Conflict of interest Dr. Taylor has received an honorarium for webinar development and presentation from Ameda. The other authors have no conflicts of interest relevant to this article to disclose. Acknowledgments Myla Ebeling was responsible for data analysis. References [1] Bombell S, McGuire W. Early trophic feeding for very low birth weight infants. Cochrane Database Syst Rev 2009;8(3):CD000504. [2] Rouwet EV, Heineman E, Buurman WA, ter Riet G, Ramsay G, Blaco CE. Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period. Pediatr Res 2002;51(1):64–70. [3] Flidel-Ramon O, Friedman S, Lev E, Juster-Reicher A, Amitay M, Shinwell ES. Early enteral feeding and nosocomial sepsis in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2004;89(4):F289–92. [4] Cakmak Celik F, Aygun C, Cetinoglu E. Does early enteral feeding of very low birth weight infants increase the risk of necrotizing enterocolitis? Eur J Clin Nutr 2009;63(4):580–4. [5] McCallie KR, Lee HC, Mayer O, Cohen RS, Hintz SR, Rhine WD. Improved outcomes with a standardized feeding protocol for very low birth weight infants. J Perinatol 2011;31(Suppl. 1):S61–7. [6] Patole SK, de Klerk N. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal Ed 2005;90(2):F147–51. [7] Fenton TR. A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format. BMC Pediatr 2003;3:13. [8] Henderson G, Craig S, Brocklehurst P, McGuire W. Enteral feeding regimens and necrotising enterocolitis in preterm infants: a multicentre case–control study. Arch Dis Child Fetal Neonatal Ed 2009;94(2):F120–3. [9] Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2011;16(3):CD001970. [10] Denne SC. Regulation of proteolysis and optimal protein accretion in extremely premature newborns. Am J Clin Nutr 2007;85:621S–4S (Suppl.).
