PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1528-e1533 (doi:10.1542/10.1542/peds.2007-2110)
ARTICLE |
Human Milk Consumption and Full Enteral Feeding Among Infants Who Weigh 
1250 Grams
a Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
b Department of Nutrition
c School of Environmental Science, University of North Carolina, Greensboro, North Carolina
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. Establishing enteral feeding is an important goal in the care of very low birth weight infants. In such infants, receipt of
50 mL/kg per day human milk during hospitalization has been associated with shorter time to full enteral feeding. The objective of this study was to determine whether high proportions (50%) of human milk during feeding advancement are associated with shorter time to full enteral feeding and improved feeding tolerance.
METHODS. This was a prospective cohort study of very low birth weight infants (n = 127) who were grouped into low (<50%; n = 34) and high (50%; n = 93) human milk consumption groups according to their human milk proportion of enteral feeding during the time of feeding advancement. The primary outcomes of interest were ages at which 100 and 150 mL/kg per day enteral feedings were achieved.
RESULTS. The high human milk group reached 100 mL/kg per day enteral feeding 4.5 days faster than the low human milk group. The high human milk group reached 150 mL/kg per day enteral feeding 5 days faster than the low human milk group. After adjustment for gestational age, gender, and respiratory distress syndrome, times to reach 100 and 150 mL/kg per day were significantly shorter for those in the high human milk group. Infants in the high human milk group had a greater number of stools per day; other indicators of feeding tolerance were not statistically different.
CONCLUSION. In infants who weighed 
1250 g, enteral feeding that contained at least 50% maternal human milk was associated with fewer days to full enteral feedings.
Key Words: human milk • enteral feeding • prematurity • very low birth weight
Abbreviations: VLBW—very low birth weight • HM—human milk • GA—gestational age • HMF—human milk fortifier • NPO—nothing by mouth • RDS—respiratory distress syndrome • NEC—necrotizing enterocolitis • HHM—high human milk • LHM—low human milk • HR—hazard ratio • CI—confidence interval
Attaining full enteral feeding is an important goal when caring for very low birth weight (VLBW) infants because of its association with a lower risk for late-onset sepsis,1–3 hepatic dysfunction,4,5 growth failure,6 and poor mineral accretion.7 Feeding intolerance occurs frequently in VLBW infants as a result of medical instability, necrotizing enterocolitis, and immaturity of the gastrointestinal tract.8–11 Centers in the National Institute of Child Health and Human Development Network reported that for extremely low birth weight infants (<1000 g), age when full enteral feedings was reached ranged from 17 to 49 days12 and the Vermont Oxford Network "Got Milk" focus group reported that for infants who weighed 750 to 1000 g, the average time to reach full enteral feedings was 26 days.13
Clinicians use a variety of feeding strategies to compensate for gastrointestinal immaturity and to improve feeding tolerance. These include early feeding (4 days of age) or late feeding (>4 days of age),14 minimal enteral feeding (105 kJ/kg per day [25 kcal/kg per day] for 5 days versus no feeding,15 continuous versus intermittent bolus feeding,16 rapid versus slow advancement,17 and gastric versus transpyloric feeding tube placement.18 In systematic reviews, early feeding, minimal enteral feeding, and rapid advancement of feeding have been associated with improved feeding tolerance and/or shorter time to full enteral feeding, but no definitive conclusions have been reached regarding the clinical benefits of each of these methods. Moreover, there are conflicting findings for continuous versus intermittent bolus feeding methods16,19 and no apparent benefit from transpyloric versus gastric feeding18 with regard to improved feeding tolerance. Consequently, uncertainty regarding the best feeding methods for VLBW infants remains, and determining optimal feeding methods presents an important issue because withholding or limiting feedings may contribute to gastrointestinal immaturity, suboptimal nutrition, and growth restriction in preterm infants.20
Feeding human milk (HM), either the infant's own mother's milk or donor milk, may improve feeding tolerance in preterm infants.21 Schanler et al22 observed that infants who received at least 50 mL/kg per day HM during hospitalization had fewer episodes of feeding intolerance and shorter time to reach full enteral feedings, regardless of other feeding interventions; however, using HM volume as the exposure variable rather than the HM proportion of the total enteral feeding volume may have confounded these findings, because compared with more unstable infants, healthier infants are usually fed sooner and the feedings advanced more rapidly.
The purpose of this study was to analyze the association between HM proportion of enteral feeding and time to full feedings and feeding tolerance. We categorized exposure to HM on the basis of the proportion received during the time of feeding advancement. We hypothesized that the infants who received at least 50% of enteral feedings as HM would reach full enteral feeding at an earlier age and experience less feeding intolerance than those who received <50%.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Sample and Setting
The study was conducted in Winston-Salem, NC, at Forsyth Medical Center, a referral center for women at high risk for obstetric complications. The study participants were infants who were delivered with birth weights between 700 and 1500 g between May 2001 and August 2003 and whose mothers agreed to participate in a study comparing anxiety levels before and after lactation counseling.23 A prospective sample of 200 mother–infant pairs was targeted to provide a basis for detecting a preintervention/postintervention difference in State Trait Anxiety Scores. Exclusion criteria for this study were maternal illicit drug use during pregnancy, HIV infection, age <18 years, and non-English speaking. Of 208 eligible mother–infant pairs, 94% (n = 196) agreed to participate in the study. For this analysis, we excluded infants with birth weight >1250 g (the 50th percentile for 28 weeks’ gestation),24 who are at very low risk for delayed enteral feeding, thereby reducing the sample to 134 infants. The institutional review boards of Wake Forest University School of Medicine, Forsyth Medical Center, and the University of North Carolina at Greensboro approved the study, and all mothers signed a written informed consent.
Research Design
The study used a prospective cohort design in which the infants and mothers were enrolled within 72 hours of birth. Parenteral nutrition was begun on the first or second day of life when the infant's gestational age (GA) was 30 weeks or when enteral feedings were not tolerated for >24 hours. Enteral feedings were begun when the infant was regarded as stable by the attending neonatologist and advanced according to the established feeding guidelines for this NICU (Table 1). When 
100 to 120 mL/kg per day feeding was achieved, parenteral nutrition was discontinued. Decisions to withhold feedings were made by the attending neonatologist according to the enteral feeding guidelines stated in Table 1 or when the neonatologist determined that the infant's medical condition was unstable.
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All mothers in the study were encouraged to express milk for their infants regardless of their feeding plan before preterm delivery and were counseled by an international board-certified lactation consultant regarding the procedure for collection and storage of HM.25 Mothers were asked to bring their milk whenever they were able to visit their infants. Infants received HM only from their own mother. Maternal milk was used (when the mother chose to express milk) in the sequence it was expressed, either fresh or frozen to –20°C. Preterm formula (Enfamil Premature Formula 24 calories/ounce [Mead Johnson, Evansville, IN]) was given when the mother chose to formula feed or when there was insufficient maternal milk to meet the infant's nutritional needs. When feeding of 100 mL/kg per day was achieved and when HM was available, HM fortifier (HMF) was added, 1 packet to 25 mL of HM (Enfamil Human Milk Fortifier or Similac Human Milk Fortifer [Abbott Laboratories, Columbus, OH]). HMF was continued until the infant's weight reached 2500 g or until hospital discharge.
Outcome Measures
The primary outcome was age at which full feedings for hydration (100 mL/kg per day) and full feedings for growth (150 mL/kg per day) were consumed. Secondary outcomes of interest were indicators of feeding tolerance, caloric intake from enteral sources during feeding advancement, time to regain birth weight, and average daily weight gain during the hospitalization. Indicators of feeding tolerance were gastric residual volumes (mL/day), episodes of emesis per day, days of nothing by mouth (NPO), stools per day, glycerin suppositories given per week, days parenteral nutrition was given, and days central line access was maintained.
Caloric intake (kJ/kg per day [kcal/kg per day]) from enteral sources was calculated from the enteral feedings during the period of feeding advancement (from the first day enteral feedings were given until 150 mL/kg per day enteral feedings was consumed). HM was assumed to be 83.68 J/oz (20 cal/oz).26 HMF contained 14.644 J per packet (3.5 cal per packet). Average weight gain (g/kg per day) during the hospitalization was calculated from the day birth weight was regained until hospital discharge. Infants were studied throughout hospitalization, and data were collected from the infant's medical chart by research study assistants at the same time the study was conducted.
Respiratory distress syndrome (RDS) was defined as supplemental oxygen requirement for >24 hours. Necrotizing enterocolitis (NEC) was defined as pneumatosis on radiograph. Patent ductus arteriosus was diagnosed by cardiac echocardiogram, and all cases were included regardless of the treatment received.
Data Analysis
Data were analyzed with SPSS computer software (SPSS Inc, Chicago, IL). The characteristics of the groups were compared with Mann-Whitney U test for continuous variables and 
2 for categorical variables. GA and birth weight were highly correlated; therefore, all statistical analyses were conducted adjusting for GA and then again for birth weight. Results were reported for both analyses when the results were significantly different. Cox proportion hazards regression analysis was used to test time-to-event data: age when 100 mL/kg per day and 150 mL/kg per day enteral feeding were achieved, number of days parenteral nutrition was given, and number of days central line access was maintained. P <.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Characteristics of Patients
The findings of this study are based on the results obtained on 127 infants. From the initial sample of 134 infants, 7 were not included in the analysis because they did not achieve 150 mL/kg per day enteral feeding during the hospitalization as a result of death (n = 3) or transfer to a hospital closer to home (n = 4). There were 11 sets of twins and 1 set of triplets. No differences in conclusions were noted when multiples were excluded; therefore, they were included in the sample. Ninety-eight percent of the mothers initiated milk expression in the hospital. Table 2 provides demographic and clinical features of the 34 infants who during the time of feeding advancement (ie, from the first feeding until 150 mL/kg per day enteral feeding was received) received <50% of enteral feeding as HM (low HM [LHM]) and the 93 infants who received
50% HM (high HM [HHM]). The HHM group had a higher incidence of male gender and RDS after birth. There were no significant differences in other clinical features before initiation of enteral feedings.
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Primary Outcome
The HHM group reached 100 mL/kg per day enteral feeding 4.5 days faster than the LHM group (median [interquartile range]: 15.0 days [13.0–20.0] vs 19.5 days [11.8–29.3]; Table 3). The HHM group reached 150 mL/kg per day enteral feeding 5 days faster than the LHM group (median [interquartile range]: 22.0 [19.0–29.5] vs 27.0 [18.7–39.3]). Time to reach 100 mL/kg per day (hazard ratio [HR]: 1.53 [95% confidence interval (CI): 1.02–2.31]; P = .04) and 150 mL/kg per day (HR: 1.80 [95% CI: 1.16–2.78]; P = .008) was significantly shorter for the HHM group. After adjustment for GA, gender, and RDS, the results were similar (100 mL/kg per day HR: 1.86 [95% CI: 1.19–2.89]; P = .006) and 150 mL/kg per day HR: 2.13 [95% CI: 1.34–3.38]; P = .001). (HRs of >1 indicate that the factor was associated with a shorter time to the event of interest, eg, attainment of 100 mL/kg per day.) The difference in time to 150 mL/kg per day is illustrated in the Kaplan-Meier curve (Fig 1).
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Nutritional Outcomes
The HHM group had a significantly greater number of stools per day than the LHM group (Table 4). There were no differences in other variables related to feeding tolerance. The HHM group received parenteral nutrition and required central line access significantly fewer days compared with the LHM group. Enteral caloric intake during the feeding advancement period (kJ/kg per day [kcal/kg per day]), age when birth weight was regained, and weight gain (g/kg per day) during the hospitalization were similar between groups.
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Clinical Diagnoses and Medical Outcomes
There was no difference in incidence of patent ductus arteriosus, late-onset sepsis, or death (Table 4). There was a lower incidence of NEC; however, the number of cases was too small to determine statistical significance. To determine whether NPO status after diagnosis of NEC contributed to differences in age of achieving 100 and 150 mL/kg per day, we conducted analyses with NEC cases excluded. With these cases excluded, the results were similar to the results with the cases of NEC included for both time to reach 100 mL/kg per day (HR: 1.76 [95% CI: 1.10–2.81]; P = .02) and 150 mL/kg per day (HR: 2.21 [95% CI: 1.34–3.62]; P = .002). There were no statistically significant differences in length of hospital stay or postconceptional age at discharge.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Enteral feeding that consisted of a high proportion (
50%) of HM during the time of feeding advancement was associated with an earlier age that full feedings for hydration (100 mL/kg per day) and for growth (150 mL/kg per day) were achieved among infants with birth weight 1250 g. In addition, HM was associated with shorter duration of parenteral nutrition and central line access; however, we found no significant differences in gastric residual volume, number of emesis episodes, or NPO days. HM feeding was associated with more frequent stool output, and this is consistent with previously observed differences in stooling patterns of infants who were fed predominately HM compared with infant formula.27 HM contains bioactive agents (hormones, growth factors, and antiinflammatory agents) that may contribute to the maturation of gastrointestinal function and protect against inflammation. In vitro28 and animal studies29 indicated that polyamines and growth factors in HM stimulate intestinal cell proliferation and intestinal villi growth by increasing epithelial cell proliferation and lactase, maltase, and sucrase activity.30 In preterm infants, studies indicated that HM promotes adaptation of the gastrointestinal tract from an intrauterine physiologic state to an extrauterine physiologic state as evidenced by decreased intestinal permeability,31 higher lactase activity,32 and shorter time to achieve full enteral feeding.32 The presence of milk lipases in HM also may be a factor contributing to better digestion and absorption of lipid and better tolerance of feeding.33,34 One additional possibility is that gastric emptying, an important clinical indicator of feeding tolerance, is faster with HM feeding.35
Our results are consistent with those of Schanler et al,22 who observed that VLBW infants who received at least 50 mL/kg per day HM during their hospital course compared with infants who received 100% preterm formula reached full tube feedings 8 days sooner and had shorter duration of parenteral nutrition. We also observed significantly shorter duration of parenteral nutrition and central line access. Although this might be expected to decrease the risk for late-onset sepsis, we previously reported finding no difference between the 2 groups,36 perhaps because the incidence for the entire sample was somewhat lower than previously reported rates.1,37
It is important to note that HM feeding was associated with an earlier age at which full enteral feeding was achieved and, as previously reported,36 a lower incidence of NEC. Our analysis in this study suggests that shorter time to full enteral feeding in the HHM group was not related solely to a lower incidence of NEC. Also, these results are consistent with the observation by Lucas and Cole38 that rate of feeding advancement was associated with NEC in formula-fed infants only. Reducing the time required to achieve full enteral feeding without an increase in NEC by increasing proportion of HM intake has important clinical and economic implications. NEC and late-onset sepsis are associated with significantly longer lengths of stay and higher hospital costs compared with VLBW infants without these complications.1,39
In contrast to the findings of Schanler et al,22 we did not observe a slower rate of growth in the predominately HM-fed infants. This difference in study findings may be attributable to a similar caloric intake during feeding advancement, use of 24-cal/oz formula, addition of HMF to HM (1 packet to 25 mL of HM) when 100 mL/kg per day feeding was achieved, and continuation of HMF until a weight of 2500 g was reached or the infant was discharged from the hospital. Also, in contrast to the findings of Schanler et al, we did not observe a difference in incidence of late-onset sepsis or length of stay; however, our study had adequate power to detect only relatively large differences in these outcomes.
Certain limitations of our study should be noted. First, the data were collected and the sample size was chosen for another purpose; thus, the sample size did not provide sufficient power to detect clinically important differences in some of the outcomes that we studied. A second limitation is that infants were not randomly assigned to HM feeding groups, so unmeasured confounders might explain the differences that we observed. A third limitation is that we did not measure the macronutrient content of HM in this study. The energy and protein content of HM is variable, and differences could have influenced growth; however, for calculations of energy intake from HM, we used an average caloric content of 280.328 J/dL (67 cal/dL [range: 267.776–301.248 J/dL (64–72 cal/dL)]).26 A fourth limitation is that our study did not measure time to full oral feeding; therefore, it is unknown if HHM intake has an impact on this important milestone. A fifth limitation is that this study was conducted at a single site. It is possible that our results were substantially affected by the particular feeding practices followed by the hospital and that alternative feeding regimens might substantially affect the time to full enteral feeding. Also, feedings were initiated or withheld by the clinicians who cared for the infants according to the nursery enteral feeding guidelines rather than a research protocol, and the clinicians were not blinded to type of enteral feeding. This could be a source of bias if clinicians had a preconceived assumption regarding the safety of HM in cases in which the physical examination was not clearly normal; however, nearly all mothers in this study initiated breast pumping, so clinicians rarely knew the exact composition of the enteral feedings. As a result of these limitations, the generalizability of our findings is limited and the replication of this study with a larger data set is needed.
Strengths of this study include the prospective and complete data on feeding composition, which enabled us to report on HM proportion of enteral feeding and the use of a standardized feeding regimen. For clinicians, the finding that feedings that consist of at least 50% HM and are given during feeding advancement are associated with an earlier age at which full enteral feeding is achieved highlights the importance of intensive lactation support to mothers in the early postpartum period. We found, as part of the larger project, that providing lactation education and lactation support is effective at achieving high lactation initiation and duration of milk expression among mothers of VLBW infants.23 For mothers of VLBW infants who do not plan to breastfeed, these findings may provide the impetus needed to express milk during their infant's hospitalization.
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ACKNOWLEDGMENTS |
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This study was funded in part by a grant from the International Lactation Consultant Association.
We thank the mothers and infants who participated in the study. We also thank Mary Showalter, IBCLC, for recruitment and lactation counseling and the research assistants from the Department of Nutrition at the University of North Carolina at Greensboro for data collection.
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FOOTNOTES |
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Accepted Dec 13, 2007.
Address correspondence to Paula M. Sisk, PhD, Department of Pediatrics, Wake Forest University School of Medicine, One Medical Center Blvd, Winston-Salem, NC 27157. E-mail: psisk{at}wfubmc.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Feeding intolerance is common and associated with late-onset sepsis in preterm infants. There are limited observational data and anecdotal evidence that human milk feeding is associated with shorter time to full enteral feeding in preterm infants.
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| What This Study Adds This study contributes a prospective cohort study of extremely preterm infants in whom the complete composition of enteral feedings is known during enteral feeding advancement and indicates that a high proportion of human milk feeding improves after time to full enteral feeding.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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