It is not known whether giving limited feedings, as compared to giving no feedings or more feedings, to premature babies receiving intravenous nutrition is safe or beneficial.
Necrotizing enterocolitis (NEC) is a life-threatening bowel illness in newborn babies born prematurely. As there is concern that feedings in the gastrointestinal tract may increase the risk of NEC, babies in some centers receive only intravenous nutrition for prolonged periods. However, there is also a concern that delaying feedings could lead to growth and feeding problems. For this reason, babies in other centers receive progressively increasing feedings during the first two weeks after birth. One alternative would be to give some minimal "trophic" feedings during this time to provide enteral nutrition without increasing the risk of NEC. Current evidence has not determined which approach to feeding is better and one or more large multi-center trials are needed to resolve this important issue.
Because of concern that feedings may increase the risk of necrotizing enterocolitis, some high-risk infants have received prolonged periods of parenteral nutrition without enteral feedings. Providing trophic feedings (small volume feedings given at the same rate for at least 5 days) during this period of parenteral nutrition was developed as a strategy to enhance feeding tolerance and decrease time to reach full feedings. Whether trophic feedings result in better outcomes than initially withholding feedings or providing progressively increasing feedings can be established only in proper clinical trials.
1. For high-risk neonates receiving parenteral feedings, to assess the effect of trophic feeding compared to no enteral nutrient intake on measures of feeding tolerance and neonatal outcome.
2. For high-risk neonates receiving parenteral feedings to assess the effect of trophic feedings compared to a specific initial feeding regimen involving a greater enteral nutrient intake on measures of feeding tolerance and neonatal outcome.
Searches were performed of MEDLINE (1966 - June 2004), CINAHL (1982 - June 2004), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), abstracts and conference proceedings, references from relevant publications in the English language, and studies identified by personal communication.
Only randomized or quasi-randomized clinical trials were considered. Trials were included if they enrolled high-risk infants randomly assigned to receive trophic feedings (defined as dilute or full strength feedings providing < = 25 kcal/kg/d for > = 5d) compared to either 1) no enteral nutrient intake (no feedings or water only) or 2) a specific feeding regimen involving a greater enteral intake of formula or human milk than with trophic feedings.
The two reviewers reached consensus for inclusion of trials. Data regarding clinical outcomes were extracted and evaluated by the two reviewers independently of each other. Authors were contacted as needed and feasible to clarify or provide missing data. The specific data that were needed were requested in writing.
1. Trophic feedings vs. no feedings (10 trials): Among infants given trophic
feedings, there was an overall reduction in days to full feeding (weighted
mean difference [WMD] = -2.6 [95% confidence limits = -4.1, -1.0]), total
days that feedings were held (WMD = -3.1 [-4.6, -1.6]), and total hospital
stay (WMD = -11.4 [-17.2, -5.7] compared to infants given no enteral nutrient
intake. Tests for heterogeneity were significant in analyses of days to
full enteral feedings, days to regain birth weight, days of phototherapy,
and hospital stay. There was no significant difference in necrotizing enterocolitis,
although the findings do not exclude an important effect (relative risk =
1.16 [0.75, 1.79]; risk difference = 0.02 [-0.03, 0.06].
2. Trophic feedings vs. advancing feedings (one trial): Infants given
trophic feedings required more days to reach full enteral feeding (13.4 [8.2,
18.6]) and tended to have a longer hospital stay (11.0 [-1.4, 23.4]) than
did infants given advancing feedings. With only eight total cases of necrotizing
enterocolitis, trophic feedings were associated with a marginally significant
reduction in necrotizing enterocolitis (relative risk =0.14 [0.02, 1.07];
risk difference = -0.09 [-0.16, -0.01].
In both comparisons, the group with the greater enteral intake (trophic feedings in the first comparison and advancing feedings in the second comparison) required significantly less time to reach full feedings and had a significant or near significant reduction in hospital stay. In both comparisons, the group with the greater intake also had a higher incidence of necrotizing enterocolitis although the difference was not statistically significant. The concern is greatest for the advancing feeding regimen. Even when trophic feedings were compared to no feedings, the relative risk for necrotizing enterocolitis was 1.16 (0.75 - 1.79), a finding consistent with a 16% increase in necrotizing enterocolitis and a number needed to harm of 50. A true increase of this magnitude might outweigh any short- or long-term benefits of trophic feedings. Moreover, the 95% confidence interval does not exclude the possibility that trophic feedings increase necrotizing enterocolitis by as much as 79% with a number needed to harm of 17.
Whether no feedings, trophic feedings, or advancing feedings should initially be used is difficult to discern for a variety of reasons--the inherent difficulty of assessing enteral feedings in high-risk infants, the limited sample size and methodologic limitations of most studies to date, unexplained heterogeneity with respect to a number of outcomes, the potential for bias to affect the findings in unblinded studies, and the large number of infants who must be studied to assess the effect on necrotizing enterocolitis. One or more large, well designed, multi-center trials are needed to compare these approaches to early feeding with respect to important clinical outcomes. A conclusive evaluation would assess effects on not only the survival rate without necrotizing enterocolitis prior to discharge from the neonatal unit but also on the survival rate without severe gastrointestinal or neurodevelopmental disability at >= 18 months age.
Because of concern that feedings may increase the risk of necrotizing enterocolitis, some high-risk infants have received prolonged periods of parenteral nutrition without enteral feedings. However, a lack of enteral nutrients may diminish gastrointestinal functional and structural integrity by diminishing hormonal activity, growth of intestinal mucosa, lactase activity, nutrient absorption, or motor maturation (Johnson 1976; Aynsley-Green 1983; Lucas 1986; Berseth 1990; Schanler 1999a; Saenz de Pipaon 2003). These problems may then compromise later feeding tolerance and growth, and prolong the hospital stay. The practice of providing trophic feedings (small volume feedings that provide minimal calories) for some period after birth was developed as a strategy to enhance the functional maturation of the gastrointestinal tract. It was reasoned that if subsequent feeding tolerance could be improved with trophic feedings (as compared to a strategy of keeping infants NPO during the same period), this could result in a decreased time to reach full feedings and a decrease in duration of parenteral nutrition and in length of hospital stay. But even if more aggressive feedings strategies result in improved growth or reduced hospital stay, it is important to evaluate whether this can be accomplished without increasing the risk of necrotizing enterocolitis.
For high-risk neonates receiving parenteral feedings, to assess the effect on measures of feeding tolerance and neonatal outcome of tropic feedings compared to either 1) no enteral nutrient intake or 2) a specific enteral feeding regimen involving a greater enteral intake of formula or human milk than with trophic feedings.
Randomized or quasi-randomized clinical trials comparing trophic feedings to either 1) no enteral nutrient intake or 2) a specific feeding regimen involving a greater enteral nutrient intake in parenterally fed high-risk infants.
Infants at high risk for feeding intolerance or necrotizing enterocolitis, based on birth weight, perinatal asphyxia, or presence of congenital anomalies.
Infants were assigned to receive trophic feedings or either 1) no enteral nutrient intake (no fluids or water only) or 2) a specific enteral feeding regimen involving a greater actual intake of formula or human milk than with trophic feedings.
Clinical outcomes included days to reach full enteral feedings, days that feedings were held, days to regain birth weight, days under phototherapy, hospital stay before death or discharge home, serum direct bilirubin exceeding 2.0 mg/dL, and necrotizing enterocolitis. We excluded studies that were focused on physiologic or biochemical measures and did not report major clinical outcomes such as necrotizing entercolitis.
Electronic searches of the MEDLINE (1966 - June 2004) and CINAHL (1982
- June 2004) databases were performed using the following strategy:
1) enteral nutrition OR enteral feeding (as MeSH terms or text word)
2) AND (infant, premature OR infant, low birth weight) (as MeSH terms or text word)
3) limited to humans
Additional searches were performed of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), references in review articles and relevant chapters of textbooks on neonatal nutrition, trials identified in a previous systematic review by different authors (Steer PA, Lucas A, Sinclair JC. Feeding the low birthweight infant. In: Sinclair JC, Bracken MB, eds, Effective Care of the Newborn Infant. New York: Oxford University Press, 1992: 130-132), review of recent American Pediatric Society - Society for Pediatric Research abstracts (1990-2004), personal files, and personal communication.
Both authors participated in identifying trials for consideration and in describing the main results and conclusions. Each author independently evaluated whether the trial met eligibility criteria for inclusion in the meta-analysis, extracted data from the trials, and evaluated their methodologic quality. Methodologic quality was evaluated with respect to treatment allocation, blinding of care givers, assessment of all or nearly all patients randomized, and blinding of outcome assessors.
Details of the studies are included in the table, Characteristics of Included Studies. Nine studies were included in the comparison of trophic feedings vs no feedings. At birth the infants generally weighed 1500g or less or were less than 33 weeks gestation. Most received mechanical ventilation. The trophic feedings group received as little as 12 cc/kg/d to as much as 24 cc/kg/d of dilute or full strength formula or breast milk, starting as early as the first day or as late as the eighth day after birth; trophic feedings were generally continued for 5 - 10 days. For studies comparing trophic feedings to no feeding, the control group was not fed milk and received no enteral nutrition for a total of 6 - 18 d after birth, although some were given water by the enteral route. Schanler et al conducted a study that involved a factorial design to assess continuous (vs. bolus) feedings as well as trophic feedings (vs. being kept NPO) from day 4 to 14. Infants were assigned to four groups (continuous trophic feedings, bolus trophic feedings, NPO followed by continuous feedings, NPO followed by bolus feedings). To facilitate the best analysis of the data, this study is listed three times in the table "Characteristics of Included Studies: Schanler 1999a refers to an evaluation of all infants (n = 171) given trophic feedings (bolus or continuous) vs. controls kept NPO (then given bolus or continuous feedings); Schanler 1999b refers to an evaluation (n = 83) comparing continuous trophic feeding vs. controls kept NPO (then given continuous feedings); Schanler 1999c refers to an evaluation (n = 88) of bolus trophic feedings vs. controls kept NPO (then given bolus feedings).
The study by Berseth 2003 compared trophic feedings with progressively advancing during the first 10 days. The group given advancing feedings was fed 20 ml/kg on day one, and feedings were advanced 20 cc/kg/d each day thereafter until 140 ml/kg/d was achieved and maintained. Fortification of breast milk was begun at an intake of 100 ml/kg/d.
Quality assessments are included in the table, Characteristics of Included Studies. Overall, the trials were of intermediate methodologic quality. Caregivers were not blinded to treatment group in any trial -- a problem that probably cannot be avoided. However, some potentially avoidable problems were not addressed in trials. In only three trials was it clear that randomization was blinded (that is, the treatment group could not be anticipated prior to randomization). Few studies involved blinded assessments for any of the outcomes, and several of the trials did not include results for all infants randomized. As described below, these problems contribute to uncertainty about the effects of trophic feedings.
1. Trophic feedings vs. no feedings (10 trials): There was an overall reduction in mean days to full enteral feeding (weighted mean difference [WMD] = 2.6 days), total days that feedings were held (WMD = 3.1 days), and total hospital stay (WMD = 11.4 days) among infants given trophic feedings. There was no significant effect on necrotizing enterocolitis (relative risk = 1.16 [95% CI(fixed) = 0.75, 1.79]; risk difference = 0.02 [-0.03, 0.06]. For several variables (days to full enteral feeding, days to regain birth weight, days of phototherapy, days of hospital stay), inconsistency in the treatment effect resulted in statistical heterogeneity. The explanation for this heterogeneity is unclear.
2. Trophic feedings vs. advancing feedings (one trial): Infants given trophic feedings required more days to reach full enteral feeding (WMD = 13.4) and tended to have a longer hospital stay (WMD = 11.0) than did infants given advancing feedings. With only eight total cases of necrotizing enterocolitis, trophic feedings were associated with a marginally significant reduction in necrotizing enterocolitis (relative risk = 0.14 [0.02, 1.07]; risk difference = -0.09 [-0.16, -0.01].
The findings of these analyses should be interpreted cautiously for several reasons:
1) Even taking the analyses at face value, there is considerable uncertainty about the effect of trophic feedings on necrotizing enterocolitis. These analyses do not rule out the possibility that trophic feedings, as compared to no feedings, substantially increase the likelihood of necrotizing enterocolitis.
2) Some of the results are not consistent across trials comparing trophic feedings with no feedings: particularly noteworthy in this respect is the statistical heterogeneity with respect to the effects on days to reach full enteral feeding, days to regain birth weight, and hospital stay.
3) There has been limited effort (only one trial) to compare trophic feedings with advancing feedings.
4) Clinically important effects of minimal enteral nutrition are quite difficult to determine for such reasons as:
a) It would be quite difficult, if not impossible, to blind the caregivers to infant feeding.
b) Feeding intolerance is difficult to define objectively, and caregiver bias might influence feeding and weight gain between birth and hospital discharge and thus days to full enteral feeding, days that feedings are held, and total hospital stay.
c) The diagnosis of necrotizing enterocolitis is subject to diagnostic surveillance bias. (At the same true risk of developing necrotizing enterocolitis, more x-rays might be ordered in one feeding group than in the other because of caregiver bias.)
d) The diagnosis of necrotizing enterocolitis on a particular x-ray is subject to evaluator bias if the evaluators are not blinded and to considerable inter-observer variation (Di Napoli, 2004) even in blinded evaluations.
e) Because of the presence of substrate within the bowel, infants who have been fed may be more likely to develop intramural gas than infants with equally severe bowel disease who have not been fed (Engel 1973). If so, feedings might increase the identification of rather than the occurrence of diseased bowel.
f) Even if very delayed feedings result in a truly lower incidence of necrotizing enterocolitis than do trophic feedings, this benefit from delayed feedings might be offset by increased mortality or long-term morbidity as a result of greater malnutrition or the hazards of prolonged use of vascular lines and parenteral nutrients. The number of infants needed to identify an effect on mortality or major long-term morbidity would of course be very large.
5) The studies to date have had a number of methodological limitations .The method of randomization was usually not stated, it was usually unclear whether the investigators could anticipate treatment group before randomization, and most studies did not include all patients in the outcome assessments. Only one study (Slagle 1988) noted that the abdominal x-rays were blindly assessed in identifying necrotizing enterocolitis. In some trials (Dunn, Slagle, Troche, Berseth) the results concerning outcomes such as days to reach full enteral feeding, days feeds held, and days to regain birth weight may be biased by the exclusion from analysis of infants who developed complications.
6) No benefit was reported from the largest study (Becerra, 190 total patients in the ['sick' patients] subgroup who received trophic feedings and were included in this meta-analysis). The infants in the Becerra trial appear to be less ill than in some other trials. This study has been published only as an abstract, and the generalizability of the findings is unclear.
Despite plausible rationale and the suggested benefits of the initial use of trophic feedings in this meta-analysis, it is unclear whether trophic feedings are beneficial relative to no feedings or advancing feedings for high-risk infants.
A large multi-center trial of trophic feedings is needed among infants
1000 g BW or less. A convincing assessment of trophic feedings (relative
to an equal period of time without enteral feeding or to a feeding regimen
involving a greater enteral nutrient intake) is likely to require a trial
sufficiently large to identify an important effect on one or more of the
following variables:
1) death before discharge home
2) death or necrotizing enterocolitis requiring surgical resection before discharge home
3) death or very prolonged hospital stay (an outcome that is associated
with major long-term morbidity and that would address not only necrotizing
enterocolitis but sepsis or other major complications of prolonged parenteral
nutrition) or the most compelling outcome
4) death or major morbidity (including severe developmental delay and
short bowel syndrome) at > = 18 months adjusted age. To be feasible, such
a large trial would require a simple protocol, a minimal expense per infant,
and a well organized group of participating centers.
None
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Becerra 1996 | Unstated method of randomization. Blinding of randomization - can't tell Blinding of caregivers - no All or almost all subjects analyzed - yes Blinding of assessors - apparently no | Healthy and sick infants less than 1500 g BW. Healthy infants were excluded from this meta-analysis because their feeding did not meet the above criteria for trophic feedings. Sick infants were those with asphyxia, an FiO2 >0.3 in first 36 h, suspected or documented sepsis, hypotension treated with volume expander or vasoactive drug, hypo- or hyperglycemia, or a hematocrit<35 or >65%). 190 "sick" infants were randomized. The mean BW of the trophic feedings and control groups were 1127 and 1086 g, respectively; although 77% and 74% of these two groups had RDS, the proportion who received mechanical ventilation was not described. | 96 "sick" infants were randomized
to the trophic feedings group; 94 were randomized to the control group.
Sick infants were fed 'approximately' 20-25 ml/kg of breast milk or premature
formula during the first week. Control sick infants were not fed until 6 to 8 days after birth. | In
addition to those shown in figure, days of IV fluids, days of parenteral
nutrition, infants with regurgitation or vomiting, days to 2000 g, weight
at 30 d, weight at 60 d, hyperglycemia, cholestasis, and exchange transfusion
were reported. | Data as reported in abstract or in correspondence
with the principle investigator in Chile. In contrast with other trials,
this trial does not provide evidence of benefit from trophic feedings with
respect to any outcome assessed, including age to reach full feedings (See
figure). Total days that feedings were held--an outcome that was reduced
in other trials--was not reported. However, the number of babies with regurgitation
or vomiting was higher in the trophic feedings group than in controls (65/
96 vs. 49/94; p reported as 0.04) and there was no trend toward an earlier
age at full feedings with trophic feedings (14.3 [SD 5.5] vs. 13.5 [SD 5.2]
days). While trophic feedings significantly reduced the proportion of infants
with a serum direct bilirubin value >2 in the trial by Dunn, there was
minimal difference in the small number of infants reported as having cholestasis
in the trophic feedings and control groups (1/96 vs. 3/96; p reported as
0.29) in this study. There were similar findings with respect to exchange
transfusion [2/96 vs 4/94; p reported as 0.23). Although this is the largest
trial to date, the details have not been published, and the explanation for
the apparent differences from other trials and the generalizability of the
findings are unclear. Some of the difference may result from assessment of
a population that was not as ill as in some of the other trials. | B |
| Berseth 1992 | Method of randomization was unspecified. Blinding of randomization - can't tell Blinding of caregivers - no All or almost all subjects analyzed - yes Blinding of observers - apparently no | Infants 28-32 weeks gestation who required mechanical ventilation for RDS. At enrollment, all infants were 'stable' with an FiO2 <0.40. 27 infants were randomized. | 14
infants were randomized to the trophic feedings group; 13 were randomized
to the control group. The trophic feedings group was fed Similac 20 kcal/oz
formula at 24 ml/kg/d beginning at 3-5 days until 10-14 days. Feedings were
not started for the control group until 10-14 days. Both groups received
150 ml/kg/d total fluids. | In addition to the outcomes shown in the figure, manometry of the gastroduodenum and plasma gastrin, gastric inhibitory peptide, neurotensin, and peptide YY were reported. | In addition to other evidence of benefit from trophic feedings in this study, trophic feeding was reported to result in more mature motor patterns and higher gastrin and gastric inhibitory peptide. | B |
| Berseth 1993 | Method of randomization unstated. Blinding of randomization - can't tell Blinding of caregivers - no All or almost all subjects analyzed - yes Blinding of assessors - can't tell | 26-33 week appropriate for gestational age (AGA) infants with initial respiratory distress. (As verified by Berseth [personal communication], there was no overlap in patients involved in this study and the study by Berseth noted above.) 32 infants were randomized. | 16 infants were randomized to the trophic feedings group; 16 were randomized to the control group. Trophic feedings group received 24 ml/kg/d Similac starting by 7 days age for 10 days. Control infants received an equal volume of water enterally during this time. Both groups received 120 kcal/kg/d by the combined enteral and parenteral routes. | In addition to the outcomes shown in the figure, manometric assessment of duodenal motor activity was reported. | Motor responses were slower to develop in control infants. | B |
| Berseth 2003 | Method
of randomization: Ward secretary or nurse not involved in patient care drew
1 of 4 lots (two marked minimal and two marked advancing). Blinding of randomization: Uncertain. Blinding of caregivers: No All or almost all subjects analyzed: No. Among 144 infants for whom consent was obtained, 4 patients were excluded because of ileal perforation or death. It is unclear how many of these infants were excluded after randomization. Three additional patients, all in the trophic feeding group, were excluded at request of the parent or physician after randomization. While it was necessary to exclude them from the treatment protocol, it is unclear the parents or physician would have allowed their clinical outcomes to be included as needed for an intention to treat analysis. Blinding of assessors: Can't tell. | Infants without congenital anomalies who were <32 weeks gestational age and had an appropriate birth weight for gestational age. See methods regarding exclusions. 144 infants were randomized. | 74 infants were randomized to the trophic feedings group; 70 were randomized to the advancing feedings group. Trophic feedings group received 20 ml/kg/d of unfortified human milk or Enfamil premature Formula 24 for 10 days in 4 hour cycles consisting of 2 hour infusions followed by 2 hours of fasting. Full parenteral nutritional support was provided this group throughout the 10 day period. Infants fed advancing feedings were fed 20 ml/kg on day 1 and advanced 20 cc/kg/d on each day thereafter as tolerated until 140/ml/kg was achieved and maintained through day 10. Parenteral nutrition was tapered as enteral feedings were in increased. Fortification of breast milk was begun when 100 ml/kg intake was reached. In both groups decisions concerning feeding intolerance were based on a previously published algorithm. | The primary outcome was NEC. Other outcomes, in addition to those shown in the figure, included maturation of intestinal motor patterns, duodeno-anal transit (by carmine red), plasma gastrin and motilin, age at full oral feedings, days of parenteral nutrition, % infants with central venous lines, incidence of late sepsis, and cholestatic jaundice. (Data for hospital stay and age at full feedings were provided by the author.) | Study was terminated early (at an enrollment of 144 of the 250 infants originally planned) because of a higher incidence of NEC in the in the advancing feeding group (7 of 70) than in the trophic feeding group than (1 of 71). (p value reported by authors<0.03) However, the findings can be considered inconclusive because: 1) The randomization method is undesirable, and relatively little information was provided to verify that the treatment groups were similar at enrollment; 2) The results may be inadvertently biased by the exclusion of 4 infants who either died or developed ileal perforation after consent was obtained; the number excluded after randomization and the treatment group to which they were assigned were not specified; 3) Unconventional stopping rules and a one-tailed statistical test were used in analyzing the difference between groups in NEC. A two tailed p, adjusted for repeated analyses, would exceed 0.06; 4) A number of outcomes beside NEC favored the advancing feeding group. The trophic feeding group was older at the age of full enteral feeds, age at full oral feeds, and age at discharge home; it also had lower plasma gastrin and motilin concentrations, longer duodeno-anal transit times, more days of parenteral nutrition, and a higher proportion of infants treated with central lines than did the advancing feeding group. Groups were comparable with respect to maturation of gastrointestinal motor patterns and rates of cholestatic jaundice, sepsis, and death. | B |
| Dunn 1988 | Quasi-randomized (cards in paired envelopes), not blinded. Blinding of randomization - no Blinding of caregivers - no All or almost all subjects analyzed - no Blinding of assessors - no | Infants less than 1500 g BW with RDS treated with mechanical ventilation and an umbilical artery catheter. 39 infants were randomized. | 19 infants were randomized to the trophic feedings group; 20 were randomized to the control group. Controls received no enteral feeds until 9 days of age. Intervention group received trophic feedings from 48 hours to 9 days at 15-20 ml/kg of 1/2 strength Enfamil Premature Formula. Both groups received the same parenteral nutrition. | In addition to the outcomes shown in the figure, liver function tests and alkaline phosphatase were reported. | Alkaline phosphatase reported to be lower in trophic feeding group. | C |
| McClure 2000 | Method of randomization - computer software (minimization program) after stratification by gestational age. Blinding of randomization - apparently yes Blinding of caregivers - no All or almost all subjects analyzed - Yes (except for exclusion of early deaths from some outcomes) Blinding of assessors - yes | Infants less than 1750 g birth weight with respiratory distress syndrome who required mechanical ventilation beyond 48 hours and who had no lethal congenital anomaly or evidence of primary gastrointestinal pathology. 100 infants were randomized. | 48 infants were randomized to the trophic feedings group; 52 were randomized to the control group. Trophic feedings (0.5 ml/h for infants with a birth weight <1 kg; 1 ml/h for infants with a birth weight of 1.0-1.75 kg) was given from day 3 until mechanical ventilation was discontinued. The control group received no enteral feedings while mechanical ventilation was provided. Both groups received parenteral nutrition. Following discontinuation of mechanical ventilation, "nutritive" enteral feedings were initiated at 1 ml/kg/h and increased by 1 ml/k/h every 8-12 h as tolerated. All enteral feedings were given hourly by bolus. | In addition to the outcomes shown in the figure, energy intake, feeding tolerance, days to full oral intake, growth, sepsis, C reactive protein, liver function, serum bilirubin, duration of parenteral nutrition, ventilatory support and oxygen administration were reported. | The trophic feedings group had a higher median birth
weight than controls (1.1 vs 9.94 g), a difference that may be clinically
important (although not statistically significant). The trophic feedings
group also tended to have a somewhat higher percentage of females and of
infants given breast milk and a lower median duration of postnatal steroid
administration. Data were not provided regarding the level of ventilatory
assistance at randomization, and it is unclear whether postnatal steroids
were administered for comparable indications and use in a comparable dose
and duration in the two groups. The generalizability of the study may be
limited by the withholding of feedings from the controls as long as they
received mechanical ventilation and by the administration of steroids to
all infants. Trophic feedings were restricted or omitted on 351/791 possible infant days (because of feeding intolerance, etc). Compared to controls, the trophic feedings group was reported to have significantly greater weight gain and increase in head circumference. The trophic feedings group was also reported to have a large reduction in mean episodes of sepsis (0.7 episodes/infant) and in mean duration of parenteral nutrition (11.5 days), oxygen administration (22 days), and hospital stay (22 days). However, the extent to which the apparent benefits of trophic feedings might result from differences between groups at enrollment is unclear. Maximum total
serum bilirubin, duration of jaundice, and duration of phototherapy were
not lower in the trophic feedings group than in controls. | B |
| Meetze 1992 | Method of randomization unstated. Blinding of randomization - can't tell Blinding of caregivers - no All or almost all subjects analyzed - no Blinding of assessors - no | Infants 501-1250 g BW and 25-32 weeks gestation. Proportion of infants receiving mechanical ventilation not stated. 47 infants were randomized. | 22 infants were randomized to the trophic feedings group; 25 were randomized to the control group. The trophic feedings group received Enfamil Premature Formula (24 kcal/oz) beginning at 2 kcal/kg/d on day 3 advancing to 18 kcal/kg/d on day 14. During this time controls were not fed. "Total nutrition" (presumably meaning total kcal/kg/d from enteral and parenteral routes) was equal for both groups during this time. | In addition to the outcomes shown in the figure, serum gastrin was reported. | Serum gastrin was reported to rise faster in the trophic feedings group. | B |
| Ostertag 1986 | Method of randomization unstated. Blinding of randomization - can't tell Blinding of caregivers - no All or almost all subjects analyzed - yes Blinding of assessors - no for clinical assessments, yes for radiologic assessment | Infants at high risk for necrotizing enterocolitis (>=6 points with 1 point given for each of the following: BW<1500 g, BW<1000 g; gestational age<32 weeks; 5 minute Apgar<6; need for oxygen supplementation; need for ventilatory assistance; suspected intraventricular hemorrhage; presence of seizures; patent ductus arteriosus; and umbilical catheter. 38 infants were randomized. | 18 infants were randomized to the trophic feedings group; 20 were randomized to the control group. Trophic feedings group started feedings on day 1, beginning with sterile water and progressing to 2.5% dextrose, half-strength formula, and full strength formula (Portagen) over 7 days. All these fluids were given at 1 ml/hour. The control group were not fed for 7 days. During the next 7 days, they received the regimen provided to the trophic feedings group during the first 7 days. Parenteral nutrition was provided to both groups with a goal of providing a total of 100 kcal/kg from both enteral and parenteral routes by 2 weeks age. | In addition to the outcomes shown in the figure, feeding intolerance and fluid and caloric intake were reported. | The same percentage of each group (59%) had feedings advanced without incident in the first 2 weeks. Trophic feedings group had higher caloric intake in the second week. | B |
| Schanler 1999a | Method of randomization - sealed opaque envelopes (with uneven block size) Binding of randomization - yes Binding of intervention - no All or almost all subjects analyzed - yes (though uncertain Binding of assessors - no | Infants 26-30 weeks gestation whose birth weight was appropriate for gestational age who had no major congenital anomalies, were less than 97 hours old, and required an inspired oxygen concentration less than 0.60 by 72 hours. 171 infants were randomized. | 82 infants were randomized to the trophic feedings group; 89 were randomized to the control group. This study used a factorial design in which infants were randomized to 4 groups (continuous trophic feedings, bolus trophic feedings, NPO followed by continuous feedings, NPO followed by bolus feedings) to allow simultaneous assessment of the use of both tropic feedings and continuous feedings vs bolus. On postnatal days 4-14, trophic feedings were provided 20 ml/kg of mother's milk or 0.5 strength Enfamil Premature formula and NPO group received no enteral feedings. Bolus feedings were given every 3 hours. Both groups received a standardized regimen of parenteral nutrition. At 15-22 days, infants received 20 ml/kg/d increasing 20 ml/kg as tolerated of mother's milk or full strength Enfamil Premature formula. A maximum of 180 ml/kg/d was provided to sustain a weight gain of 15 g/kg/d. Infants with feeding intolerance > 1 week were allowed to change from bolus to continuous feedings or more commonly, from continuous to bolus feedings. | Primary outcome was time to attain full oral feedings (8 breast or bottle feedings per day). Other outcomes, besides those shown in the figure, included growth rate, feeding tolerance, major clinical morbidities, serum protein and minerals every 2 weeks, nutritional balance and gastrointestinal transit time at 6 and 9 weeks, and bone mineral content (photon absorptiometry of distal radius) | In this review, Schanler 1999a refers to outcomes reported for all infants in trophic feedings group vs all control infants. Intake of human milk was greater in the trophic feedings than the NPO groups. There were no differences between groups in nutrient intake, clinical morbidities, or time to full oral feedings (primary outcome). Trophic feedings were associated with better calcium and phosphorus retention, higher serum calcium and alkaline phosphotase activity, and shorter intestinal transit times. (In a previously reported study of a subgroup [J Pediatr 1998;133:645-9], trophic feedings were associated with increased intestinal lactase activity.) Bolus feeding compared to continuous feeding was associated with greater weight gain and less feeding intolerance (lower recorded gastric residual volume but not abdominal distention, hours that feedings were held or necrotizing enterocolitis). | A |
| Schanler 1999b | Method of randomization - sealed opaque envelopes (with uneven block size) Binding of randomization - yes Binding of intervention - no All or almost all subjects analyzed - yes (though uncertain Binding of assessors - no | Infants 26-30 weeks gestation whose birth weight was appropriate for gestational age who had no major congenital anomalies, were less than 97 hours old, and required an inspired oxygen concentration less than 0.60 by 72 hours. 83 infants were randomized. | 39 infants were randomized to the trophic feedings group; 44 were randomized to the control group. This study used a factorial design in which infants were randomized to 4 groups (continuous trophic feedings, bolus trophic feedings, NPO followed by continuous feedings, NPO followed by bolus feedings) to allow simultaneous assessment of the use of both tropic feedings and continuous feedings vs bolus. On postnatal days 4-14, trophic feedings were provided 20 ml/kg of mother's milk or 0.5 strength Enfamil Premature formula and NPO group received no enteral feedings. Bolus feedings were given every 3 hours. Both groups received a standardized regimen of parenteral nutrition. At 15-22 days, infants received 20 ml/kg/d increasing 20 ml/kg as tolerated of mother's milk or full strength Enfamil Premature formula. A maximum of 180 ml/kg/d was provided to sustain a weight gain of 15 g/kg/d. Infants with feeding intolerance > 1 week were allowed to change from bolus to continuous feedings or more commonly, from continuous to bolus feedings. | Primary outcome was time to attain full oral feedings (8 breast or bottle feedings per day). Other outcomes, besides those shown in the figure, included growth rate, feeding tolerance, major clinical morbidities, serum protein and minerals every 2 weeks, nutritional balance and gastrointestinal transit time at 6 and 9 weeks, and bone mineral content (photon absorptiometry of distal radius) | In this review,
Schanler 1999b refers to outcomes reported separately for infants in continuous
trophic feedings group vs control infants. Intake of human milk was greater in the trophic feedings than the NPO groups. There
were no differences between groups in nutrient intake, clinical morbidities,
or time to full oral feedings (primary outcome). Trophic feedings were associated
with better calcium and phosphorus retention, higher serum calcium and alkaline
phosphotase activity, and shorter intestinal transit times. (In a previously
reported study of a subgroup [J Pediatr 1998;133:645-9], trophic feedings
were associated with increased intestinal lactase activity.) Bolus feeding
compared to continuous feeding was associated with greater weight gain and
less feeding intolerance (lower recorded gastric residual volume but not
abdominal distention, hours that feedings were held or necrotizing enterocolitis). | A |
| Schanler 1999c | Method of randomization - sealed opaque envelopes (with uneven block size) Binding of randomization - yes Binding of intervention - no All or almost all subjects analyzed - yes (though uncertain Binding of assessors - no | Infants 26-30 weeks gestation whose birth weight was appropriate for gestational age who had no major congenital anomalies, were less than 97 hours old, and required an inspired oxygen concentration less than 0.60 by 72 hours. 88 infants were randomized. | 43 infants were randomized to the trophic feedings group; 45 were randomized to the control group. This study used a factorial design in which infants were randomized to 4 groups (continuous trophic feedings, bolus trophic feedings, NPO followed by continuous feedings, NPO followed by bolus feedings) to allow simultaneous assessment of the use of both tropic feedings and continuous feedings vs bolus. On postnatal days 4-14, trophic feedings were provided 20 ml/kg of mother's milk or 0.5 strength Enfamil Premature formula and NPO group received no enteral feedings. Bolus feedings were given every 3 hours. Both groups received a standardized regimen of parenteral nutrition. At 15-22 days, infants received 20 ml/kg/d increasing 20 ml/kg as tolerated of mother's milk or full strength Enfamil Premature formula. A maximum of 180 ml/kg/d was provided to sustain a weight gain of 15 g/kg/d. Infants with feeding intolerance > 1 week were allowed to change from bolus to continuous feedings or more commonly, from continuous to bolus feedings. | Primary outcome was time to attain full oral feedings (8 breast or bottle feedings per day). Other outcomes, besides those shown in the figure, included growth rate, feeding tolerance, major clinical morbidities, serum protein and minerals every 2 weeks, nutritional balance and gastrointestinal transit time at 6 and 9 weeks, and bone mineral content (photon absorptiometry of distal radius) | In this review,
Schanler 1999c refers to outcomes reported separately for infants in bolus
trophic feedings group vs control infants. Intake of human milk was greater in the trophic feedings than the NPO groups. There
were no differences between groups in nutrient intake, clinical morbidities,
or time to full oral feedings (primary outcome). Trophic feedings were associated
with better calcium and phosphorus retention, higher serum calcium and alkaline
phosphotase activity, and shorter intestinal transit times. (In a previously
reported study of a subgroup [J Pediatr 1998;133:645-9], trophic feedings
were associated with increased intestinal lactase activity.) Bolus feeding
compared to continuous feeding was associated with greater weight gain and
less feeding intolerance (lower recorded gastric residual volume but not
abdominal distention, hours that feedings were held or necrotizing enterocolitis). | A |
| Slagle 1988 | Randomization by sealed envelope. Blinding of randomization - yes Blinding of caregivers - no All or almost all subjects analyzed - no Blinding of assessors - no | Infants 500-1500g BW and <33 weeks gestation at increased risk for necrotizing enterocolitis (mechanical ventilation for at least 3 days, oxygen administration for at least 7 days, and at least 2 of 4 other risk factors: 5 minute Apgar score <= 5, umbilical artery catheter, hypotension treated with volume expanders, and patent ductus arteriosus requiring medical and surgical treatment in the first week after birth). 46 infants were randomized. | 22 infants were randomized to the trophic feedings group; 24 were randomized to the control group. Trophic feedings group received 12 ml/kg/d milk feedings from day 8 to day 18. Control group received no feedings during this time. Both groups received the same caloric intake from enteral and parenteral routes. | In addition to the outcomes shown in the figure, peak serum bilirubin was reported. | Peak total serum bilirubins were comparable in the two groups. | A |
| Troche 1995 | Method
of randomization not stated. (Although use of random numbers table noted,
it is unclear how treatment was allocated and whether investigators could
anticipate treatment assignment for individual infants.) Blinding of randomization - can't tell Blinding of caregivers - no All or almost all subjects analyzed - no Blinding of assessors - no | Infants 25-30 weeks gestation who had RDS, an umbilical artery catheter, and anticipated need for mechanical ventilation for at least 3 days. Infants with asphyxia (5 min Apgar<= 3) or persistent hypoxemia (PaO2<45 torr) or hypercapnia (>60 torr with a pH<7.25) despite aggressive ventilatory management were excluded. 29 infants were randomized. | 16 infants were randomized to the trophic feedings group; 13 were randomized to the control group. Trophic feedings group received mother's milk or Similac Special Care (10-20 kcal/oz) formula beginning prior to 24 hours age. These feedings were advanced from 0.5 ml/h to 0.75 ml/h (infants <800 g BW) or 1.0 ml/h (infants 800-1200 g BW) over the next 24 h, a rate continued until the umbilical artery catheter was removed. Control infants were not fed until the umbilical artery catheter was removed. Both groups received parenteral fat and amino acids beginning day 3. | In addition to the outcomes shown in the figure, caloric intake,
weight at 30 days, serum diamine oxidase, and somatomedin C were reported.
| Trophic feedings group had a greater caloric intake than did
controls on days 1-30 (92 [SD 13] vs. 79 [SD 16] g) and a greater increase
in weight to day 30 over BW (223 [SD 125] vs 95 [SD 161] g) (p reported as
0.05). Episodes of feeding intolerance, serum diamine oxidase and somatomedin
C were comparable in the two groups. | B |
| Study | Reason for exclusion |
| Saenz de Pipaon 2003 | This study was a relatively small study focused on a biochemical outcome (splanchnic uptake of leucine). It was excluded for a combination of reasons: 1) It is unclear how the randomization method resulted in an imbalance in number of patients between infants receiving no enteral feedings (n=14) and those given trophic feedings (n=24); 2) The data reported did not allow comparison of all infants assigned to no enteral feedings with those for all infants given trophic feedings. The mean and standard deviation for outcomes in the trophic feeding group were provided separately for the two subgroups (those given breast milk and those given formula) but not for both subgroups combined; 3) An intention to treat analysis was not feasible. The authors indicated that data for two patients enrolled in the study but later excluded from the study were not included in the final report; 4) Data were not collected for some important outcomes (e.g., hospital stay). |
Becerra M, Ambiado S, Kuntsman G, Figueroa A, Balboa P, Fernandez P, Uauy R. Feeding VLBW infants; Effect of early enteral stimulation (EES) [abstract]. Pediatric Research 1996;39:304A.
Berseth 1992 {published data only}
Berseth CL. Effect of early feeding on maturation of the preterm infant's small intestine. Journal of Pediatrics 1992;120:947-53.
Berseth 1993 {published data only}
Berseth CL, Nordyke C. Enteral nutrients promote postnatal maturation of intestinal motor activity in preterm infants. American Journal of Physiology 1993;264:G1046-51.
Berseth 2003 {published and unpublished data}
* Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2003;111:529-34.
Dunn 1988 {published data only}
Dunn L, Hulman S, Weiner J, Kleigman R. Beneficial effects of early hypocaloric enteral feeding on neonatal gastrointestinal function: Preliminary report of a randomized trial. Journal of Pediatrics 1988;112:622-9.
McClure 2000 {published and unpublished data}
McClure RJ, Newell SJ. Randomised controlled trial of clinical outcome following trophic feeding. Archives of Disease in Childhood Fetal and Neonatal Edition 2000;82:F29-F33.
Meetze 1992 {published data only}
Meetze WH, Valentine C, McGuigan JE, Conlon M, Sacks N, Neu J. Gastrointestinal priming prior to full enteral nutrition in very low birth weight infants. Journal of Pediatric Gastroenterology and Nutrition 1992;15:163-70.
Ostertag 1986 {published data only}
Ostertag SG, LaGamma EF, Reisen CE, Ferrentino FL. Early enteral feeding does not affect the incidence of necrotizing enterocolitis. Pediatrics 1986;77:275-80.
Schanler 1999a {published data only}
Schanler RJ, Shulman RJ, Lau C, Smith EO, Heitkemper MM. Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics 1999;103:434-9.
Schanler 1999b {published data only}
Schanler RJ, Shulman RJ, Lau C, Smith EO, Heitkemper MM. Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics 1999;103:434-9.
Schanler 1999c {published data only}
Schanler RJ, Shulman RJ, Lau C, Smith EO, Heitkemper MM. Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics 1999;103:434-9.
Slagle 1988 {published data only}
Slagle TA, Gross SJ. Effect of early low-volume enteral substrate on subsequent feeding tolerance in very low birth weight infants. Journal of Pediatrics 1988;113:526-31.
Troche 1995 {published data only}
Troche B, Harvey-Wilkes K, Engle WD, Nielsen HC, Frantz ID, Mitchell ML, Hermos RJ. Early minimal feedings promote growth in critically ill premature infants. Biology of the Neonate 1995;67:172-81.
* Saenz de Pipaon M, VanBeek RH, QueroJ, Perez J, Wattimena DJ, Sauer PJ. Effect of minimal enteral feeding on splanchnic uptake of leucine in the postabsorptive state in preterm infants. Pediatric Research 2003;53:281-7.
* indicates the primary reference for the study
Aynsley-Green A. Hormones and postnatal adaptation to enteral nutrition. Journal of Pediatric Gastroenterology and Nutrition 1983;2:418-27.
Berseth CL. Neonatal small intestinal motility: the motor responses to feeding in term and pretem infants. Journal of Pediatrics 1990;117:777-82.
Di Napoli A, Di Lallo D, Perucci CA, Schifano P, Franco F, De Carolis MP. Inter-observer reliability of radiological signs of necrotising enterocolitis in a population of high-risk newborns. Paediatric and Perinatal Epidemiology 2004;18:80-7.
Engel RR, Virnig NL, Hunt CE, Levitt MD. Origin of mural gas in necrotizing enterocolitis [abstract]. Pediatric Research 1973;7:292.
Johnson CR. The trophic action of gastrointestinal hormones. Gastroenterology 1976;70:277-8.
Kennedy KA, Tyson JE. Early versus delayed initiation of progressive enteral feedings for parenterally fed low birth weight or preterm infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.
Kennedy KA, Tyson JE. Rapid versus slow rate of advancement of feedings in parenterally fed low-birth-weight infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2005.
Lucas A, Bloom R, Aynsley-Green A. Gut hormones and minimal enteral feeding. Acta Paediatrica Scandinavica 1986;75:719-23.
McClure RJ, Newell SJ. Randomised controlled trial of trophic feeding and gut motility. Archives of Disease in Childhood Fetal and Neonatal Edition 1999;80:54-8.
McClure RJ, Newell SJ. Randomized controlled study of digestive enzyme activity following trophic feeding. Acta Paediatrica 2002;91:292-6.
Saenz de Pipaon M, VanBeek RH, QueroJ, Perez J, Wattimena DJ, Sauer PJ. Effect of minimal enteral feeding on splanchnic uptake of leucine in the postabsorptive state in preterm infants. Pediatric Research 2003;53:281-7.
Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou C, Smith EO. Early feeding, feeding tolerance, and lactase activity in preterm infants. Journal of Pediatrics 1998;133:645-9.
Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou C, Smith EO. Early feeding, antenatal glucocorticoids, and human milk decrease intestinal permeability in preterm infants. Pediatric Research 1998;44:519-23.
Tyson JE, Kennedy KA. Minimal enteral nutrition for promoting feeding tolerance and preventing morbidity in parenterally fed infants. In: The Cochrane Database of Systematic Reviews, Issue 4, 1997.
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Effects of trophic feedings vs no feedings in neonates receiving parenteral feeding | ||||
| 01 Days to reach full enteral feeding | 9 | 617 | WMD (fixed), 95% CI | -2.55 [-4.12, -0.99] |
| 02 Days feeds held | 4 | 129 | WMD (fixed), 95% CI | -3.09 [-4.56, -1.63] |
| 03 Days to regain birth weight | 8 | 590 | WMD (fixed), 95% CI | -0.44 [-1.32, 0.44] |
| 04 Days under phototherapy | 3 | 171 | WMD (fixed), 95% CI | 0.36 [-0.27, 0.98] |
| 05 Days of hospital stay | 6 | 370 | WMD (fixed), 95% CI | -11.44 [-17.17, -5.70] |
| 06 Serum direct bilirubin >2.0mg/dL | 2 | 201 | RR (fixed), 95% CI | 0.92 [0.46, 1.85] |
| 07 Necrotizing enterocolitis | 9 | 650 | RR (fixed), 95% CI | 1.16 [0.75, 1.79] |
| 02 Effects of trophic feedings vs advancing feedings in infants receiving parenteral nutrition | ||||
| 01 Serum direct bilirubin > 2.0 mg/dL | 1 | 141 | RR (fixed), 95% CI | 0.33 [0.01, 7.93] |
| 02 Necrotizing entercolitis | 1 | 144 | RR (fixed), 95% CI | 0.14 [0.02, 1.07] |
| 03 Days to reach full enteral feeding | 1 | 141 | WMD (fixed), 95% CI | 13.40 [8.18, 18.62] |
| 04 Days of hospital stay | 1 | 141 | WMD (fixed), 95% CI | 11.00 [-1.40, 23.40] |
| The review is published as a Cochrane review in The
Cochrane Library, Issue 3, 2005 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |