Successful transition from parenteral nutrition to full enteral feedings during the immediate neonatal period is associated with improved growth outcomes in preterm infants (Ehrenkranz 1999; Lee 1996; Wright 1993). Adequate growth and nutrition in this population has been shown to be closely linked to outcomes such as chronic lung disease and neurodevelopment, and has implications for future adult health (Hack 2003). Early postnatal nutrition in the very low birth weight (VLBW) preterm infant is primarily supported parenterally, but this does little to support the function of the gastrointestinal tract. Early enteral feedings are beneficial to the gastrointestinal tract because of their trophic effects, positive effect on motility, and stimulation of gastrointestinal hormone secretion (Berseth 1995). However, studies have shown that full enteral feeds are not established in critically ill VLBW preterm infants until an average of 30 days of age (Shulman 1998; Ehrenkranz 1999; Griffin 1999; Steward 2002).
One of the primary setbacks to establishing full enteral feeds in preterm infants is feeding intolerance. This presents clinically as residual feeds in the stomach prior to the next scheduled feeding, sometimes associated with abdominal distension, bile stained aspirates, or emesis. Consequences of feeding difficulties include withholding of feedings, reductions in the amount of feeding, and the need for repeated abdominal radiographs to rule out the possibility that the feeding intolerance is related to necrotizing enterocolitis. In addition, the slow advancement of enteral feeding often leads to prolonged use of parenteral nutrition which predisposes these infants to nosocomial infections, hepatic dysfunction, and prolonged hospitalizations (Schanler 1996).
There are a number of possible reasons for feeding intolerance in preterm infants, including the inability to digest lactose caused by inadequate lactase activity (Raul 1986). Lactase is the last of the major intestinal disaccharidases to develop in preterm infants. At 26 to 34 weeks gestation, lactase activity is only 30% of the level of activity at term (Auricchio 1965; Antonowicz 1974). Thus, preterm infants presumably have less capacity for lactose digestion and absorption than term infants. In addition, prolonged starvation in preterm infants in the early postnatal period induces atrophy of the gastrointestinal tract. With mucosal damage, the portion of the intestinal villus that is primarily affected is its tip, where lactase is produced (Levine 1974; Hughes 1980). As a result, lactase is the first enzyme to be lost and the last to return to full activity (Neu 1996). Despite the reduced lactase level in preterm infants, gross malabsorption of lactose, presenting clinically as diarrhea, seldom occurs. This is partly because of colonic fermentation of lactose (Kien 1996). Thus, lactose malabsorption in the preterm infant manifests more commonly as large gastric residuals or abdominal distension (Hamosh 1996).
Enhanced endogenous lactase activity is associated with improved feeding tolerance in preterm infants, with a decrease in the time to transition to full enteral feeds (Shulman 1998). Breast milk, shown to be better tolerated by preterm infants, induces higher lactase activity than formula (Shulman 1998). Direct and indirect trophic effects of minimal enteral nutrition in the early postnatal period demonstrated by human and animal studies can be related to its effects of increasing intestinal lactase activity (Shulman 1998; McClure 2002).
Lactose intolerance is often managed with low-lactose or lactose-free formulas (Sinden 1991). However, these formulas developed for term infants do not meet the requirements for growth and development of the preterm infant (NCCPS 1995; AAP 1998). In the adult and pediatric population, lactose malabsorption is often treated with commercial lactase preparations. The recommended technique of lactase supplementation suggested by the manufacturer of commercially available lactase is to store milk with added enzyme (crushed tablet or drops of liquid) for 24 hours in the refrigerator before its use (PDR 2003).
Commercial lactase preparations can be used to hydrolyze lactose in
formulas and breast milk to minimize lactose malabsorption in preterm infants.
The concern, however, is that the addition of lactase enzyme following the
manufacturer-recommended 24-hour incubation period can increase osmolality
to levels that exceed current guidelines for preterm infant feedings. There
is evidence that hyperosmolar solutions may place the preterm population
at higher risk for development of necrotizing enterocolitis (Book 1975; Willis 1977). The 24-hour incubation period has also raised concerns regarding bacterial contamination of milk (Malone 1999) which has been shown to occur within eight hours in an unsterile environment (White 1979).
This lengthy incubation, which results in near elimination of lactose, may
not be necessary for the purpose of improving feeding tolerance in the preterm
infant. Studies have demonstrated that incubating milk with lactase for 15
minutes at 37 degrees Celsius was sufficient to accomplish over half of the
24-hour digestion (Fenton 2002) and minimize the rise in osmolality to levels that are still within current guidelines (Carlson 1991).
To our knowledge, the topic of lactase-treated feeds for preterm infants
and its effects on growth and nutrition has not been systematically reviewed.
Secondary Outcomes
1. Duration of parenteral nutrition (PN) expressed in number of days
2. Days enteral feeds held
3. Number of times enteral feeding is interrupted for gastric residuals
4. Days to regain birthweight
5. Duration of hospitalization expressed in total days since birth
6. Incidence of necrotizing enterocolitis (NEC) defined as suspected or confirmed positive Bell's Stage II or greater.
7. Incidence of bacteremia defined as blood cultures positive for bacteria.
8. Incidence of sepsis defined as signs and symptoms of infection and positive culture from blood.
9. Incidence of chronic lung disease defined as requiring supplemental
oxygen at 28 days of age or 36 weeks corrected gestational age
10. Adverse effects reported by the investigators
The review started by review of personal files. MEDLINE (1966-January
2005) was searched using MESH terms: beta-galactosidase/therapeutic use,
lactase, weight gain, feeding tolerance, infant nutrition/physiology, newborn,
infant, premature (or preterm).
Other databases that were searched included: EMBASE (1980-January 2005);
CINAHL (1982-January 2005); the Cochrane Central Register of Controlled Trials
(CENTRAL, The Cochrane Library, Issue 4, 2004) and the reference list of
identified trials and abstracts published in Pediatric Research (1991-2004)
from conference proceedings of the Academic Pediatric Societies (American
Pediatric Society, Society of Pediatric Research) and the European Society
of Pediatric Research. A search by first author and coauthors of any abstracts
identified in Pediatric Research were to be performed in MEDLINE and EMBASE
to try and identify any corresponding full manuscripts published. Identified
trials were entered into Science Citation Index to identify articles that
quote the original studies and to ascertain any additional potential studies
for inclusion in the review. Reference lists of published narrative and systemic
reviews were to be reviewed. Unpublished data were not sought, but authors
of published trials were to be contacted to clarify or provide additional
information. No language restriction were applied.
All abstracts and published full reports identified as potentially relevant by the literature search were assessed for the inclusion in the review by the two reviewers. Each reviewer extracted data separately on to predesigned data abstraction forms, then compared and resolved differences. One reviewer (AO) entered data into RevMan and the other (TD) cross checked the printout against her own data abstraction forms and errors were corrected by consensus.
For studies identified as abstracts, primary authors were to be contacted
to ascertain whether a full publication is available if the full paper is
not identified in an electronic database.
Quality of included trials were evaluated independently by the reviewers, using the following criteria:
Blinding of randomizations?
Blinding of intervention?
Blinding of outcome measure assessment?
Completeness of follow up?
There are three potential answers to these questions - yes, can't tell, no.
Information from the primary author were to be obtained if the published article provided inadequate information for the review. Retrieved articles were assessed and data were abstracted independently by the reviewers. Independent quality assessment was conducted by the two reviewers, who were not blinded to authors, institution or journal of publication.
The statistical analyses followed the recommendations of the CNRG. A mean treatment effect was calculated using the RevMan 4.2 package. The statistical methods included relative risk (RR), risk difference (RD), number needed to treat (NNT) or number needed to harm (NNH) for dichotomous outcomes, and mean difference (WMD) for continuous outcomes. All estimates of treatment effects are reported with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests were not performed as only one study was identified. As we have commonly noted discrepancies between numbers enrolled in trials as reported in abstracts and full text reports (Walia 2000) sensitivity analyses were to be performed excluding abstracts. No additional sensitivity analyses were planned a priori but exploratory (post-hoc) analyses were to be performed depending on the results of the review. No subgroup analyses were planned. We included outcomes reported by the authors but that had not been included in our protocol.
For additional details see the 'Characteristics of included studies table'.
The literature search did not identify any study that was later excluded.
One study enrolling 130 preterm infants in a prospective, double-blind,
randomized, controlled trial in one neonatal intensive care unit in Canada
between April 1997 and July 2000 was identified. The inclusion criteria were
26-34 weeks postconceptual age at birth, > 75% estimated energy
requirement from enteral feeds, absence of major congenital malformations
or gastrointestinal diseases, including necrotizing enterocolitis (NEC),
and no postnatal steroids or diuretics. Small, appropriate and large for
gestational age infants were eligible for the study. The study intervention
started when enteral feedings provided > 75% of the daily intake and was
terminated when the infant reached 36 weeks or was discharged from the unit,
whichever came first. Infants randomly assigned to the 'lactase treated feeds
group' received feeds treated with Lactacid drops (McNeil Consumer Products
Company). According to a previus study by Carlson et al (Carlson 1991)
this would result in a 70% decrease in lactose concentration (from 35.3
to 10.3 g/kg) after a two-hour incubation period. A study placebo solution
composed of the identical carrier agent as in Lactacid was used in the control
group. The enzyme and matched placebo solutions were packaged in identical
bottles labeled "lactase study drops" and were identifiable only by the research
nurse according to assigned code numbers.. Researchers and care-givers remained
blinded for the duration of the study. The primary outcome measure was weight
gain (g/day) measured at study day 7, 10, 14 and at study exit. Additional
outcomes included gains in length and head circumference; serum concentrations
of protein, albumin, sodium and potassium; and measurements of feeding tolerance.
In addition withdrawal from the study because of feeding intolerance or NEC
was recorded.
Although not clearly stated by the authors we assumed that there was concealed allocation of the infants to one of the two groups. The authors write "...only the research nurse and central food production staff had access to randomization information and did not participate in patient care". Of the 66 infants randomly assigned to the lactase group 52 reached study day 14. Of the 64 infants randomly assigned to the control group 50 reached study day 14. The average (mean +/- standard error of the mean) length of the study in the lactase group was 24.1 +/- 1.7 days and in the placebo group 25.7 +/- 1.9 days. None of the important primary outcomes that we had identified in the protocol and only one secondary outcome (the incidence of NEC) were reported on. A sample size calculation was performed to allow for a 33% increase in mean weight gain per day in the treatment group, with a power of .80. It is however unclear if the authors had decided a priori at what points in time after study entry to measure growth.
Primary Outcomes
1. Weight gain expressed as grams/kilogram/day
Data for this outcome were not reported.
Weight gain (g/day) was reported at 7 days, 10 days, 14 days after entry
to study (or at study exit if this occurred earlier) and at study exit (Outcome
Tables 01.01; 01.02; 01.03; 01.04). Weight gain (g/day) on day seven after
study entry was higher in the lactase treated feeds group [mean difference
(MD) 4.5 g (95% CI -0.76, 9.76)] but this was not statistically significant.
Weight gain (g/day) on day 10 after study entry was significantly higher
in the lactase treated feeds group [MD 4.9 g/day (95% CI 0.18, 9.62)]. Weight
gain (g/day) on day 14 after study entry was higher in the lactase treated
feeds group [MD 2.7 g/day (95% CI -1.47, 6.87)] and on study exit it was
higher in the lactase treated feeds group [MD 2.2 g/day (95% CI -0.98, 5.38)]
(neither of these were statistically significant).
2. Growth expressed as weight, length and head circumference percentile
for gestational age, assessed at birth and at 40 weeks post-menstrual age
Data for these outcomes were not reported.
Length gain (cm/week) (Outcome Table 01.05) and head circumference gain
(cm/week) (Outcome Table 01.06) were reported on study day 14 or study exit
if this occurred earlier, and were higher in the lactase treated feeds group,
but not significantly so. Mean difference (MD) for length gain was 0.30 cm/week
(95% CI -0.13, 0.73). MD for head circumference gain (cm/week) was 0.10 (95%
CI -0.18, 0.38).
3. Days to achieve full enteral feeds
Data for this outcome were not reported.
Secondary Outcomes
1. Duration of parenteral nutrition (PN) expressed in number of days
Data for this outcome were not reported.
2. Days enteral feeds held
Data for this outcome were not reported.
3. Number of times enteral feeding is interrupted for gastric residuals
Data for this outcome were not reported.
The authors reported that feeding intolerance (not defined) (Outcome
Table 01.07) was lower in the lactase group than in the control group. The
RR was 0.65 (95% CI 0.19, 2.18) the RD was -0.03 (95% CI -0.12, 0.06) (none
of these were statistically significant).
4. Days to regain birthweight
Data for this outcome were not reported.
5. Duration of hospitalization expressed in total days since birth
Data for this outcome were not reported.
6. Incidence of necrotizing enterocolitis (NEC) defined as suspected
or confirmed positive Bell's Stage II or greater (Outcome table 01.08)
NEC (stage not mentioned) was reported as lower in the lactase treated
feeds group. The RR was 0.32 (95% CI 0.01, 7.79); the RD was - 0.02 (95%CI
-0.06, 0.03) (none of these were statistically significant).
7. Incidence of bacteremia defined as blood cultures positive for bacteria
Data for this outcome were not reported.
8. Incidence of sepsis defined as signs and symptoms of infection and positive culture from blood
Data for this outcome were not reported.
9. Incidence of chronic lung disease defined as requiring supplemental
oxygen at 28 days of age or 36 weeks corrected gestational age
Data for this outcome were not reported.
10. Adverse effects reported by the investigators
The authors reported on the number of infants with at least one episode
of emesis during the study period (Outcome Table 01.09) and the number was
smaller in the lactase treated feeds group. The RR was 0.95 (95% CI 0.80,
1.13) and the RD was -0.04 (95% CI -0.18, 0.10) (none of these were statistically
significant).
11. Serum albumin on study day 14 or at study exit if this occurred earlier
This outcome was not predetermined in our protocol. There was a statistically
significant increase in serum albumin (g/L) on study day 14 in the lactase
treated feeds group
with a mean difference of 2.20 g/L (95% CI 0.78, 3.62).
Only one study was identified and no identified study was excluded. The authors enrolled 130 infants of approximately 31 weeks gestational age at around 11 days of age, when they were tolerating > 75% of enteral feeds. The study was of high quality, but none of the predetermined primary outcomes in our protocol for this review were reported on. Only one of the secondary outcomes (NEC) was reported on. The authors reported on growth at 7, 10 and 14 days after study entry and at exit from the study. It is uncertain that the time points for measuring growth were predetermined. None of these individual analyses can be interpreted as showing a significant effect on weight gain. There was a statistically significant increase in serum albumin on study day 14 or at study exit if this occurred earlier. There were no serious side effects reported. Lactase treated feeds appear to be well tolerated by preterm infants of approximately 31 weeks gestation at initiation of treatment. Further studies should include the most immature preterm infants (24-25 weeks gestation) as the lactase levels in the intestinal tract are even lower in that group of infants. Likewise in future studies lactase should be introduced at the initiation of enteral feeds to confer a potentially greater benefit. The studies need to be of adequate sample size to confirm the potential effectiveness of lactase treated feeds.
The only randomized trial to date provides no evidence of significant benefit to preterm infants from adding lactase to their feeds. Further research is required before benefits and risks can be reliably determined.
Randomized controlled trials of lactase-treated feeds enrolling very preterm infants when enteral feeds are started are recommended. The primary and secondary outcomes should include those identified in this review.
We are thankful to Dr. Koravangattu Sankaran, Royal University Hospital, Saskatoon, Saskatchewan, Canada for providing additional information on the study.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Erasmus 2002 | Randomized, double-blind, controlled trial Blinding of randomizations? - Yes Blinding of intervention? - Yes Blinding of outcome measure assessment? - Yes Completeness of follow up? Yes - see Notes section | 130
preterm infants (GA 26-34 weeks) admitted to one NICU in Saskatoon, Saskatchewan,
Canada were enrolled between April 1997 and July 2000. Entry characteristics expressed as mean and SEM 66 infants were assigned to the lactase group (numbers indicate mean +/- SEM); GA (weeks) 31.4 +/-0.3; BW (g) 1394.0 +/-49.1; Age at study entry (d) 11.2 +/- 0.9; Weight at study entry 1408.8 +/- 41.6; Body length at study entry (cm) 40.7 +/- 0.5; Head circumference at study entry (cm) 27.9 +/-0.3 64 infants were assigned to the placebo group; GA (weeks) 31.4 +/- 0.2; BW (g) 1420.9 +/- 56.3; Age at study entry (d) 10.8 +/- 0.9; Weight at study entry 1434.2 +/- 48.7; Body length at study entry (cm) 41.0 +/- 0.4; Head circumference at study entry (cm) 27.9 +/-0.3 | Infants randomly assigned to the lactase group received feeds treated with Lactacid drops (McNeil Consumer Products Company) which according to Carlson et al (Carlson 1991) would result in a 70% decrease in lactose concentration. A study placebo solution composed of the identical carrier agent as in Lactacid was used in the control group. The enzyme and matched placebo solutions were packaged in identical bottles labeled "lactase study drops" and were identifiable only by the research nurse according to assigned code numbers.. Researchers and care-givers remained blinded for the duration of the study. | Primary outcome was weight gain (g per day). Secondary outcomes included gains in length and head circumference, biochemical indexes of nutritional status, feeding intolerance, NEC | 52
of 66 infants assigned to the lactase group reached study day 14; 50 of 64
infants assigned to the control group reached study day 14 One of the authors of the study was contacted and confirmed that outcomes were reported as per the numbers of infants randomized The study intervention started when enteral feedings provided > 75% of the daily intake. The study was terminated when the infant reached 36 weeks or was discharged from the unit, whichever came first. Study infants were fed according to parental choice. Infants fed human milk received human milk alone on study day 1 and 2. On study day 3, each infant received a 1:1 ratio of human milk and a liquid human milk fortifier (Natural Care, Ross Laboratories) (providing 81 kcal/100 ml) and continued with this feeding regimen for the duration of the study. Infants fed formula received the preterm formula Similac Special Care (SSC) (Ross Laboratories). On study days 1 and 2 these infants received SSC 20 (68 kcal/100 ml) and on study day 3 they were advanced to SSC 24 (81 kcal/100 ml). | A |
Erasmus HD, Ludwig-Auser HM, Paterson PG, Sun D, Sankaran K. Enhanced weight gain in preterm infants receiving lactase-treated feeds: a randomized, double blind, controlled trial. Journal of Pediatrics 2002;141:532-7.
* indicates the primary reference for the study
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| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Lactase treatment vs. placebo | ||||
| 01 Weight gain (g/d) on day 7 after study entry | 1 | 130 | WMD (fixed), 95% CI | 4.50 [-0.76, 9.76] |
| 02 Weight gain (g/d) on day 10 after study entry | 1 | 130 | WMD (fixed), 95% CI | 4.90 [0.18, 9.62] |
| 03 Weight gain (g/d) on day 14 after study entry or at study exit (if this occurred earlier) | 1 | 130 | WMD (fixed), 95% CI | 2.70 [-1.47, 6.87] |
| 04 Weight gain (g/d) on study exit | 1 | 130 | WMD (fixed), 95% CI | 2.20 [-0.98, 5.38] |
| 05 Length gain (cm/week) on day 14 after study entry or at study exit (if this occurred earllier) | 1 | 130 | WMD (fixed), 95% CI | 0.30 [-0.13, 0.73] |
| 06 Head circumference gain (cm/week) on day 14 after study entry or at study exit (if this occurred earlier) | 1 | 130 | WMD (fixed), 95% CI | 0.10 [-0.18, 0.38] |
| 07 Feeding intolerance (not specified) | 1 | 130 | RR (fixed), 95% CI | 0.65 [0.19, 2.18] |
| 08 Necrotizing enterocolitis | 1 | 130 | RR (fixed), 95% CI | 0.32 [0.01, 7.79] |
| 09 Number of infants with at least one episode of emesis during the study period | 1 | 130 | RR (fixed), 95% CI | 0.95 [0.80, 1.13] |
| 10 Serum albumin (g/L) on study day 14 or at study exit if this occurred earlier | 1 | 130 | WMD (fixed), 95% CI | 2.20 [0.78, 3.62] |
| The review is published as a Cochrane review in The
Cochrane Library, Issue 2, 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. |