Description of the condition
Feeding intolerance is a common clinical problem in preterm infants, especially in infants < 29 weeks gestational age (GA) (Ringer 1996). It may be an early sign of necrotizing enterocolitis (NEC), sepsis, or other serious conditions, or may result from gut immaturity. The definition of feeding intolerance varies and is based on assessment of the amount and colour of gastric residuals and associated clinical manifestation such as vomiting, abdominal distension and a delay in passage of meconium (Newell 2000; Jadcherla 2002; Patole 2005). Factors that contribute to feeding intolerance include poor coordination of sucking and swallowing, incompetent lower oesophageal sphincter, small gastric capacity and delayed gastric emptying time, intestinal hypomotility (Mansi 2011), immaturity of the intestinal motor mechanisms (Newell 2000), and increased viscosity of meconium. Timing of the first and last meconium stool is critical for oral feeding tolerance and proper gastrointestinal function (Meetze 1993). In contrast to term infants, many preterm infants pass their first meconium only after considerable delay of up to 27 days (median, 43 hours) (Meetze 1993; Wang 1994). Consequences of feeding intolerance include prolonged need for total parenteral nutrition (TPN), infection, liver damage and cholestasis secondary to TPN and prolonged stay in the hospital (Unger 1986; Stoll 2002). Therefore, the priority is to establish full enteral feeds as soon as possible in preterm infants (Kaufman 2003).
In an observational study by Shim et al in 2007 (Shim 2007), the authors reported that full enteral feeds were tolerated earlier in infants with routine administration of glycerin enema as compared to those infants in the control group (rectal stimulation usually two to three days after no meconium passage and glycerin enema in cases of prolonged meconium passage failure) with hazard ratio (HR) and 95% confidence interval (CI) of 2.9; (1.8 to 4.8). Similarly, the rate of sepsis was lower in infants who received glycerin enema compared to the control group (7.7% versus 27.8%; P = 0.02) in very low birth weight (VLBW) infants (Shim 2007).
Description of the intervention
Glycerin laxatives in the form of enemas or suppositories are widely used in neonatal intensive care units (NICUs) (Zenk 1993). They act by virtue of the mildly irritant action of glycerol (BNF 2010). We use them to enhance bowel evacuation to prevent or treat feeding intolerance. The safety of glycerin has been proven by long-term clinical use (Shim 2007). It is relatively inexpensive and does not require medical devices for administration. The possible side-effects include hyperosmotic damage to the bowel epithelial cells which may manifest by hematochezia (passage of stools containing blood), occult (hidden) bleeding, or even perforation.
How the intervention might work
Glycerin laxatives stimulate the passage of meconium by acting as an osmotic dehydrating agent and increasing the osmotic pressure in the gut and stimulating rectal contractions (Gilman 1990).
Why it is important to do this review
In a recent review on glycerin use in preterm infants, the reviewers identified two studies: one randomized controlled trial (RCT) and one observational study. They concluded that the evidence regarding the effectiveness of glycerin laxatives for improving feeding intolerance is inconclusive in infants at ≤ 32 weeks GA or weighing ≤ 1500 grams at birth (Shah 2011).
As the utilization of glycerin laxatives in preterm infants is widespread, it is important to critically review the literature regarding its effectiveness and safety for prevention or treatment of feeding intolerance.
- To assess the effectiveness and safety of glycerin laxatives (enemas/suppositories) for preventing feeding intolerance in VLBW infants.
- To assess the effectiveness and safety of glycerin laxatives (enemas/suppositories for treating feeding intolerance in VLBW infants.
Criteria for considering studies for this review
Types of studies
We will include randomized or quasi-randomized controlled trials that have evaluated the effectiveness of glycerin laxatives for prevention or treatment of feeding intolerance in VLBW infants.
Types of participants
We will include studies on VLBW infants at birth who received glycerin laxatives for preventing or treating feeding intolerance. We will accept all definitions of feeding intolerance.
For studies using GA, we will accept 32 weeks as equivalent to VLBW infants.
For studies using glycerin for treatment of feeding intolerance, we will include any postnatal age.
For prevention of feeding intolerance, we will accept up to 72 hours of age to initiate prophylaxis.
Types of interventions
Prophylactic or therapeutic glycerin laxatives versus placebo or no intervention in VLBW infants will be included. For the purpose of this review, any dose of glycerin enemas/suppositories, preparation, or mode of delivery will be accepted.
Types of outcome measures
Time to full enteral feeds (days) (tolerating ≥ 120 ml/kg/day of enteral feeds with no additional intravenous (IV) fluids or parenteral nutrition).
- Duration of hospitalization (days).
- Duration of total parenteral nutrition (TPN) (days).
- Mortality (death during hospital stay).
- Late-onset sepsis (positive blood or cerebrospinal fluid culture beyond 72 hours of age) (Stoll 2004).
- Weight gain (grams/day).
- Stage II or III necrotizing enterocolitis (NEC) as per Bell's criteria (Bell 1978).
- Cholestasis (defined as a serum conjugated bilirubin concentration greater than 1.0 mg/dL [17.1 micromol/L] if the total serum bilirubin is < 5.0 mg/dL [85.5 micromol/L] or greater than 20 percent of the total serum bilirubin if the total serum bilirubin is > 5.0 mg/dL [85.5 micromol/L] at any time during hospital stay).
- Any reported adverse effects by investigators of original trials (e.g. diarrhea, rectal bleeding, or colonic perforation).
Search methods for identification of studies
We will formulate a search strategy in an attempt to identify all relevant studies, regardless of language or publication status (published, unpublished, in press and in progress).
We will search the following databases: the Cochrane Central Register of Controlled Trials (current issue of The Cochrane Library), MEDLINE (1950 to November 2012), EMBASE (1980 to November 2012), and CINAHL (1982 to November 2012) . We will restrict our search to randomized controlled trials and will not apply any language restriction.
The search strategy will include text terms “preterm” OR “premature” OR “very low birth weight” OR “VLBW” OR “neonate” OR “newborn” OR “infan*” AND “Glycerin enema” OR “suppository” OR “glycerol”.
Searching other resources
References from the studies identified and reviews on this topic will be handsearched for additional articles. We will search the database maintained by the United States National Institutes of Health (www.clinicaltrials.gov) and European trial registries to identify ongoing trials whose methods meet the criteria for inclusion in this review and record them in the review for future updates. We will exclude the following types of articles: studies published only in abstract form, letters (without original data), editorials, reviews, lectures and commentaries. We will not consider unpublished studies.
Data collection and analysis
Selection of studies
The authors will independently review all identified citations (study titles and abstracts) retrieved by the search strategy for relevance to the topic of this review. We will assess the studies for relevance based on study design, types of participants, interventions and outcome measures. We will remove duplicate trials and resolve any disagreement or discrepancies by discussion. We will include the reasons for exclusion of potentially relevant studies in the table 'Characteristics of excluded studies'.
Data extraction and management
We will design a data extraction form and authors will extract data directly on the form. Extracted data will include: author and citation, study location, GA of patients, birth weight, postnatal age at enrolment, inclusion/exclusion criteria within each study, the type and dose of glycerin laxatives used, sample size for the intervention and control groups and outcomes data (effectiveness and adverse events). We will resolve discrepancies in data extraction by discussion.
Assessment of risk of bias in included studies
The risk of bias of the included studies will be assessed using the method described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Each study will be assessed under the following six domains:
- Sequence generation (Was the allocation sequence adequately generated?) might lead to selection bias (biased allocation to interventions) due to inadequate generation.
- Allocation concealment (Was allocation adequately concealed?) might lead to selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
- Blinding of participants, personnel and outcome assessors (Was knowledge of the allocated intervention adequately prevented during the study?) might lead to performance bias due to knowledge of the allocated interventions by participants and personnel during the study or detection bias due to knowledge of the allocated interventions by outcome assessors.
- Incomplete outcome data (Were incomplete outcome data adequately addressed?) might lead to attrition bias due to amount, nature or handling of incomplete outcome data.
- Selective outcome reporting (Are reports of the study free of suggestion of selective outcome reporting?) might lead to reporting bias due to selective outcome reporting.
- Other sources of bias (Was the study apparently free of other problems that could put it at a high risk of bias?).
An overall assessment will be made based on the findings of the six domains.
Two review authors will assess each domain according to preset criteria and judge it as either "Low risk of bias", "High risk of bias", or "Unclear" (uncertain risk of bias). We will resolve discrepancies in judgements by discussion. Review authors will not be blinded to the study authors, locations of the studies, author funding, or study acknowledgements.
Measures of treatment effect
We will calculate risk ratio (RR), risk difference (RD), and the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) along with the 95% CI for dichotomous outcomes. Treatment effect will be expressed as mean difference (MD) along with 95% CI for continuous outcomes.
Unit of analysis issues
We will only consider parallel studies for this review.
Dealing with missing data
We will contact the primary author of the study to provide additional data in cases where data are missing. Two review authors will estimate the values from the graphs in studies where results are presented graphically and it is not possible to reach authors, or they are contacted and do not provide original data. If the numbers are not similar then results will be presented as descriptive data in the results section. When median, range, and sample size are reported, the mean and standard deviation will be estimated using established methods. A sensitivity analysis will be conducted to determine the impact of imputed data.
Assessment of heterogeneity
We will assess between-study heterogeneity using the I
Assessment of reporting biases
We will describe how we investigated the possibility of selective outcome reporting bias and what we found for each included study. If the protocol is available, then outcomes in the protocol and published report can be compared. If not, then outcomes listed in the methods section of an article can be compared with those whose results are reported. If non-significant results are mentioned but not reported adequately, bias in a meta-analysis is likely to occur. Further information can also be sought from authors of the study reports, although it should be realized that such information may be unreliable (Chan 2004).
We will assess the methods as:
- adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
- inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
Other sources of bias:
For each included study, we will describe any important concerns we have about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We will assess whether each study was free of other problems that could put it at risk of bias as yes; no; or unclear.
If needed, we plan to explore the impact of the level of bias through undertaking sensitivity analyses.
If appropriate, meta-analysis of pooled data will be performed assuming a fixed-effect model. Review Manager version 5 software (RevMan 2011) will be utilized for statistical analysis. For estimates of typical risk ratio and risk difference, we will use the Mantel-Haenszel method.
We will have two primary comparisons:
- glycerin prophylaxis versus placebo or no intervention;
- glycerin treatment versus placebo or no intervention.
Subgroup analysis and investigation of heterogeneity
If data allows for subgroup analysis, we will stratify our analysis by the following: birth weight (< 1500 g and < 1000 g), gestational age at birth (28 to 32 and < 28 weeks), age at first treatment, intervention preparation (enemas or suppositories), and any other possible sources of heterogeneity.
Sensitivity analysis will be conducted for the following: studies determined to be at high risk of bias compared with those at low risk of bias and unclear risk of bias.
Contributions of authors
JA, AA and KA wrote the first draft of the protocol.
VS commented on the draft.
Declarations of interest
None to declare.
Sources of support
- No sources of support supplied
- Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.Editorial support of the Cochrane Neonatal Review Group has been funded with federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C