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Erythromycin for the prevention and treatment of feeding intolerance in preterm infants

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Authors

Eugene Ng1, Vibhuti S Shah2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, Toronto, Canada [top]
2Department of Paediatrics, Mount Sinai Hospital, Toronto, Canada [top]

Citation example: Ng E, Shah VS. Erythromycin for the prevention and treatment of feeding intolerance in preterm infants. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD001815. DOI: 10.1002/14651858.CD001815.pub2.

Contact person

Eugene Ng

Department of Newborn and Developmental Paediatrics
Sunnybrook Health Sciences Centre
C/O Women's College Hospital
76 Grenville Street
Toronto Ontario M5S1B2
Canada

E-mail: eugene.ng@sunnybrook.ca

Dates

Assessed as Up-to-date: 05 February 2008
Date of Search: 28 December 2007
Next Stage Expected: 05 February 2010
Protocol First Published: Issue 4, 1999
Review First Published: Issue 2, 2000
Last Citation Issue: Issue 3, 2008

What's new

Date / Event Description
28 February 2008
New citation: conclusions changed

For the purpose of this update, the review was expanded to include trials that addressed the use of erythromycin in both the prevention and treatment of feeding intolerance in preterm infants. In addition, the review addresses the use of both high and low doses of erythromycin.

A new search was done in December 2007, with 14 additional studies identified. One study (Patole 2000) is a full publication of a previously included abstract (Almonte 1999). A total of ten randomized controlled trials were included in this review update and five were excluded.

28 February 2008
Updated

This review updates the existing review "Erythromycin for feeding intolerance in preterm infants", published in The Cochrane Database of Systematic Reviews, Issue 2, 2001 (Ng 2001).

06 February 2008
Amended

Converted to new review format.

History

Date / Event Description
01 April 2001
Updated

No change.

Abstract

Background

Functional immaturity of gastrointestinal motility predisposes preterm infants to feeding intolerance. Erythromycin is a motilin agonist that exerts its prokinetic effect by stimulating propagative contractile activity in the interdigestive phase.

Objectives

To evaluate the efficacy of erythromycin in the prevention and treatment of feeding intolerance in preterm infants.

Search methods

Systematic literature search was performed according to the Cochrane Neonatal Collaborative Review Group search strategy. Randomized controlled trials of erythromycin in preterm infants to promote gastrointestinal motility were identified from the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007), EMBASE (1980 - December 2007), CINAHL (1982 - December 2007), cross-references, abstracts, and journal hand searching.

Selection criteria

The initial selection criteria limited the review to studies using erythromycin at 3 - 12 mg/kg/day in preterm infants less than 36 weeks gestational age with feeding tolerance. However, a significant number of studies using erythromycin at a higher dose (> 12 mg/kg/day) or as prophylaxis for those at risk of feeding intolerance were identified. A post hoc decision was made to include these studies in the review.

Data collection and analysis

Studies were categorized into prevention and treatment studies, and data from each category were analyzed separately. Within each category, subgroup analyses were performed based on low (3 to 12mg/kg/day) and high doses (> 12mg/kg/day) of erythromycin. Primary outcome was days to full enteral feeding. Secondary outcomes included adverse effects associated with erythromycin, duration of total parenteral nutrition (TPN), weight gain, necrotizing enterocolitis (NEC), and length of hospital stay.

Results

Ten randomized controlled studies (three prevention and seven treatment studies) were included. Studies varied greatly in the definition of feeding intolerance and how outcomes were measured, analyzed and reported, so meta-analysis of most outcomes was impossible. It was observed, however, that the studies using erythromycin at higher treatment doses (40 to 50 mg/kg/day) or in infants > 32 weeks' GA reported more positive effects in improving feeding intolerance.

Meta-analysis of high dose prevention studies showed no significant difference in NEC (typical RR 0.59, 95% CI 0.11, 3.01; typical RD -0.021, 95% CI -0.087, 0.045). Meta-analysis of high dose treatment studies showed no significant difference in septicemia (typical RR 0.83, 95% CI 0.47, 1.45; typical RD -0.04, 95% CI -0.17, 0.08).

Authors' conclusions

There is insufficient evidence to recommend the use of erythromycin in low or high doses for preterm infants with or at risk of feeding intolerance. Future research is needed to determine if there is a more precise dose range where erythromycin might be effective as a prokinetic agent in preterm infants > 32 weeks' GA.

Plain language summary

Erythromycin for preventing and treating preterm infants with feeding difficulties

There is not enough evidence to show any benefit from erythromycin used in large or small doses for the prevention or treatment of feeding problems in premature infants. Premature infants who need intensive care often have feeding problems. Frequently, some food stays in the stomach without being digested. Earlier feeding can facilitate normal development of the gastrointestinal tract and can avoid health problems related to feeding by intravenous lines. Erythromycin is an antibiotic that has an effect on the gastrointestinal tract and may help infants with feeding problems. However, this review found that there is not enough evidence to recommend the use of erythromycin in small or large doses to prevent or treat premature infants with feeding problems.

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Background

Feeding intolerance is a common problem in preterm infants undergoing intensive care. It usually manifests as residual feeds in the stomach prior to the next scheduled feeding and may be associated with abdominal distension, bile-stained aspirates, or lack of stooling. The slow advancement of enteral feeding often leads to prolonged use of parenteral nutrition, which predisposes the infants to nosocomial infections, hepatic dysfunction, and prolonged hospitalization.

The presence of food in the gastrointestinal tract is important for its structural and functional integrity. It has been shown in animal studies that enteral nutrition promotes gastrointestinal cell growth directly via a trophic effect and indirectly via stimulation of local hormones (Dworkin 1976; Johnson 1976; Aynsley-Green 1983). Thus, early establishment of full enteral feeding may have physiologic advantages for the infant.

During the interdigestive period, adults as well as term infants exhibit multi-phasic cycles of intestinal motor activity, termed migratory motor complex (MMC). Physiologic studies have shown a lack of the propagative phase III of the MMC in the duodenum of preterm infants less than 32 weeks gestational age (al Tawil 1996). These infants' interdigestive activity consists of random periods of quiescence and non-propagated contractions. This functional immaturity predisposes them to feeding intolerance. Further studies have shown that gastrointestinal motility matures as gestational age increases (Tomomasa 1985; Berseth 1989; Berseth 1990).

Motilin, a gastrointestinal peptide, stimulates propagative contractile activity during phase III of the MMC in the interdigestive state. In-vitro studies have shown that erythromycin, a macrolide antibiotic commonly used in preterm infants for treatment of Ureaplasma urealyticum infection, is a motilin agonist (Peeters 1989). Its prokinetic effect is seen at doses much lower than the antimicrobial dose in humans. Animal studies have shown that the prokinetic effect of erythromycin is dose dependent. At a low intravenous dose (1mg/kg), erythromycin has been shown to induce phase III of the MMC along the small intestine. At higher doses (7 to 10 mg/kg), however, erythromycin has been shown to cause sustained contractile activity in the small intestine, followed by a prolonged disruption of the baseline MMC (Itoh 1984a; Itoh 1984b; Zara 1985; Otterson 1990). In clinical studies, erythromycin has been shown to improve gastric motility in children with postoperative intestinal dysmotility and in children with neuropathic pseudo-intestinal obstruction (Simkiss 1994; Miller 1990). It has also been shown to be an effective aid for postpyloric intubation (Di Lorenzo 1990).

There are a limited number of gastrointestinal motility agents currently available. Cisapride was commonly used to promote gastrointestinal motility in preterm infants. However, because of concerns regarding the development of prolonged QT interval and arrhythmias (Lewin 1996), this drug is no longer recommended for use in this population.

The purpose of this review was to evaluate the efficacy of erythromycin in the prevention and treatment of feeding intolerance in preterm infants.

This review updates the existing review of erythromycin for feeding intolerance in preterm infants originally published in The Cochrane Library, Issue 2, 2000.

Objectives

The primary objective of this review was to determine the efficacy of erythromycin in preventing and treating feeding intolerance in preterm infants. The primary outcome was defined as days to achieve full enteral feeds.

Secondary objectives included:

  1. Duration (days) of total parenteral nutrition (TPN);
  2. Weight gain;
  3. Occurrence of adverse effects associated with the use of erythromycin: diarrhea, cardiac arrhythmias, potentiation of theophylline toxicity, nosocomial bacterial and fungal infections, and hypertrophic pyloric stenosis;
  4. Incidence of necrotizing enterocolitis (NEC);
  5. Duration (days) of hospitalization.

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Methods

Criteria for considering studies for this review

Types of studies

All randomized and quasi-randomized clinical trials in which the use of erythromycin was compared to placebo for preterm infants. Because of the nature of the outcomes measured, crossover studies were not included.

The initial inclusion criteria for this review included only studies where low dose erythromycin (3 to 12mg/kg/day) was used for treatment of feeding intolerance in preterm infants. However, a search of the literature has since identified a significant number of studies using erythromycin at doses higher than 12mg/kg/day, and other studies using erythromycin as prophylaxis for preterm infants at risk of feeding intolerance. A post hoc decision was made to include these studies in the review. Studies of erythromycin use for prevention of feeding intolerance (prevention studies) and those for treatment of feeding intolerance (treatment studies) were separately considered according to the criteria listed below. Where possible, subgroup analyses were performed for data from studies using erythromycin at low and high doses.

Types of participants

Prevention studies: Preterm infants less than/or equal to 36 weeks' gestational age (GA) who were ready to commence enteral feeds.

Treatment studies: Preterm infants less than/or equal to 36 weeks' GA who were identified as having feeding intolerance. Feeding intolerance was defined as: increased residuals on nasogastric aspiration (> 50% of previous feed, or > 30% of previous feed on more than one occasion, or > 10% of daily feed volume), or the presence of abdominal distension or bloody stools, which preclude the continuation of feeds in the absence of culture positive sepsis or radiographic evidence of NEC.

Types of interventions

Prevention studies: Treatment with oral or intravenous erythromycin versus placebo once enteral feeding has begun. Erythromycin administered at a dose range of 3 to 12 mg/kg/day (low dose), or > 12 mg/kg/day (high dose) for up to two weeks to promote gastrointestinal motility.

Treatment studies: Treatment with oral or intravenous erythromycin versus placebo once feeding intolerance is diagnosed. Erythromycin administered at a dose range of 3 to 12 mg/kg/day (low dose), or > 12 mg/kg/day (high dose) for up to two weeks to promote gastrointestinal motility.

Types of outcome measures

For both prevention and treatment studies:

Primary outcome:
  1. Days to achieve full enteral feeding, which is the point when all intake (at least 150 ml/kg/day) is given as milk (breast milk or formula) by gavage or by mouth.
Secondary outcomes:
  1. Duration (days) of TPN;
  2. Weight gain, measured by grams per kilogram per week during therapy;
  3. Occurrence of adverse effects associated with the use of erythromycin: diarrhea (report of watery stools more than once per day); any form of cardiac arrhythmia diagnosed by electrocardiogram or by Holter monitoring; theophylline toxicity (signs of seizure, arrhythmia, hypotension, or theophylline level > 110 μmol/L); any culture positive nosocomial bacterial or fungal infection (positive culture from normally sterile sites), and hypertrophic pyloric stenosis;
  4. Incidence of NEC (presence of pneumatosis intestinalis and/or portal air on an abdominal X-ray);
  5. Duration of hospitalization [length of stay (days) in NICU from admission until discharge].

Search methods for identification of studies

See: Collaborative Review Group Search Strategy

Randomized controlled trials of erythromycin treatment in preterm infants were identified from the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007, MEDLINE (1966 - December 2007) using the MeSH headings: Erythromycin, infant, newborn; infant, premature; gastrointestinal motility or gastric emptying; motilin; prokinetic agent.tw, EMBASE (1980 - December 2007), CINAHL (1982 - December 2007) and clinical trial registries (ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy). Relevant medical journals, bibliographies of articles from the database search, personal files, scientific meeting proceedings, and abstracts published in Pediatric Research (1990 - 2007) were manually searched. Language restrictions were not applied. Attempts were made to contact investigators of studies meeting the inclusion criteria to gather additional data for analysis. An attempt was made to identify unpublished studies from clinical trial registries.

Data collection and analysis

Standard methodology for performing systematic reviews according to the Cochrane Neonatal Review Group was used.

Studies included in the review were randomized or quasi-randomized controlled trials involving preterm infants with a treatment group and a placebo group.

Quality of the trials included were evaluated by the following criteria:

  1. Blinding of randomization;
  2. Blinding of intervention;
  3. Complete follow-up;
  4. Blinding of outcome measurement.

The decision to include or exclude a specific study in the review was made by consensus of the two reviewers (EN, VS). Studies involving neonates and older infants and children were excluded if data for neonates could not be extracted.

A data collection form was created and the following information was extracted from the included studies: baseline characteristics of the participants, age at enrollment into study, inclusion and exclusion criteria, sample size, treatment and control group regimen, feeding protocol, and outcome measures. The reviewers were not blinded to the study authors or institutions. Each reviewer (EN, VS) abstracted data independently, and the results were compared and differences resolved by consensus.

Statistical analysis:
When there were at least two randomized controlled studies that evaluated the efficacy of erythromycin for prevention or treatment of feeding intolerance in preterm infants using the same outcome measures, data from those studies were combined to obtain an overall estimate of effect size. Treatment effects were described using risk ratio (RR) and risk difference (RD) for categorical outcomes, and weighted mean difference (WMD) for outcomes measured on a continuous scale. Statistical tests for categorical and continuous variables as recommended by the Cochrane Neonatal Review Group were used.

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Results

Description of studies

For details see: table of included studies.

Sixteen studies were identified, including 14 published manuscripts and two abstracts. One of the published manuscripts (Patole 2000) and one of the abstracts (Almonte 1999) were reports of the same study; this study is referred to as Patole 2002. Two studies were excluded because of their design as crossover studies (Costalos 2001; Costalos 2002). One study (Nogami 2001) was excluded because treatment assignment was not randomized (treatment or placebo was given based on the time period during which they were recruited). One study (Curry 2004) was excluded because it only involved infants with post-operative gastroschisis. One study (Jadcherla 2002) was excluded because it was a dose-response study with no placebo group included. Ten eligible randomized controlled trials were included in this review.

These ten studies used different inclusion criteria and used erythromycin in variable doses in different clinical settings. Three studies (Cairns 2002; ElHennawy 2003; Aly 2007) used low dose erythromycin (3 to12 mg/kg/day) as the study drug for preterm infants with feeding intolerance and thus fulfilled the a priori inclusion criteria for this review. The other seven studies did not meet the initial inclusion criteria, either because of the use of high dose erythromycin (> 12mg/kg/day) (Patole 2000; Stenson 1998; Ng PC 2001; Ng SC 2003; Madani 2004; Nuntnarumit 2006) and/or because erythromycin was used as a prophylactic treatment (Patole 2000; Stenson 1998; Oei 2001). Nonetheless, since these studies were still relevant to the objective of this review and might contribute to the knowledge of how erythromycin might be used to promote enteral feeding in preterm infants, a post hoc decision was made to broaden the scope of the review to include these studies.

For the description of studies and analyses of relevant outcome data, these included studies were grouped based on the clinical settings where erythromycin was used: Prevention (for at risk infants prior to or at initiation of feeds) and Treatment (for infants who exhibit signs of feeding intolerance). Where possible, subgroup comparisons of outcomes from studies using Low dose (defined a priori as 3-12mg/kg/day) versus High dose (> 12mg/kg/day) erythromycin were made.

PREVENTION STUDIES

Studies using low dose erythromycin (3 - 12 mg/kg/day)

Oei 2001 (10mg/kg/day): In the single centre randomized controlled trial by Oei 2001, 50 preterm infants with GA less than/or equal to 32 weeks who were ready to start enteral feeds were enrolled into the study. Infants with major congenital anomalies, perinatal hypoxia, NEC and other abdominal pathological conditions, confirmed sepsis or intraventricular/periventricular hemorrhage more severe than grade I were excluded from the study. Infants enrolled in the study were given either erythromycin or a manufactured placebo.

Erythromycin-ethyl-succinate or placebo was administered enterally 30 minutes before feeding at a dose of 2.5 mg/kg/dose every six hours (10 mg/kg/day) for 10 days. The infants were fed according to a standardized protocol. The study medication was held if the infants' conditions required cessation of enteral feed or if the infant was transferred back to the referral nursery.

Primary outcome was days to achieve full enteral feeds. Secondary outcomes were number of episodes of emesis, gastric residuals > 30% of previous 6-hour feed volume, number of bile-stained gastric aspirates, and duration of total parenteral nutrition. Adverse events associated with the administration of erythromycin, such as increased toxicity to theophylline, abnormal liver functions, or sepsis were also reported. Outcomes were reported on 43 of the 50 infants who completed the trial.

Studies using high dose erythromycin (> 12mg/kg/day)

Stenson 1998 (45mg/kg/day): Seventy-five ventilated preterm infants with GA less than/or equal to 30 weeks were enrolled at birth to determine the effect of erythromycin on reducing the early inflammatory response and, subsequently, the occurrence and severity of chronic lung disease in preterm infants (Lyon 1998). In a separate publication, Stenson (1998) reported the effect of erythromycin on establishment of enteral feeding in this study population. A discrepancy between the two publications (Lyon 1998; Stenson 1998) was noted in the number of infants reported [76 in Stenson (1998) vs. 75 in Lyon (1998)]. The infants were randomly assigned to receive erythromycin or standard treatment without erythromycin or a placebo. Erythromycin was started on day one at 15mg/kg/dose given intravenously three times daily (45 mg/kg/day) for seven days. The infants were fed according to a standardized protocol. The primary goal was to compare the concentration of inflammatory cytokines (interleukins IL-1 beta and IL-8, tumor necrosis factor alpha) in the treatment and control groups. Secondary outcomes included time to full enteral feed (defined as the point when milk intake of at least 150 ml/kg/day was given enterally), feed tolerance as evaluated by net enteral balance (nasogastric feed volume minus nasogastric feed residual volume) for the first 14 days of age, number of infants who vomited, number of glycerin suppositories given because of concern for delayed passage of meconium, and incidence of NEC. Data on feeding pattern were obtained from review of the nursing and medical records after the infant was discharged from the nursery. The staff responsible for the infants' feeding were not aware that the feeding pattern would be studied at a later date. Outcomes were reported on all 76 infants.

Patole 2000 (48mg/kg/day): In the study by Patole (2000), 73 preterm infants with GA less than/or equal to 32 weeks who were ready for enteral feeding were enrolled. Infants with congenital anomalies were excluded. Infants were randomly assigned to receive erythromycin or a manufactured placebo. Erythromycin-ethyl-succinate or placebo was administered in a dose of 12 mg/kg every six hours (48 mg/kg/day) via orogastric tube from the time feeds were begun until full enteral feeds of 150 ml/kg/day were achieved or a total of two weeks of therapy was reached. The infants were fed according to a standardized protocol. Administration of other prokinetic agents was not allowed during the study period. Primary outcome was time to full enteral feed (defined as the point when milk intake of 150 ml/kg/day was achieved). Secondary outcomes included: feeding intolerance, defined by the presence of two major or one major plus two minor criteria or isolated bile-stained aspirate (Major: gastric aspirates > 30% of feed volume given over the previous four hours; bile-stained aspirates. Minor: vomiting; abdominal distension - increase in abdominal girth > 1.5 cm from measurement before feed), incidence of treatment failure (no clinical improvement in feeding intolerance or isolated bile stained/large gastric aspirates despite appropriate management on four consecutive occasions), duration of hospital stay, incidence of NEC, and occurrence of side effects associated with erythromycin [sepsis (positive blood culture with clinical deterioration), loose stool, hepatic dysfunction, cardiac arrhythmias]. Outcomes were reported on all 73 infants.

TREATMENT STUDIES

Studies using low dose erythromycin (3 - 12 mg/kg/day)

Cairns 2002 (12 mg/kg/day): In the multicenter randomized controlled trial by Cairns 2002, 60 preterm infants with GA < 37 weeks who failed to initiate or advance feeds for three or more days were enrolled in the study. Infants with NEC (suspect or confirmed) and ileus were excluded. Enrolled infants were given erythromycin at 3 mg/kg/dose or a normal saline placebo intravenously every six hours (12 mg/kg/day) until full enteral feeds (150 ml/kg/day) were achieved. The infants were fed according to a standardized protocol. Primary outcome was time to reach full feeds. Outcomes were reported on all 60 patients.

ElHennawy 2003 (6 mg/kg/day): In the single center randomized controlled trial by ElHennawy 2003, 27 preterm infants with GA between 29 to 36 weeks and birth weight (BW) between 900 to 2000 grams who were unable to achieve full feeds (150 ml/kg/day) within eight days of feeding initiation were eligible. Infants with NEC, intestinal myopathy, hepatitis, hepatic failure, congenital or chromosomal abnormalities, and sepsis within 48 hours of study entry were excluded. In addition, infants with unstable cardiorespiratory status requiring inotropic support, infants on opioids, or continuous feeding and those with arrhythmia were also excluded. Enrolled infants were randomized to receive erythromycin or a manufactured placebo.

Erythromycin-ethyl-succinate or placebo was administered in a dose of 1.5 mg/kg/dose every six hours (6 mg/kg/day) by orogastric tube 30 minutes before feeding for eight days. On the first day of the study (day 0), antroduodenal motor contractions were assessed using manometric probe two hours during fasting, two hours after a dose of erythromycin or placebo, and during and until one hour after a 10 ml/kg milk feed. Whole gut transit time was measured using 2 ml of carmine red dye one hour after the above milk feed, followed by gastric emptying time measurement according to method of George (George 1968) 20 minutes after the milk feed.

From days one to eight, feeding was advanced using a standardized protocol. Feeding intolerance was defined by the presence of abdominal distention (abdominal circumference > 15% of baseline measurement), gastric residuals > 25% of the volume of feed, or frank blood detected in the stool. Feeding volume was not advanced for 24 hours in the presence of feeding intolerance, although the criteria for withholding feeds were not explained.

Primary outcome was volume of feeding achieved by study day eight. Short-term secondary outcomes included the acute changes in antroduodenal motor pattern and gastric emptying in response to a single dose of medication; longer term secondary outcomes included number of hours where feeding was held, number of gastric residuals over 1 ml 2 ½ hrs post-feed, number of stools, weight and number of infants reaching full enteral feeds at study day eight, days to reach full enteral feeds and full oral feeds. Outcomes were reported on all 27 patients.

Aly 2007 (3 mg/kg/day): In the single center randomized controlled trial by Aly 2007, 60 preterm infants with GA < 37 weeks who were fed bovine protein-based formula and presented with feeding intolerance (defined by repeated gastric residual > 30% of previous six hour feed) were included in the study. Infants with major congenital anomalies, structural gastrointestinal anomalies, birth asphyxia, presence or history of NEC, confirmed sepsis, and organic abdominal illness were excluded.

Erythromycin-ethyl-succinate diluted to 4 mg/ml or equal volume of normal saline placebo was mixed into the milk feed prior to administration. Erythromycin was given at a dose of 1 mg/kg every eight hours until full enteral feeding (150 ml/kg/d for at least 24 hours) was established. Enteral and parenteral feedings were administered according to a standardized protocol.

The primary outcome was days required to achieve full enteral feeds (150 ml/kg/d for at least 24 hours). Secondary outcomes were number of episodes of feeding intolerance (as defined), weight gain since enrollment into study, duration of TPN, incidence of NEC, and length of hospital stay. Outcomes were reported on 49 of the 60 infants who survived to reach full enteral feeds.

Studies using high dose erythromycin (> 12mg/kg/day)

Ng PC 2001 (50 mg/kg/day): In the single center randomized controlled trial by Ng PC 2001, 56 preterm infants with BW < 1500 g who achieved less than half of full enteral feed (or < 75 ml/kg/day of milk feeds) by day 14 of age were enrolled into the study. Infants with lethal congenital anomalies, structural gastrointestinal abnormalities, NEC, or cyanotic congenital heart diseases, and those with major gastrointestinal surgery within the first two weeks of age were excluded. Enrolled infants were randomized to receive either erythromycin or normal saline placebo.

Erythromycin-ethyl-succinate or placebo was mixed into the milk feed and administered orally at a dose of 12.5 mg/kg every six hours (50 mg/kg/day). Treatment was initiated on all subjects on day 15 of age for a total of 14 days. The medication was held if the infants' conditions require cessation of enteral feed during the study period. Administration of other prokinetic agents was not allowed during the study period. Enteral and parenteral feedings were administered according to a standardized protocol.

Primary outcome was time (days) to achieve half, three quarters, and full enteral feeds. Secondary outcomes included adverse effect from erythromycin administration (prolonged QT interval, pyloric stenosis, bacterial colonization in the stool) and from the use of parenteral nutrition (culture positive sepsis and TPN cholestasis). Length of hospital stay and mortality were also recorded. Outcomes were reported on all 56 infants in the study.

Ng SC 2003 (15 mg/kg/day): In the single center randomized controlled trial by Ng SC 2003, 24 preterm infants with BW less than/or equal to 1500 grams who either fail to start minimal enteral feeding by one week of age or to advance feeding up to 20 ml/kg/day one week after initiation of feeds were included. Infants with sepsis, major congenital anomalies, or growth restricted infants with a history of absent or reversed end-diastolic flow in the umbilical Dopplers in-utero were excluded from the study. Enrolled infants were randomized to receive erythromycin or a manufactured, isotonic placebo.

Erythromycin-ethyl-succinate or placebo was administered at a dose of 5 mg/kg every eight hours orally until one week after full enteral feeding (130 ml/kg/day) was achieved.

Primary outcome was time taken to achieve full enteral feeds. Secondary outcomes included time to regain birth weight, days of total parenteral nutrition, incidence of cholestatic jaundice, incidence of necrotizing enterocolitis, number of glycerin suppositories used, adverse event associated with the use of erythromycin (cardiac arrhythmias, pyloric stenosis, sepsis with multi-resistant organisms) and duration of hospital stay. In addition, with continuous pH probe monitoring from the time of study entry to one day after full feeds was achieved, the reflux index (percentage of monitored time with esophageal pH < 4 for 15 or more seconds) before and after the study was measured and the number of infants with reduction in reflux was calculated. Outcomes were reported on all 24 patients.

Madani 2004 (50 mg/kg/day): In the single center randomized controlled trial by Madani 2004, 57 preterm infants with GA < 36 weeks at birth who failed to tolerate half (75 ml/kg/d) of the full enteral feeds within five days of initiation of feeding were eligible. Infants with hypoxic injury, cyanotic congenital heart disease, previous gastrointestinal surgery, intestinal atresia or other congenital gastrointestinal conditions were excluded from the study. Enrolled infants were randomized to receive erythromycin or no treatment. A placebo was not used in this study.

Erythromycin-ethyl-succinate was administered at a dose of 12.5 mg/kg every six hours orally until full enteral feeding (150 ml/kg/day) was achieved.

Primary outcome was days required to achieve full enteral feeding (150 ml/kg/day), with subgroup analyses done on this outcome measure (infants greater than/or equal to 32 weeks, and < 32 weeks). Secondary outcomes included age at discharge from hospital, incidence of necrotizing enterocolitis and adverse effects associated with erythromycin use (stool colonization, prolonged QT interval, and pyloric stenosis). Outcomes were reported on all 57 infants.

Nuntnarumit 2006 (enteral administration 40 mg/kg/day for two days, then 16 mg/mg/day for five days): In the multicenter randomized controlled trial by Nuntnarumit 2006, 46 preterm infants with GA < 35 weeks and BW < 1800 g who were at least five days of age and clinically stable (normal blood pressure and no recurrent hypoxemic/bradycardic episode) and who had feeding intolerance (defined by gastric residual > 50% of the previous three hour feed volume on more than occasions in 24 hours) were included in the study. Infants with major congenital anomalies, suspected or proven NEC within seven days prior to the onset of feeding intolerance, cyanotic congenital heart disease, major gastrointestinal surgery within two weeks, sepsis, metabolic or electrolyte abnormalities were excluded. Infants treated with fentanyl, indomethacin, pancuronium or vecuronium at the onset of feeding intolerance were also excluded. Enrolled infants were randomized to receive either erythromycin or a manufactured placebo. Erythromycin-ethyl-succinate diluted to 40 mg/ml or placebo was administered 30 minutes prior to feeding. Erythromycin was given enterally at a dose of 10 mg/kg/dose orally every six hours for the first two days, and 4 mg/kg every six hours for another five days. Administration of other prokinetic agents was not allowed during the study period. Enteral and parenteral feedings were administered according to a standardized protocol.

Primary outcome was time after initiation of treatment to achieve full enteral feeding (150 ml/kg/day) and maintained for at least three consecutive days. Secondary outcomes included incidence of NEC, septicemia, length of hospital stay, adverse effects associated with erythromycin (elevated liver enzymes, hypertrophic pyloric stenosis), and complications relating to the use of TPN (cholestasis and catheter-related sepsis). Outcomes were reported on all 46 infants.

Risk of bias in included studies

For details see: table of included studies.

PREVENTION STUDIES

Oei 2001: Randomization was performed by parallel group design into blocks of 10 and was stratified by gestational age (over or less than 30 weeks). The randomization codes were concealed and were only available to the trial pharmacist off-site. The placebo was made to look identical to the treatment drug. Thus, blinding of randomization and intervention were accomplished. However, it was unclear whether outcome assessments were blinded. A sample size calculation was performed.

Stenson 1998: Infants were randomized to treatment or no treatment group by sealed envelopes. Blinding of intervention was not ensured, as a placebo was not given. Although the staff providing care were unaware of the investigators' intention to study the effect of the study drug on feeding tolerance, blinding of outcome assessments could not be ascertained. A sample size calculation was performed for the original study (Lyon 1998) to detect an effect of erythromycin on measures of lung injury and inflammation, but this sample size was inadequate to detect any effect of erythromycin on the primary outcome of time to full enteral feeds in the subsequent study (Stenson 1998).

Patole 2000: Infants were randomized using computer generated random numbers to treatment or placebo groups. Infants were allocated into the groups using sealed, coded envelopes. Blinding of intervention and outcome assessment were achieved. A sample size calculation was performed.

TREATMENT STUDIES

Cairns 2002: The randomization was stratified by study center and by postmenstrual age (over or less than 32 weeks). No other methodological information was available from the abstract.

ElHennawy 2003: Study infants were allocated to the treatment or placebo group using random number assignment generated by the pharmacy staff. The placebo was made to look identical to the treatment drug. The laboratory technician who analyzed the antroduodenal manometry recordings was unaware of the treatment assignment. Staff physicians, nurses, and investigators were all blinded to the treatment assignment. Therefore, blinding of randomization, intervention and outcome assessment were achieved. A sample size calculation was performed.

Aly 2007: Infants were randomized to erythromycin or placebo by opaque sealed envelopes. Randomization was done by parallel block of 10 stratified by gestational age (less than/or equal to 32 weeks and > 32 weeks). Blinding of randomization, intervention and outcome assessment were achieved. A sample size calculation was performed.

Ng PC 2001: Computer-generated randomization was performed by a designated staff member not involved in clinical care. The treatment drug and saline placebo were mixed into the milk feeds by non-clinical care staff as an attempt to mask the difference in appearance between the treatment drug and placebo. This method of masking was incomplete, as the treatment drug still had a distinct odor, so blinding of intervention could not be achieved. Microbiologists who were unaware of the treatment assignment analyzed stool cultures for colonization studies. Therefore, randomization, intervention, and outcome assessments were adequately blinded. A sample size calculation was performed.

Ng SC 2003: Study infants were randomly allocated to the two groups by sealed envelopes. The assignment was known only to a pharmacist, who was blinded to the care of the infants. The placebo was made to look identical to the treatment drug. Thus, blinding of randomization and intervention were achieved. However, it was unclear whether outcome assessments were blinded. A sample size calculation was performed.

Madani 2004: There was no information in the published paper regarding the method of randomization and blinding procedures. No sample size calculation was performed.

Nuntnarumit 2006: Infants were randomized to erythromycin or placebo by opaque sealed envelopes. Randomization was stratified by gestational age (< 32 weeks or greater than/or equal to 32weeks), and block of four randomizations were done to ensure balanced allocation. Blinding of randomization, intervention, and outcome assessments were achieved. A sample size calculation was performed.

Effects of interventions

PREVENTION STUDIES

1. Patient demographics

Oei 2001: Twenty-five infants were enrolled into the erythromycin group, and 25 in the placebo group. One infant in each group was withdrawn prior to the start of the study because of withdrawal of parental consent. Two infants in the placebo group were given cisapride during the trial due to recurrent vomiting and were taken out of the study. One infant in the erythromycin group was transferred back to the referring hospital before full feed was established. Finally, 1 infant in each group died of NEC and sepsis before feeding was established. The author reported data on the remaining 43 infants (22 in the erythromycin group and 21 in the placebo group). There was no significant difference in the baseline characteristics between the two groups.

Stenson 1998: Thirty five infants were enrolled in the erythromycin group and 41 in the control group. All infants were enrolled at birth. The two groups were similar in their demographic characteristics, except that the control group had a much higher male: female ratio than the treatment group (18/17 vs. 30/11, p = 0.05). Infants in the erythromycin group and the control group were started on enteral feedings at a similar median age of 3 (IQR 2 to 4) vs. 3 (IQR 2 to 5) days, p = 0.34.

Patole 2000: Thirty six infants were enrolled in the erythromycin group and 37 in the placebo group. There was no significant difference in the demographic characteristics between the two groups. Infants in the the treatment and placebo groups were started on enteral feedings at a similar median age of 5 (IQR 3 to 7.7) vs. 5 (IQR 3 to 7.5) days, p = 0.84.

2. Time to established full enteral feeds

Using low dose erythromycin (10 mg/kg/day), Oei (Oei 2001) showed that infants in the erythromycin group achieved full feeds significant earlier than the placebo group [mean (SD) days to establish full feeds of 6.0 (2.3) vs. 7.9 (3.5) days, p = 0.04]. However, the other two studies using high dose erythromycin (Stenson 1998; Patole 2000) failed to show any significant difference between the erythromycin and placebo group in days to achieve full feeds [median (IQR) of 8 (5 to 12) vs. 9 (6 to 14) days, p = 0.45] in Stenson 1998 and [median (IQR) of 3.9 (3.4 to 5.9) vs. 4.3 (3.4 to 6.8) days, p = 0.6] in Patole 2000. In addition, Patole (Patole 2000) found no significant difference between the treatment and placebo group in age at full feeds [median (IQR) of 9.5 (7 to 13) vs.11 (7 to 16) days of age, p = 0.9].

Meta-analysis of this primary outcome could not be performed because data in all but one study were reported as median and interquartile range. Studies were also different in the dose and duration of erythromycin used.

3. Duration of TPN

Only one study (Oei 2001) reported on the duration of TPN, which was not different between the erythromycin and placebo group during the study period [mean (SD) of 4.6 (5.1) vs. 4.0 (3.9) days, p = 0.68].

4. Weight gain

Two studies (Oei 2001; Patole 2000) reported on weight gain. In the study by Oei (Oei 2001), there was no difference in the time to regain birth weight between the erythromycin and placebo groups [mean (SD) of 14.9 (2.6) vs.15.3 (6.6) days, p = 0.83]. Similarly, Patole (Patole 2000) did not find a statistically significant difference between the erythromycin and placebo group in median (IQR) weight gain from birth to discharge [425 (162.5 to 1190) vs. 715 (450 to 1117) grams, p = 0.15].

Meta-analysis of this outcome could not be performed because one of the two studies reported this outcome in median and interquartile range, and because of the difference in the way weight gain was defined and reported in the two studies.

5. Adverse effects associated with the use of erythromycin

Two studies (Oei 2001; Patole 2000) reported on adverse effects associated with the use of erythromycin, but none was noted in either the erythromycin or placebo group during the study period.

6. NEC

All three studies reported on NEC. In the study by Oei (Oei 2001), one infant in each of the erythromycin and placebo group developed NEC. However, they were excluded from further analysis in the study. NEC was defined by pneumatosis intestinalis on radiograph or by findings on laparotomy in the two remaining studies (Stenson 1998; Patole 2000). In the study by Patole (Patole 2000), none of the infants developed NEC during the study period. In the study by Stenson (Stenson 1998), no significant difference in the number of infants with NEC was noted between the erythromycin and placebo group [2 (6%) vs. 4 (10%), p = 0.41].

Meta-analyses of this outcome from the two studies that reported on this outcome (Stenson 1998; Patole 2000) showed no difference in the incidence of NEC between erythromycin and placebo group. (typical risk ratio 0.59; 95% confidence interval 0.11 to 3.01; typical risk difference -0.02; 95% confidence interval -0.09 to 0.05).

7. Duration of hospitalization

One study (Patole 2000) reported on this outcome and found no difference in duration of hospitalization [43 (30.5-57) vs. 46 (23.7-69) days, p=0.89] between the erythromycin and placebo group.

8. Other outcomes

Studies by Oei (Oei 2001) and Stenson (Stenson 1998) reported on the incidence of feeding intolerance, although the definition of feeding tolerance differed in the two studies. Oei (Oei 2001) reported a significantly lower number of gastric aspirates (> 30% of previous feed) in the erythromycin group compared with the placebo group [mean (SD) of 1.1 (1.9) vs. 3.6 (2.4), p = 0.0007]. Stenson (Stenson 1998) reported that feeding tolerance [defined by the median net enteral balance (nasogastric feed volume minus nasogastric feed residual volume)], was not different between the erythromycin and control group at any day during the 14 days study period.

Oei 2001 reported no difference in the number of vomiting episodes between the erythromycin and placebo group [mean (SD) of 4.7 (6.4) vs. 3.9 (5.8) episodes, p = 0.66] and Stenson (Stenson 1998) did not find any difference in the number of infants who vomited [12 (34%) vs. 10 (24%) episodes, p = 0.59] between the erythromycin and placebo group during the study period.

Stenson (Stenson 1998) reported no statistically significant difference between the erythromycin and placebo group in the number of glycerin suppositories used [15 (43%) vs. 24 (58%), p = 0.17].

Stenson (Stenson 1998) reported no difference in mortality rate between the erythromycin and placebo group [7 (20%) vs. 8 (20%), p = 0.92].

TREATMENT STUDIES

1. Patient demographics

Cairns 2002: Thirty-two infants were enrolled in the erythromycin group and 28 in the placebo group. There was no significant difference in the baseline characteristics between the two groups. Infants in the erythromycin and placebo group entered the study at similar mean postmenstrual age of 29.4 (SD 1.7) vs. 29.1 (SD 1.9) weeks. Infants in the two groups did not differ in the number of days feeds were attempted before entering the study [8.1 (SD 4.7) vs. 8.6 (SD 6.6) days]. Eighty-five percent of all study infants were fed with breast milk.

ElHennawy 2003: Fifteen infants were enrolled in the erythromycin group and 12 in the placebo group. There was no significant difference in the baseline characteristics between the two groups. Infants in the erythromycin and placebo groups were started on enteral feedings at a similar mean age [8 (SD 12) vs. 5 (SD 4) days, p > 0.05], and the mean age at study entry [24 (SD 13) vs. 26 (SD 13) days, p > 0.05) ] and mean feeding volume at study entry [36 (SD 39) vs. 28 (SD 21) ml/kg/day, p > 0.05] were also similar.

Aly 2007: Sixty infants meeting the inclusion criteria were enrolled. Eleven infants (five in erythromycin group and 6 in placebo group) died before reaching full feeds. Among those who completed the study, 25 (13 infants less than/or equal to 32 weeks and 12 infants > 32 weeks) were given erythromycin and 24 (12 infants less than/or equal to 32 weeks and 12 infants > 32 weeks) placebo. Infants in the erythromycin and placebo group did not differ in baseline characteristics. Median age at enrollment between the erythromycin and the placebo group was similar [2 (IQR 2 to 24) vs. 2 (IQR 2 to 10) days, p = NS].

Ng PC 2001: Twenty-seven infants were enrolled into the erythromycin group, and 29 in the placebo group. There was no significant difference in the baseline characteristics between the two groups. Infants in the erythromycin group and placebo group were started on enteral feeding at a similar median age [median (IQR) of 6 (4 to 11) vs. 8 (5 to 11) days, p = NS) ]. The volume of feeds at the time of study entry was also similar [median (IQR) of 43 (17 to 58) vs. 51 (39 to 68) ml/kg/day, p = NS]. The percentage of infants on breast milk, formula, or a combination of both were also similar [breast milk 19 vs. 10%, p = NS; formula 30 vs. 28%, p = NS; mixed 51 vs. 62%, p = NS].

Ng SC 2003: Thirteen infants were enrolled in the erythromycin group and 11 in the placebo group. Infants in the two groups did not differ significantly in baseline characteristics. However, a statistically insignificant difference was noted in the mean BW of infants in the erythromycin group compared to the placebo group [mean (SD) of 806 (216) vs. 981 (285) g, p = 0.18], which might be attributed to the trend toward larger number of small-for-gestational age infants in the erythromycin group [4/13 (31%) vs. 1/11 (9%), p = 0.22]. Infants in the erythromycin group and those in the placebo group were similar in age at initiation of feeds [mean (SD) of 5.5 (3.6) vs. 6.3 (3.7) days, p = 0.90], age at study entry [mean (SD) of 19.7 (9.0) vs. 17.3 (5.3) days, p = 0.77], gestational age at study entry [mean (SD) of 29.9 (1.4) vs. 30.0 (2.6) weeks, p = 0.88], and volume of feeds at study entry [median (SEM) of 19.6 (4.1) vs. 19.6 (2.8) ml/kg/day, p = 0.42].

Madani 2004: Twenty-nine infants were enrolled in the erythromycin group, and 28 in the control group. Infants in the two groups did not differ in baseline characteristics. Infants in the erythromycin group and the control group were started on enteral feeds at similar age [mean of 3.8 vs. 3.0 days, p = 0.27].

Nuntnarumit 2006: Forty-six infants meeting the inclusion criteria were enrolled. That included 42 infants < 32 weeks and four infants greater than/or equal to 32 weeks. Twenty-three infants each were allocated to the erythromycin and the placebo group. There was no significant difference in the baseline characteristics between the two groups. Infants in the erythromycin and placebo groups were enrolled at a similar age [median (IQR) of 7 (6 - 8) days vs. 6 (6-8) days, p = 0.41]. The volume of feeds at study entry, although not statistically significant, was higher in the erythromycin group compared to the placebo group [median (IQR) of 25 (9 to 40) vs. 15 (7 to 31) ml/kg/d, p = 0.17]. A similar, statistically insignificant trend was seen in the percentage of infants fed breast milk, where the percentage was higher in the erythromycin group compared to the placebo group (39% vs. 17%, p = 0.19). However, the type of feeds was deemed an insignificant independent variable by a Cox regression analysis model.

2. Time to establish full enteral feeds

The three studies that used low dose erythromycin (Cairns 2002; ElHennawy 2003; Aly 2007) failed to show any significant difference between erythromycin and placebo in the times to establish full feeds in preterm infants < 32 weeks' gestation with feeding intolerance. In the study by Cairns (Cairns 2002), no significant difference in times to full enteral feeds between the erythromycin and the placebo group was found [mean (SD) of 13.6 (10.1) vs. 16.4 (7.1) days, mean difference adjusted for strata was -2.7 days; 95% confidence interval (CI) -7.5 to 2.2, p = 0.27]. The study by ElHennawy (ElHennawy 2003) found no significant difference in the number of days to reach full enteral feeds [mean (SD) of 31 (15) vs. 36 (16) days, p > 0.05] and full oral feeds [mean (SD) of 54 (27) vs. 57 (25) days, p > 0.05 ] between the erythromycin and the placebo group. In the study by Aly (Aly 2007), erythromycin use was not associated with an earlier achievement of full feeds in infants born less than/or equal to 32 weeks' gestation [mean (SD) 18.7 (8.1) vs. 20.7 (6.1) days, p=0.5]. While the first two studies (Cairns 2002; ElHennawy 2003) included only preterm infants < 32 weeks' gestation, the study by Aly (Aly 2007) is the only study that included infants > 32 weeks' gestation, and, in a subgroup analysis, found that erythromycin was associated with a significantly earlier achievement of full enteral feeds compared to placebo [mean (SD) of 10.5 (4.1) vs. 16.3 (5.7) days, p = 0.01] in that gestational age group.

For studies using high dose erythromycin (Ng PC 2001; Ng SC 2003; Madani 2004; Nuntnarumit 2006), the treatment effect of erythromycin compared to placebo on time taken to establish full feeds in preterm infants was not consistently demonstrated. In the study by Ng PC (Ng PC 2001), infants in the erythromycin group took a significantly shorter time to achieve 50% of enteral feeds [median (IQR) of 3.5 (2 to 7) vs. 6 (4 to 11.5) days, p < 0.05], 75% of enteral feeds [median(IQR) of 8.5 (6 to 19) vs. 13 (9 to 22) days, p < 0.05 ] and full enteral feeds [median (IQR) of 13.5 (8 to 22) vs. 25 (16 to 33) days, p < 0.0001] than those in the placebo group. The study by Nuntnarumit (Nuntnarumit 2006) found similar results, with infants in the erythromycin group taking a significantly shorter time to achieve full feeds than those in the placebo group [median (IQR) 7 (6 to 9) days vs. 13 (9 to 15) days, p < 0.001]. However, the study by Ng SC (Ng SC 2003) found no statistically significant effect of erythromycin in the number of days to achieve full enteral feeds (130 ml/kg/d) compared with placebo [mean (SEM) of 24.9 (2.9) vs. 30.8 (4.1) days, p = 0.17]. The age at full feeds were not different between groups as well [mean (SD) of 46.6 (18) vs. 52.1 (17.5) days, p = 0.37]. The study by Madani (Madani 2004), the only study among the four with subgroup analyses for infants < and greater than/or equal to 32 weeks' gestation, found that erythromycin was associated with a significantly earlier achievement of full enteral feeds compared to placebo only in those born greater than/or equal to 32 weeks' gestation [mean (SD) of 9.2 (1.5) vs. 13.5 (6.3) days, p = 0.03]. The studies by Ng PC, Ng SC, and Nuntnatumit (Ng PC 2001; Ng SC 2003; Nuntnarumit 2006) included preterm infants with a wide range of gestational age, although the majority of subjects in these studies were < 32 weeks' gestation at birth. Contrary to these three studies, Madani (Madani 2004) found that erythromycin was not associated with an earlier achievement of full feeds in preterm infants < 32 weeks groups [mean (SD) of 18.3 (11.4) vs. 17.6 (6.9) days, p = 0.84].

Meta-analysis of the primary outcome was not appropriate because all seven studies defined feeding intolerance differently; therefore, the patients chosen for each study were inherently different and the primary outcome measure cannot be combined for analysis.

3. Duration of TPN

Three studies (Aly 2007; Ng SC 2003; Nuntnarumit 2006) reported on this outcome. Aly (Aly 2007) used low dose erythromycin and found that erythromycin was associated with a shorter duration of TPN but only in infants > 32 weeks' gestation [mean (SD) of 5.5 (3.3) vs. 9.4 (4.8) days in those > 32 weeks, p = 0.03 and 12.6 (6.3) vs. 12.6 (5.4) days in those less than/or equal to 32 weeks, p = 0.9]. The other two studies (Ng SC 2003; Nuntnarumit 2006) that used high dose erythromycin and studied infants mostly < 32 weeks found no difference in this outcome between groups [mean (SD) of 39.4 (13.8) vs. 43.3 (18.3) days (p=0.74) in Ng SC (Ng SC 2003); and median (IQR) of 13 (11 to 15) vs. 17 (13 to 25) days (p = 0.03) in Nuntnatumit (Nuntnarumit 2006)].

Meta-analysis of this secondary outcome was not performed because the three studies defined feeding intolerance differently, so comparing the duration of TPN in the three studies or combining such data for meta-analysis was not appropriate.

4. TPN-related cholestasis

Four studies (Aly 2007; Ng PC 2001; Ng SC 2003; Nuntnarumit 2006) reported on cholestatic jaundice as an outcome. However, only in one study (Ng PC 2001) was cholestatic jaundice defined (as conjugated bilirubin level >34 mmol/L). None of the studies noted any significant difference in the incidence of cholestatic jaundice between the erythromycin and the placebo group [2 (6.7%) vs. 4 (13.3%) (p=NS) in Aly (Aly 2007); 5 (19%) vs. 10 (35%) with conjugated bilirubin > 34 mmol/L (p = NS) in Ng PC (Ng PC 2001); 4 (31%) vs. 7 (64%) (p = 0.113) in Ng SC (Ng SC 2003); 3 (13%) vs. 2 (9%) (p = 1.00) in Nuntnarumit (Nuntnarumit 2006)].

The lack of information in how TPN cholestasis was defined made it inappropriate to combine this outcome for meta-analysis.

5. Weight gain

The four studies that reported on weight gain (ElHennawy 2003; Aly 2007; Ng SC 2003; Nuntnarumit 2006) showed no significant difference between infants in the erythromycin group versus those in the placebo group. Using low dose erythromycin, the study by ElHennawy (ElHennawy 2003) showed no significant difference in weight at study day eight between the erythromycin and placebo group [mean (SD) of 1625 (430) vs. 1611 (476) grams, p > 0.05]; similarly, in the study by Aly (Aly 2007), the erythromycin and placebo groups did not differ in weight gain since enrollment for study infants in either gestational age strata (less than/or equal to 32 or > 32 weeks). Using high dose erythromycin, Ng SC (Ng SC 2003) showed no difference between the erythromycin and placebo group in age when birth weight was regained [mean (SD) of 12.8 (4.4) vs. 16.8 (6.2), p = 0.11]; similarly, the study by Nuntnarumit (Nuntnarumit 2006) showed no difference between groups in days to regain birth weight [median (IQR) of 11 (10 to 14) vs. 12 (11 to 15) days, p = 0.49] and in the weight at discharge [median (IQR) of 2170 (1987 to 2587) vs. 2560 (2130 to 3600) grams, p = 0.06].

Meta-analysis of this outcome was not possible because weight gain was measured differently in the four studies. In addition, patients in the four studies were different because feeding intolerance was defined differently in these studies.

6. Adverse effects associated with the use of erythromycin

The six studies (ElHennawy 2003; Aly 2007; Ng PC 2001; Ng SC 2003; Madani 2004; Nuntnarumit 2006) that reported on adverse effects related to the use of erythromycin found no difference in incidence between the erythromycin and placebo groups. The study by Ng PC (Ng PC 2001) specifically reported no difference between erythromycin and placebo group in the QT interval during treatment [median (IQR) of 0.36 (0.35 to 0.4) vs. 0.38 (0.35 to 038) ms, p = NS]. No case of hypertrophic pyloric stenosis was reported in any of the studies.

In terms of septicemia, four studies (Aly 2007; Ng PC 2001; Madani 2004; Nuntnarumit 2006) reported on this outcome and found no significant difference between erythromycin and placebo group in incidence of sepsis 11 (36.7%) vs.15 (50%) of study infants (p = NS) in Aly (Aly 2007); 11 vs. 9 episodes of bacterial and fungal septicemia in Ng PC (Ng PC 2001); 5 (17%) vs. 7(25%) infants (p = NS) in Madani (Madani 2004); 3 (13%) vs. 4 (17%) of study infants (p = 1.00) in Nuntnarumit (Nuntnarumit 2006)]. Meta-analysis of this outcome from the four trials showed no difference in the incidence of septicemia (typical risk ratio 0.83; 95% confidence interval 0.47 to 1.45; typical risk difference -0.04; 95% confidence interval -0.17 to 0.08)

7. NEC

Five studies (Aly 2007; Ng PC 2001; Ng SC 2003; Madani 2004; Nuntnarumit 2006) reported on the incidence of NEC, but only one study (Nuntnarumit 2006) clearly defined NEC (as > Bell stage I). None of the five studies reported a significant difference in the incidence of NEC between the erythromycin and placebo group 3 (10%) vs. 4 (13.3%) (p = NS) in Aly (Aly 2007); 2 (7%) vs. 3 (11%), (p = NS) in Madani (Madani 2004); 1 (4%) vs. 4 (13%), (p = 0.61) in Nuntnarumit (Nuntnarumit 2006)]. The study by Ng PC (Ng PC 2001) reported no NEC events and Ng SC (Ng SC 2003) reported one infant in the placebo group who developed NEC one month after full feeds were attained.

Meta-analysis of this outcome was not appropriate. The inclusion criteria of feeding intolerance was defined differently in all five studies, thus the risk of developing NEC in these patients might also be different.

8. Duration of hospitalization

Five studies (Aly 2007; Ng PC 2001; Ng SC 2003; Madani 2004; Nuntnarumit 2006) reported on this outcome. Four of the five studies [all except Madani (Madani 2004)] failed to show any significant difference in length of hospital stay between the erythromycin and placebo group 33.2 (14) vs. 29.2 (13.8) days, p = 0.48 for GA less than/or equal to 32 weeks strata; 18.3 (13.9) vs. 27.8 (10.4) days, p = 0.07 for GA > 32 weeks strata in Aly (Aly 2007); median (IQR) of 73 (64 to 97) vs. 86 (64 to 109) days (p = NS) in Ng PC (Ng PC 2001); mean (SD) of 98.3 (35.9) vs. 99.6 (58.6) days (p = 0.68) in Ng SC (Ng SC 2003); median (IQR) of 46 (24 to 74) vs. 60 (43 to 89) days (p=0.07) in Nuntnarumit (Nuntnarumit 2006). In the study by Madani (Madani 2004), sub-group analysis of the two gestational age strata showed that infants greater than/or equal to 32 weeks' gestation who received erythromycin were discharged at a significantly earlier age [mean (SD) of 12.9 (3.2) vs. 22.3 (8.9) days, p = 0.003]. However, for infants < 32 weeks' gestation, those who received erythromycin and those in the control group were discharged at a similar age [mean (SD) of 28.3 (10.8) vs. 26.4 (11.1) days, p = 0.64].

Meta-analysis of this outcome was not appropriate because the inclusion criteria of feeding intolerance was defined differently in all five studies, so the factors contributing to the hospital length of stay might also be different.

9. Other outcomes
Gastric residuals or feeds held

Three studies reported gastric residuals as a secondary outcome (ElHennawy 2003; Aly 2007; Nuntnarumit 2006). Using low dose erythromycin, ElHennawy (ElHennawy 2003) reported no significant difference between the erythromycin and placebo group in number of gastric residuals over 1 ml 2 ½ hrs post-feed [mean (SD) of 16 (8) vs. 21 (11) episodes, p > 0.05], and the number of hours where feeding was held [mean (SD) of 42 (44) vs. 37 (38) hours, p > 0.05 ]. However, using a similar dose of erythromycin, Aly (Aly 2007) found fewer episodes of significant gastric residuals (> 30% of previous 6 hour feed volume) in those treated with erythromycin but only in those born > 32 weeks [median (IQR) of 0 (0 to6) vs. 2 (0 to 8) episodes, p = 0.03] and not in those less than/or equal to 32 weeks [median (IQR) of 2 (0 to 6) vs. 2.5 (0 to 8) episodes, p = 0.77]. Using high dose erythromycin, Nuntnarumit (Nuntnarumit 2006) reported a composite outcome of the number of feeds held/significant gastric residuals (>50% of feed) and found a significantly smaller number in the erythromycin group compared with the placebo group [median (IQR) 1 (0 to 2) vs. 9 (2 to 13), p < 0.001].

Physiologic outcomes

The study by ElHennaway (ElHennawy 2003) reported gastrointestinal physiologic outcomes. Using low dose erythromycin, the study showed no significant difference between the erythromycin and placebo group in rate of gastric emptying [mean (SD) of 47 (23) vs. 32 (20)% of a feed, 20 minutes after feeding, p = NS; 71 (20) vs. 64 (26)% of a feed, one hr after feeding, p = NS ], and whole gut transit time [mean (SD) of 83 (48) vs. 78 (77) p = NS. Antroduodenal motor contractions showed similar characteristics in both groups. Although the number of antral motor contractions was higher in the erythromycin group [numbers not shown, p < 0.02], they were similar after drug administration and after feeding [numbers not shown, p = NS]. Within the erythromycin group, the number of antral contractions varied significantly (ANOVA for repeated measures F = 10.0; p < 0.001).

The study by Ng SC (Ng SC 2003) evaluated the effects of high dose erythromycin on gastroesophageal reflux and showed no difference in the reflux indices before and after the study between the erythromycin and placebo groups [mean (SD) of 7.3 (15.5) vs. 13.6 (17.3)% before, p = 0.72 and 4.3 (7.1) vs. 0.3 (0.6)% after, p = 0.07]; the percentage of infants with a reduction in reflux in each group as a result of the study drug also did not differ significantly [23% vs. 36%, p = 0.57].

Discussion

This systematic review summarizes the use of erythromycin as a prokinetic agent in preterm infants with or at risk of feeding intolerance at both high and low doses. Among included studies, however, there exist great heterogeneity in study design and methodology, particularly in terms of the study population chosen, dose and duration of erythromycin used, the primary and secondary outcomes measured, the definition of outcomes measured, and in the method with which data were analyzed and reported. An example was the vast differences in definition of feeding intolerance in all of the treatment studies; without such uniform criteria for inclusion, the patient population studied was incomparable, rendering it impossible (and inappropriate) to combine outcomes amongst these studies for meta-analyses.

Based on the currently available information, it is difficult to draw any clear conclusion on the effectiveness of erythromycin as a prokinetic agent in preterm infants. Nevertheless, a few observations were made, which may provide some insights into how future research directions in this area should be focused.

Neither the prevention nor the treatment strategy as outlined in this review has demonstrated a consistent effect of erythromycin in the primary outcome of time required to achieve full feeds. It is unclear from this review whether erythromycin works better if used prophylactically or in those who had established feeding intolerance.

There was significant variability in the dosage of erythromycin used in all the included studies. This review has attempted to further categorize the studies by the dose range of erythromycin used (low dose 3 to 12 mg/kg/day or high dose >12 mg/kg/day). Although neither dose range has consistently been shown to be efficacious, studies using higher doses of erythromycin seem to have reported more success in preterm infants with feeding intolerance. Three of these studies (Ng PC 2001; Madani 2004; Nuntnarumit 2006) using erythromycin at doses between 40 to 50 mg/kg/day reported a statistically significant effect on feeding tolerance, and one study using erythromycin at a slightly smaller dose (but still considered high dose) of 15 mg/kg/day (Ng SC 2003) showed a trend toward improved feeding tolerance. Similar effect of erythromycin at higher doses has previously been observed in uncontrolled studies (Kubota 1994; Ng 1997; Su 1998), where preterm infants with feeding intolerance were able to achieve full enteral feeds within one to two weeks of erythromycin treatment. These findings seem contradictory to animal studies (Itoh 1984a; Itoh 1984b; Zara 1985; Otterson 1990) and human adult studies (Annese 1992; Tack 1992; Coulie 1998) where erythromycin's prokinetic effects were demonstrated primarily at low doses. However, one must consider that the clinical effect of a given dose of erythromycin is dependent on highly complex pharmacokinetic and metabolic functions and the presence of multiple confounders in preterm infants.

Another observation in this review regarded the relationship between the gestational age at birth and the response to the prokinetic effect of erythromycin. Among all the included studies in this review, only two (Aly 2007; Madani 2004) had separate analyses of outcome data for gestational age subgroups. The study by Aly (Aly 2007) showed that, compared to placebo, erythromycin was effective in achieving full enteral feeds earlier, with fewer episodes of significant gastric residuals, and less days on TPN, but only in the subgroup of infants > 32 weeks' gestation. Similarly, Madani (Madani 2004) found that erythromycin was effective in earlier achievement of full enteral feeds and a shorter length of hospital stay, but only in those greater than/or equal to 32 weeks’ gestation. This finding supports the previous observation that the propagative phase III of the MMC is not well developed until 32 weeks' GA (al Tawil 1996). As the prokinetic effect of erythromycin is based on stimulation of the propagative phase III of the MMC (Peeters 1989), it is not surprising that erythromycin was found to be more effective in treating preterm infants > 32 weeks' GA with feeding intolerance.

In conclusion, at present, there is insufficient evidence to recommend the use of erythromycin at any dose for the prevention and treatment of feeding intolerance, especially for preterm infants less than 32 weeks' GA. Future research effort should be directed towards identifying a more precise dose range where erythromycin may be effective as prokinetic agent in preterm infants. Based on the limited number of studies included in this review, a dose larger than what was defined a priori (3 to 12mg/kg/day) as a prokinetic dose for preterm infants at least 32 weeks' GA may need to be closely examined; longer term follow-up of study patients will also be required to establish the safety of erythromycin used in this setting.

Authors' conclusions

Implications for practice

At present, administration of erythromycin in low or high doses cannot be recommended for the treatment of feeding intolerance, or for prophylaxis against feeding intolerance in preterm infants.

Implications for research

Further studies are needed to determine whether erythromycin in lower or higher doses is effective as a prokinetic agent in preterm infants > 32 weeks' GA with feeding intolerance or at risk of developing feeding intolerance.

Acknowledgements

Dr. Sanjay Patole, Department of Neonatology, Kirwan Hospital for Women, Thuringowa, Queensland, Australia for providing data on the abstract by Almonte et al (1999).

Contributions of authors

Ng E:
Development and writing of protocol
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data independent of co-reviewer
Contacting author of one trial for additional data
Entering data into Revman
Writing of result section
Writing of discussion section

Shah V:
Development and writing of protocol
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data independent of co-reviewer
Verifying data entered into Revman
Help with writing of results and discussion

Declarations of interest

  • None noted.

Differences between protocol and review

The initial inclusion criteria from the protocol were to only include studies where low dose erythromycin (3 to 12 mg/kg/day) was used for treatment of feeding intolerance in preterm infants. However, literature search has since identified a significant number of studies using erythromycin at doses higher than 12 mg/kg/day, and other studies used erythromycin as prophylaxis for preterm infants at risk of feeding intolerance. A post hoc decision was made to include these studies in the updated review. Studies of erythromycin use for prevention of feeding intolerance (prevention studies) and those for treatment of feeding intolerance (treatment studies) were separately considered according to the criteria listed below. Where possible, subgroup analyses were performed for data from studies using erythromycin at low and high doses.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Aly 2007

Methods

Single center, double-blind, placebo-controlled trial.

Blinding of randomization: Yes
Blinding of intervention: Yes
Blinding of outcome measures: Yes
Complete follow up: Yes

Participants

Preterm infants < 37 wks' GA fed cow's protein-based formula who had feeding intolerance (repeated gastric residual >30% of previous 6 hr feed) were eligible.

Exclusion criteria:
Major congenital malformations, structural gastrointestinal abnormalities, birth asphyxia, presence or history of NEC, confirmed sepsis, organic abdominal illness.

60 infants were enrolled in the study.

Demographic data: values presented as mean (SD) unless otherwise indicated. (Marked with * if statistically significant different between groups)

Erythromycin group (n=30)
GA (wks): 32.2 (2.3)
BW (g): 1488 (292)
% Male: 53.3
% SGA: 13.3
% Antenatal steroids: 36.7
% with PDA: 13.3
Median (range) age (d) at enrollment: 2 (2-24)

Placebo group (n=30)
GA (wks): 32.4 (4.5)
BW (g): 1516 (298)
% Male: 53.3
% SGA: 16.7
% Antenatal steroids: 40% with PDA: 10
Median (range) age (d) at enrollment: 2 (2-10)

Interventions

Erythromycin-ethyl-succinate (Abbott Laboratories) diluted to 4mg/ml with sterile water

Placebo: Equal volume of normal saline

Drug dose: 1mg/kg/dose every 8 hours
Route: oral
Treatment duration: until full feeds (150ml/kg/d) was achieved.

Outcomes

Primary outcome: time to establish full enteral feeds (150ml/kg/d) for at least 24 hrs

Secondary outcomes: number of episodes of feeding intolerance (as defined), weight gain after enrollment into trial, duration of TPN, incidence of NEC, length of hospital stay.

Adverse effect of erythromycin: Monitored during study

Notes

Feeding was advanced according to a standardized protocol.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Cairns 2002

Methods

Multi-center, double-blind, randomized, placebo-controlled trial.

Blinding of randomization: Yes
Blinding of intervention: Yes
Blinding of outcome measures: Cannot tell
Complete follow up: Yes

Participants

Preterm infants < 37wks GA who failed to initiate or advance enteral feeds despite attempts for 3 or more days were eligible.

Exclusion criteria: infants with suspected or confirmed necrotizing enterocolitis or ileus were excluded.

60 infants were enrolled in the study.

Demographic data: Values presented as mean (SD). (Marked with * if statistically significant different between groups)

Erythromycin group: n= 32
GA: No data
BW: No data
Age at start of feeding: No data
GA at study entry: 29.4 (1.7) wks
Time from start of feeds to study entry: 8 (4.7) days

Placebo group: n= 28
GA: No data
BW: No data
Age at start of feeding: No data
GA at study entry: 29.1 (1.9) wks
Time from start of feeds to study entry: 8.6 (6.6) days

Interventions

Erythromycin or normal saline placebo

Drug dose: 3mg/kg/dose given every 6 hours
Route: Intravenous
Duration of treatment: Until full enteral feeding (150ml/kg/d) was achieved.

Outcomes

Primary outcome: Time to achieve full enteral feeds (150ml/kg/day)

Secondary outcomes: No data

Adverse effects associated with erythromycin use: No data.

Notes

Feeding was advanced according to a standardized protocol.

Use of other prokinetic agents: Not specified

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

ElHennawy 2003

Methods

Single center, randomized, double-blind, placebo-controlled trial.

Blinding of randomization: Yes
Blinding of intervention: Yes
Blinding of outcome measures: Yes
Complete follow up: Yes

Participants

Preterm infants 29-36 wks GA and 900-2000 g BW who failed to achieve full (150ml/kg/d) enteral feeding within 8 days of initiation and had intravenous access were eligible.

Exclusion criteria:
Necrotizing enterocolitis
Sepsis within 48hrs of enrollment
Hemodynamic instability requiring dopamine or epinephrine
Intestinal myopathy, hepatitis or liver failure
Cardiac arrhythmia
Use of opioids
Congenital/chromosomal abnormalities
Continuous feeding

27 infants were enrolled in the study. One infant in the erythromycin group developed ileal stricture after one treatment dose and did not complete the study.

Demographic data: Values presented as mean (SD). (Marked with * if statistically significant different between groups)

Erythromycin group: n= 15
GA: 29(3) wks
BW: 1178 (416) g
Age at start of feeding: 8(12) d
Age at study entry: 24(13) d
Feed volume at study entry: 36(39) ml/kg/d
Wt at study entry: 1430(360) g

Placebo group: n= 12
GA: 29(2) wks
BW: 1212 (527) g
Age at start of feeding: 5(4) d
Age at study entry: 26(13) d
Feed volume at study entry: 28(21) ml/kg/d
Wt at study entry: 1320(560) g

Interventions

Erythromycin-ethyl-succinate (EryPed, Abbott Laboratories) diluted 1:10 in Oral-Plus suspending vehicle

Placebo: Ora-plus (Paddock Laboratories) with yellow food coloring.

Drug dose: 1.5mg/kg/dose of erythromycin or equal volume of placebo every 6 hours, 30 minutes prior to a feed
Route: via orogastric tube
Duration of treatment: 8 days (study day 1-day 8)

Outcomes

Primary outcome: Feeding volume by study day 8

Secondary outcomes:
Antroduodenal motor contractions (using a neonatal antroduodenal manometry system) were assessed on day 0 with fasting, erythromycin/placebo administration, and a 10ml/kg feed
Gastric emptying (using 10ml/kg of formula containing 1% polyethylene glycol) according to the method of George on day 0
Whole gut transit time (using 2ml of carmine red dye 20 minutes after a feed) on day 0
Weight on study day 8
Number of infants reaching full enteral feeding by study day 8
Number of residuals (>1ml gastric aspirate 2 ½ hrs after a feed) during treatment
Number of stools during treatment
Number of hrs where feeds were held due to feeding intolerance during treatment
Postnatal age at full enteral feeds
Postnatal age at full oral feeds

Adverse effects associated with erythromycin use: Paroxysomal loud crying >30 minutes not responding to holding, prone-lying, or feeding; recurrent vomiting with >10% wt loss; watery diarrhea; frank bloody stool; cardiac arrhythmias

Notes

Feeding was advanced according to a protocol

Feeding intolerance was defined as severe abdominal distention (>15% baseline abdominal girth), gastric residuals >25% of feed volume, or frank blood in stool

Other prokinetic agents: Not specified

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Madani 2004

Methods

Randomized controlled trial.

Blinding of randomization: Can't tell
Blinding of intervention: Can't tell
Blinding of outcome measures: Can't tell
Complete follow up: Yes

Participants

Preterm infants < 36wks GA who fail to tolerate half (75ml/kg/d) of the full enteral feeds within 5 days of initiation of feeding were eligible.

Exclusion criteria:
Hypoxic injury
Cyanotic heart disease
Previous gastrointestinal surgery
Intestinal atresia or other congenital gastrointestinal conditions

57 infants were enrolled in the study.

Demographic data: Values presented as mean (range) or mean (SD) as indicated (Marked with * if statistically significant different between groups).

Erythromycin group: n=29
GA: mean(range) 30.9(28-34) wks
BW: mean(range) 1292(830-1660) g
%Male: 41
% Antenatal steroids: 24
Age at start of feeding: mean of 3.8 days

Control group: n=28
GA: mean (range) 31.5 (28-35) wks
BW: mean (range) 1371 (900-1770) g
%Male: 61
% Antenatal steroids: 21
Age at start of feeding: mean of 3.0 days

Interventions

Erythromycin-ethyl-succinate (no other details given)

Placebo: The control group did not receive placebo.

Drug dose: 12.5mg/kg every 6 hours
Route: oral
Duration of treatment: From study entry for a maximum of 10 days or until full enteral feeding (150ml/kg/d) was achieved.

Outcomes

Primary outcome: Days required to achieve full enteral feeding (150ml/kg/day), with subgroup analyses done on this outcome measure (greater than/or equal to 32wks, and < 32wks)

Secondary outcomes:
Age at discharge from hospital (with subgroup analyses done on this outcome measure (greater than/or equal to32wks, and < 32wks)
Incidence of necrotizing enterocolitis

Adverse effects associated with erythromycin use:
Stool colonization
QT interval
Pyloric stenosis

Notes

All infants were fed according to a standard feeding protocol

Other prokinetic agents: Infants were not given any other prokinetic agent during the study period.

Risk of bias table
Item Judgement Description
Allocation concealment? Unclear

B - Unclear

Ng PC 2001

Methods

Single-center, double-blind, randomized, placebo-controlled trial.

Blinding of randomization: Yes
Blinding of intervention: Yes
Blinding of outcome measures: Cannot tell
Complete follow up: Yes

Participants

Preterm infants with BW < 1500g who is receiving less than half of the total daily fluid intake by enteral route by day 14 were eligible.

Exclusion criteria:
Lethal congenital anomalies
Anatomical gastrointestinal abnormalities
Infants who had major gastrointestinal surgery in the first 2 weeks of age
Necrotizing enterocolitis
Cyanotic congenital heart disease

56 infants were enrolled in the study.

Demographic data: All values presented as median (quartile range) unless specified otherwise. (Marked with * if statistically significant different between groups)

Erythromycin group: n=27
GA: 29.6(28.6-30.7) wks
BW: 1180 (985-1395) g
% Antenatal steroids: 89
%Male: 56
Age at start of feeding: 6(4-11) days
Volume of feeds at enrollment: 43(17-58) ml/kg/d
% with patent ductus arteriosus: 33
% Treated with indomethacin: 37
% Received exchange transfusion: 7

Placebo group: n=29
GA: 29.3(27.5-31.0) wks
BW: 1160(1004-1389) g
% Antenatal steroids: 86
%Male: 48
Age at start of feeding: 8(5-11) days
Volume of feeds at enrollment: 51(39-68) ml/kg/d
% with patent ductus arteriosus: 45
% Treated with indomethacin: 41
% Received exchange transfusion: 7

Interventions

Erythromycin-ethyl-succinate (EryPed, Abbott Laboratories) diluted to 12.5mg/ml with sterile water

Placebo: normal saline in equal volume

Drug dose: 12.5mg/kg dose every 6 hours mixed completely into milk feed
Route: via enteral route
Duration of treatment: Start day 15 of life for a 14-day treatment course

Remark: If feeding was held, the study drug was also held until feeding resumed

Outcomes

Primary outcome: Time taken to establish 50%, 75% and full enteral feeds

Secondary outcomes:
Cholestatic jaundice
Necrotizing enterocolitis
Duration of hospital stay
Mortality

Adverse effects associated with erythromycin use:
QTc interval during treatment
Pyloric stenosis
Sepsis (gram positive, gram negative, fungal)
Stool colonization during and 4 weeks after treatment finished

Notes

Enteral and parenteral nutrition was advanced according to a set protocol

Other prokinetic agents: Use of all other prokinetic agent was not allowed during the trial period

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Ng SC 2003

Methods

Single center, randomized, double-blind, placebo-controlled trial

Blinding of randomization: Yes
Blinding of intervention: Yes
Blinding of outcome measures: Cannot tell
Complete follow up: Yes

Participants

Preterm infants less than/or equal to 1500g who failed to initiate minimal feed by 1wk or failed to reach 20ml/kg/d of enteral feeds 1 wk after initiation of feeds were eligible.

Exclusion criteria:
Overwhelming sepsis
Major congenital anomalies
Growth restriction with evidence of absent or reverse end-diastolic flow in umbilical Dopplers in-utero

24 infants were enrolled in the study.

Demographic data: Values presented as mean (SD) unless stated otherwise (Marked with * if statistically significant different between groups)

Erythromycin group: n=13
GA: 27.1(1.9) wks
BW: 806.3(215.6) g
% Growth restricted with BWless than/or equal to 3rd percentile: 31
% antenatal steroids (greater than/or equal to 1 course): 62%
% postnatal steroids (greater than/or equal to 3 days): 38%
Days on xanthine derivatives: 51.2(28.8) d
Age at start of feeds: 5.5(3.6) d
Age at study entry: 19.7(9.0) d
GA at study entry: 29.9(1.4) wks
Feed volume at enrollment: Median (SEM) of 19.6(4.1) ml/kg/d

Placebo group: n=11
GA: 27.5(2.9) wks
BW: 981.4(285.4) g
% Growth restricted with BWless than/or equal to 3rd percentile: 9
% antenatal steroids (greater than/or equal to 1 course): 45%
% postnatal steroids (greater than/or equal to 3 days): 27%
Days on xanthine derivatives: 45.2(39.5) d
Age at start of feeds: 6.3(3.7) d
Age at study entry: 17.2(5.3) d
GA at study entry: 30.0(2.6) wks
Feed volume at enrollment: Median (SEM) of 19.6(2.8) ml/kg/d

Interventions

Erythromycin-ethyl-succinate powder reconstituted with water to 10mg/ml

Placebo: D5W with 0.1% saline and 5% novolose.

Drug dose: 5mg/kg every 8 hours
Route: oral
Duration of treatment: from study entry to 1 week after full feeds (130ml/kg/d) achieved

Outcomes

Primary outcome: Days to achieve full enteral feeds

Secondary outcomes:
Time to regain birth weight
Days of total parenteral nutrition
Incidence of cholestatic jaundice
Incidence of necrotizing enterocolitis
Glycerin suppositories used
duration of hospital stay
Reflux index (percentage of monitored time with esophageal pH < 4 for 15 or more seconds) before and after the study
Number of infants with reduction in reflux

Adverse event associated with the use of erythromycin
Cardiac arrhythmias
Pyloric stenosis
Sepsis with multi-resistant organisms

Notes

Feeding protocol: Enteral and parenteral nutrition was initiated and advanced according to a protocol.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Nuntnarumit 2006

Methods

Multicenter, randomized, double-blind, placebo-controlled trial.

Blinding of randomization: Yes
Blinding of intervention: Yes
Blinding of outcome measures: Yes
Complete follow up: Yes

Participants

Preterm infants < 35 wks GA and BW < 1800g who were at least 5 days old and clinically stable, and with feeding tolerance (residual >50% of previous feed for >2 occasions in 24 hrs) were eligible.

Exclusion criteria:
Major congenital anomalies, Suspected or proven NEC within 7 days of onset of feeding intolerance, major gastrointestinal surgery within 2 wks, cyanotic heart disease, metabolic or electrolyte disturbance. Infants treated with fentanyl, indomethacin, pancuronium or vecuronium at the onset of feeding intolerance were also excluded.

46 infants were enrolled in the study.

Demographic data: values presented as median (quartile range) or percentage (Marked with * if statistically significant different between groups)

Erythromycin group: n=23
GA (wks): 30 (29-32)
BW (g): 1100 (870-1500)
% Male: 39
% Small for GA: 30
% Antenatal steroids: 65
% with PDA: 52
% Indomethacin use: 48
% Fed with breast milk: 39
Volume of feed at enrollment (ml/kg/d): 25(9-40)

Placebo group: n=23
GA (wks): 29 (28-31)
BW (g): 1065 (940-1270)
% Male: 56
% Small for GA: 13
% Antenatal steroids: 74
% with PDA: 73
% Indomethacin use: 61
% Fed with breast milk: 17
Volume of feed at enrollment (ml/kg/d): 15 (7-31)

Interventions

Erythromycin-ethyl-succinate (Erysil, Siam Pharmaceutical Ltd, Bangkok, Thailand) diluted to 40mg/ml with sterile water

Placebo: manufactured liquid with same appearance and ingredients except for active drug

Drug dose: 10mg/kg given every 6 hrs for 2 days, followed by 4mg/kg every 6 hrs for 5 days
Route: orally
Duration: 7 days

Outcomes

Primary outcome: Days to achieve full enteral feeds (150ml/kg/d).

Secondary outcomes:
Incidence of NEC, septicemia, length of hospital stay;
Adverse effect associated with erythromycin use: elevated liver enzymes, hypertrophic pyloric stenosis;
Complications of TPN use: Cholestasis, catheter-related sepsis

Notes

Feeding protocol: Enteral and parenteral nutrition was initiated and advanced according to a protocol.

Use of prokinetic agents: not allowed.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Oei 2001

Methods

Single center, double-blind, randomized, placebo-controlled trial.

Blinding of randomization: Yes
Blinding of intervention: Yes
Blinding of outcome measures: Cannot tell
Complete follow up: Yes

Participants

Preterm infant less than/or equal to 32 wks who are initiating enteral feeds were eligible.

Exclusion criteria:
Major congenital malformation
Perinatal hypoxia
Necrotizing enterocolitis
Proven sepsis
Pathologic abdominal conditions
Periventricular hemorrhage > grade I

50 infants were enrolled in the study.

Demographic data: Values presented as mean (SD) unless stated otherwise. (Marked with * if statistically significant different between groups)

Erythromycin group: n=22
GA: 28.6(2.2) wks
BW: 1226(380) g
% Requiring ventilation: 86
Median (range) age extubated: 5 (0-67)

Placebo group: n=21
GA: 29.3(1.7) wks
BW: 1355(228) g
% Requiring ventilation: 74
Median (range) age extubated: 3 (0-53)

Interventions

Erythromycin-ethyl-succinate 10mg/ml suspension (Abbott Australasia)

Placebo: Prepared with an identical base as erythromycin

Drug dose: 2.5mg/kg/dose every 6 hours, 30 minutes prior to a feed
Route: enterally
Duration of treatment: from initiation of feeds for 10 days

Outcomes

Primary outcome: Days to reach full enteral feeds (150ml/kg/day)

Secondary outcomes:
Number of vomiting episodes during treatment period
Number of episodes with gastric aspirate>30% of previous feed
Number of bile-stained aspirates during treatment period
Days on total parenteral nutrition

Adverse effects associated with erythromycin use:
Theophylline toxicity
Abnormal liver function tests
Sepsis
Necrotizing enterocolitis

Notes

Feeding protocol: Enteral and parenteral nutrition was advanced according to a set protocol

Other prokinetic agents: Reported

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Patole 2000

Methods

Randomized, double-blind, placebo-controlled trial.

Blinding of randomization: Yes
Blinding of intervention: Yes
Complete follow up: Yes
Blinding of outcome measure: Yes

Participants

Preterm infants less than/or equal to 32 wks GA who were ready to commence enteral feeding were eligible.

Exclusion criteria: Presence of congenital anomaly, failure to obtain consent.

73 infants were enrolled in the study.

Demographic data: values presented as median (interquartile range) or percentage. (Marked with * if statistically significant different between groups)

Erythromycin group: n=36
GA (wks): 29 (27-30)
BW (g): 1232 (906-1493)
% Male: 53
% antenatal steroids: 86
% IUGR: 14
% requiring ventilation: 89
% with PDA: 36
Age at start of feeding (days): 5 (3-7.7)

Placebo group: n=37
GA (wks): 30 (27-31)
BW (g): 1280 (890-1562)
% Male: 49
% antenatal steroids: 87
% IUGR: 14
% requiring ventilation: 86
% with PDA: 40
Age at start of feeding (days): 5 (3-7.5)

Interventions

Erythromycin - ethyl -succinate (EES, 200mg/5ml, Abbott Australasia Pty Ltd)

Placebo (manufactured placebo with similar content as commercial preparation of erythromycin but without EES as active ingredient)

Drug dose: 12mg/kg/dose of erythromycin or placebo given every 6 hours
Route: via orogastric tube
Duration: from time of starting enteral feeds until full feeds of 150ml/kg/day or until 14 days of treatment were completed.

Outcomes

Primary outcome: time to establish full enteral feeds (150ml/kg/day).

Secondary outcomes:
age (days) at full feeds;
Feeding intolerance;
NEC;
Adverse effects associated with erythromycin use: sepsis, loose stool, hepatic dysfunction, cardiac arrhythmias;
Duration of hospitalization

Notes

Feeds were advanced according to a standardized protocol.

Use of other prokinetic agents was not permitted unless justified by attending neonatologist. Additional data on baseline characteristics and on secondary outcomes were provided by Dr. S. Patole.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Stenson 1998

Methods

Randomized, controlled trial.

Blinding of randomization: Yes
Blinding of intervention: No (placebo was not given)
Complete follow up: Yes
Blinding of outcome measures: can't tell

Participants

Preterm infants < 31 wks GA who were ventilated on day 1 of life were eligible.
In the original study, infants < 30 weeks GA were included.

Exclusion criteria: Presence of congenital anomaly.
76 infants were enrolled in the study.
In the original study, only 75 infants were enrolled

Demographic data: values presented as median (range) or percentage. (Marked with * if statistically significant different between groups)

Erythromycin group: n=35
GA (wks): 28(24-30)
BW (g): 1025 (590-2300)
% IUGR: 9
% Male: 51
% Breast fed: 84
% Received antenatal steroids: 63
% Received morphine: 66
% Received pancuronium: 29

Control group: n=41
GA (wks): 29 (23-30)
BW (g): 1050 (500-1670)
% IUGR: 7
% Male: 73
% Breast fed: 86
% Received antenatal steroids: 78
% Received morphine: 59
% Received pancuronium: 27

Interventions

Treatment group received erythromycin infusion.

Control group did not receive a placebo.

Drug dose: 15mg/kg/dose of erythromycin given 8 hourly as intravenous infusion.
Duration: First 7 days of life.

Outcomes

Primary outcome: concentration of inflammatory cytokines (interleukins IL-1 beta and IL-8, tumor necrosis factor alpha).

Secondary outcomes: Time to establish full enteral feeds (at least 150ml/kg/day),
feed tolerance (net enteral balance)
Number of infants who had vomited
Number of infants requiring glycerin suppository for concern of delayed meconium passage
Incidence of NEC

Notes

Feeds were advanced according to the standard nursery policy.

There were no restriction on the use of prokinetic agents, although none of the infants received them.

Infants were enrolled in a randomized controlled trial of the effect of erythromycin on the concentration of inflammatory cytokines in tracheal secretions and subsequently the incidence and severity of chronic lung disease in preterm infants.
Data on feeding establishment were collected retrospectively.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Abbreviations: BW, birth weight; GA, gestational age; IUGR, intrauterine growth restriction; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; Wt, weight

Characteristics of excluded studies

Costalos 2001

Reason for exclusion

This is a randomized cross-over study using whole-gut transit time as a short term outcome after each treatment.

Costalos 2002

Reason for exclusion

This is a randomized cross-over study using gastric emptying and whole-gut transit time as short term outcomes after each treatment.

Curry 2004

Reason for exclusion

This is a randomized controlled trial of erythromycin in infants >32 wks gestation with uncomplicated gastroschisis post primary repair.

Jadcherla 2002

Reason for exclusion

This is a dose response study with enrolled infants given three different doses of erythromycin. No placebo group was included.

Nogami 2001

Reason for exclusion

Infants were not randomized. Eligible infants admitted during the pre-intervention period received no treatment, and those admitted during the intervention period received erythromycin. Blinding procedure was not performed.

Additional tables

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References to studies

Included studies

Aly 2007

Aly H, Abdel-Hady H, Khashaba M, El-Badry N. Erythromycin and feeding intolerance in premature infants: a randomized trial. Journal of Perinatology 2007;27:39-43.

Cairns 2002

Cairns PA, Craig S, Tubman R, Roberts RS, Wilson J, Schmidt B. Randomised controlled trial of low-dose erythromycin in preterm infants with feed intolerance. Pediatric Research 2002;51:379A.

ElHennawy 2003

ElHennawy AA, Sparks JW, Armentrout D, Huseby V, Berseth CL. Erythromycin fails to improve feeding outcome in feeding-intolerant preterm infants. JPGN 2003;37:281-6.

Madani 2004

Madani A, Pishva N, Pourarian Sh, Zarkesh M. The efficacy of oral erythromycin in enhancement of milk tolerance in premature infants: A randomized controlled trial. Iranian Journal of Medical Sciences 2004;29:1-4.

Ng PC 2001

Ng PC, So KW, Fung KSC, Lee CH, Fok TF, Wong E, et al. Randomised controlled study of oral erythromycin for treatment of gastrointestinal dysmotility in preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 2001;84:F177-82.

Ng SC 2003

Ng SC, Gomez JM, Rajadurai VS, Saw S, Quak S. Establishing enteral feeding in preterm infants with feeing intolerance; A randomized controlled study of low-dose erythromycin. JPGN 2003;37:554-8.

Nuntnarumit 2006

Nuntnarumit P, Kiatchoosakun P, Tantiprapa W, Boonkasidecha S. Efficacy of oral erythromycin for treatment of feeding intolerance in preterm infants. Journal of Pediatrics 2006;148:600-5.

Oei 2001

Oei J, Lui K. A placebo-controlled trial of low-dose erythromycin to promote feed tolerance in preterm infants. Acta Paediatrica 2001;90:904-8.

Patole 2000

Published and unpublished data

Almonte R, Patole SK, Kadalraja R, Muller R, Whitehall JS. Erythromycin for feed intolerance in preterm neonate: a randomised, controlled trial. Pediatric Research 1999;45:276A.

* Patole SK, Almonte R, Kadalraja R, Tuladhar R, Muller R, Whitehall JS. Can prophylactic oral erythromycin reduce time to full enteral feeds in preterm neonates? International Journal of Clinical Practice 2000;54:504-8.

Stenson 1998

* Stenson BJ, Middlemist L, Lyon AJ. Influence of erythromycin on establishment of feeding in preterm infants: observations from a randomised controlled trial. Archives of Disease in Childhood 1998;79:F212-4.

Excluded studies

Costalos 2001

Costalos C, Gavrili V, Skouteri V, Gounaris A. The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants. Early Human Development 2001;65:91-6.

Costalos 2002

Costalos C, Gounaris A, Varhalama E, Kokori F, Alexiou N, Kolovou E. Erythromycin as a prokinetic agent in preterm infants. JPGN 2002;34:23-5.

Curry 2004

Curry JI, Lander AD, Stringer MD. A multicenter, randomized, double-blind, placebo-controlled trial of the prokinetic agent erythromycin in the postoperative recovery of infants with gastroschisis. Journal of Pediatric Surgery 2004;39:565-9.

Jadcherla 2002

Jadcherla SR, Berseth CL. Effect of erythromycin on gastroduodenal contractile activity in developing neonates. JPGN 2002;34:16-22.

Nogami 2001

Nogami K, Nishikubo T, Minowa H, Uchida Y, Kamitsuji H, Takahashi Y. Intravenous low-dose erythromycin administration for infants with feeding intolerance. Pediatrics International 2001;43:605-10.

Other references

Additional references

al Tawil 1996

al Tawil Y, Berseth CL. Gestational and postnatal maturation of duodenal motor responses to intragastric feeding. Journal of Pediatrics 1996;129:374-81.

Annese 1992

Annese V, Janssens J, Vantrappen G, Tack J, Peeters TL, Willemse P, Van Cutsem E. Erythromycin accelerates gastric emptying by inducing antral contractions and improved gastroduodenal coordination. Gastroenterology 1992;102:823-8.

Aynsley-Green 1983

Aynsley-Green A. Hormones and postnatal adaptation to enteral nutrition. Journal of Pediatric Gastroenterology and Nutrition 1983;2:418-27.

Berseth 1989

Berseth CL. Gestational evolution of small intestine motility in preterm and term infants. Journal of Pediatrics 1989;115:646-51.

Berseth 1990

Berseth CL. Neonatal small intestinal motility: motor responses to feeding in term and preterm infants. Journal of Pediatrics 1990;117:777-82.

Coulie 1998

Coulie B, Tack J, Peeters T, Janssens J. Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans. Gut 1998;43:395-400.

Di Lorenzo 1990

Di Lorenzo C, Lachman R, Hyman PE. Intravenous erythromycin for postpyloric intubation. Journal of Pediatric Gastroenterology and Nutrition 1990;11:45-7.

Dworkin 1976

Dworkin LD, Levine GM, Farber NJ, Spector MH. Small intestinal mass of the rat is partially determined by indirect effects of intraluminal nutrition. Gastroenterology 1976;71:626-30.

George 1968

George, JD. New clinical method for measuring the rate of gastric emptying: the double sampling test meal. Gut 1968;9:237-42.

Honein 1999

Honein MA, Paulozzi LJ, Himelright M, et al. Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromycin: a case review and cohort study. Lancet 1999;354:2101-5.

Itoh 1984a

Itoh Z, Nakaya M, Suzuki T, Arai H, Wakabayashi K. Erythromycin mimics exogenous motilin in gastrointestinal contractile activity in the dog. American Journal of Physiology 1984;247:G688-94.

Itoh 1984b

Itoh Z, Suzuki T, Nakaya M, Inoue M, Mitsuhashi S. Gastrointestinal motor-stimulating activity of macrolide antibiotics and analysis of their side effects on the canine gut. Antimicrobial Agents and Chemotherapy 1984;26:863-9.

Johnson 1976

Johnson LR. The trophic action of gastrointestinal hormones. Gastroenterology 1976;70:278-88.

Kubota 1994

Kubota M, Nakamura T, Motokura T, Mori S, Nishida A. Erythromycin improves gastrointestinal motility in extremely low birthweight infants. Acta Paediatrica Japonica 1994;36:198-201.

Lewin 1996

Lewin MB, Bryant RM, Fenrich AL, Grifka RG. Cisapride-induced prolonged QT interval. Journal of Pediatrics 1996;128:279-81.

Lyon 1998

Lyon AJ, McColm J, Middlemist L, Fergusson S, McIntosh N, Ross PW. Randomised trial of erythromycin on the development of chronic lung disease in preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 1998;78:F10-4.

Miller 1990

Miller SM, O'DorisioTM, Thomas FB, Mekhjian HS. Erythromycin exerts a prokinetic effect in patients with chronic idiopathic intestinal pseudo-obstruction. Gastroenterology 1990;98:A375.

Ng 1997

Ng PC, Fok TF, Lee CH, Wong W, Cheung KL. Erythromycin treatment for gastrointestinal dysmotility in preterm infants. Journal of Paediatrics and Child Health 1997;33:148-50.

Otterson 1990

Otterson MF, Sarna SK. Gastrointestinal motor effects of erythromycin. American Journal of Physiology 1990;259:G355-63.

Peeters 1989

Peeters T, Matthijs G, Depoortere I, et al. Erythromycin is a motilin receptor agonist. American Journal of Physiology 1989;257:G470-4.

Sarna 1991

Sarna SK, Soergel KH, Koch TR, et al. Gastrointestinal motor effects of erythromycin in humans. Gastroenterology 1991;101:1488-96.

Simkiss 1994

Simkiss DE, Adams IP, Myrdal U, Booth IW. Erythromycin in neonatal postoperative intestinal dysmotility. Archives of Disease in Childhood 1994;71:128-9.

Su 1998

Su BH, Lin HC, Peng CT, Tsai CH. Effect of erythromycin on feeding intolerance in very low birth weight infants: a preliminary observation. Acta Paed Sin 1998;39:324-6.

Tack 1992

Tack J, Janssens J, Vantrappen G, Peeters T, Annese V, Depoortere I, Muls E, Bouillon R. Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis. Gastroenterology 1992;103:72-9.

Tomomasa 1985

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Zara 1985

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Other published versions of this review

Ng 2000

Ng E, Shah V. Erythromycin for feeding intolerance in preterm infants. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD001815. DOI: 10.1002/14651858.CD001815.

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Data and analyses

1 Prevention Studies of Erythromycin versus Placebo (High dose)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Incidence of NEC 2 149 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.11, 3.01]

2 Treatment Studies of Erythromycin versus Placebo (High dose)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Incidence of Septicemia 3 159 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.47, 1.45]

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Sources of support

Internal sources

  • Sunnybrook Health Sciences Centre, Toronto, Canada
  • Mount Sinai Hospital, Toronto, Canada

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2008 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.