An unpublished study (Lawrence, 1996), included in the preceding version of the review, has been published (Lawrence, 2001) and new information from the published version of the study has been added to the review. No new trials have been identified.
Necrotizing enterocolitis (NEC) is the most common emergency of the gastrointestinal tract occurring in the neonatal period with reported mortality rates of 20-25% (Stoll 1994a). Long-term outcome is less certain. At discharge, many of the neonates remain at significant risk of frequent and prolonged hospitalisations due to nutritional compromise and stricture as a consequence of NEC. This, in turn, may lead to increased resource utilisation and impaired developmental outcome. Additional morbidity arises from parental emotional grief and financial costs (Simon 1994).
NEC is a disease of the newborn which indicates that the pathogenesis is somehow linked to physiologic characteristics unique to the newborn intestine (Edelstone 1982). The majority of neonates with NEC are premature or low birth-weight (Cikrit 1984). The pathogenesis of NEC appears to be multifactorial with any unifying hypothesis of its cause and prevention remaining unproven (Stoll 1994a). NEC is reported to be due to contributory factors such as mucosal injury caused by ischemia, infection and intraluminal injury with subsequent circulatory, immunologic and inflammatory host responses to the injury (Stoll 1994b). NEC is defined radiologically by the presence of pneumatosis intestinalis. The origin of the intramural gas has been presumed to be from bacterial fermentation from gas-producing bacteria and a substrate (milk) (Willoughby 1994).
Expressed human milk has been reported to reduce the incidence of NEC. The value of expressed breast milk in preventing NEC, however, remains uncertain (Vasan 1994). IgA, being a secretory immunoglobulin, might be expected to be more efficacious in protecting the neonatal gut than the more readily available IgG. There have been reports of the effectiveness of enteral antibiotics as prophylaxis against NEC. A Cochrane systemic review concluded, however, that there is insufficient evidence to support the use of enteral antibiotic prophylaxis for NEC in clinical practice (Bury 2001). Bauer 1992 reviewed three trials of prophylactic intravenous immunoglobulin administration and reported a borderline statistically significant reduction of NEC.
There have also been reports of the effectiveness of using oral immunoglobulins as prophylaxis against NEC in premature and low birth-weight neonates. It has been proposed that oral immunoglobulins produce an immunoprotective effect in the gastrointestinal mucosa. There are concerns, however, about the strength of the evidence of the effectiveness of the use of oral immunoglobulins. The authors have been unable to identify any previous systematic reviews on the use of oral immunoglobulin for the prevention of NEC.
To assess whether oral immunoglobulin administered to preterm and/or low birth-weight neonates reduces the incidence of necrotizing enterocolitis without adverse effects.
Sub-group analysis was planned for the following pre-specified sub-categories:
Dose of oral immunoglobulin; timing of administration of oral immunoglobulin
(early vs. late); type of oral immunoglobulin (IgG or IgA); gestation of
participants (<28wks; 28-32wks; 33-36wks); birth-weight of participants
(<1000g; 1000-1500g;>1500-<2500g).
Randomised or quasi-randomised controlled trials.
Preterm (<37 weeks gestation) and/or low birth-weight (<2500 g) neonates.
Immunoglobulin administered orally as prophylaxis against necrotizing enterocolitis, versus placebo or nothing.
Primary outcome measure:
Diagnosis of definite NEC during the study period, defined as clinical evidence
of gastrointestinal and systemic illness, confirmed by pneumatosis intestinalis,
pneumoperitoneum, portal venous gas, surgery or postmortem.
Secondary outcome measures:
Suspected NEC during the study period
Surgery for NEC during the study period
NEC related death; by 28 days post-delivery, by discharge and, by 1 year
(late or post-discharge)
Length of stay in hospital
Hospital readmissions within the first year of life
Days receiving total parenteral nutrition
Growth and development in childhood
Parental emotional and financial costs
Adverse effects of treatment (if any)
Searches were made of the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003), MEDLINE, CINAHL, EMBASE back to 1966 or as available to October 26, 2003 using the text words 'necrotising enterocolitis OR necrotizing enterocolitis' AND 'immunoglobulin' with constraints 'neonate OR infant'. In July 2000 the proceedings of the Perinatal Society of Australia and New Zealand were hand searched from 1996 to 2000. Additionally, all references in the identified trials were checked. Computer neonatal discussion site 'Nicu Net' was used. No new trials were identified.
The procedures of the Cochrane Neonatal Review Group (CNRG) were followed throughout.
Titles and abstracts identified from the database were checked by two reviewers. The full text of all studies of possible relevance were obtained. The two reviewers independently assessed the trials for their methodological quality and subsequent inclusion in the review. Any disagreement was resolved by discussion between the reviewers. Additional information from investigators was sought when necessary.
The methodological quality of the included trials was assessed with particular emphasis on the allocation concealment, which was ranked using the Cochrane approach: Grade A: Adequate concealment; Grade B: Uncertain; Grade C: Clearly inadequate concealment; Grade D: Not used.
Methods used to synthesise data:
Statistical analysis followed the procedures of the Cochrane Neonatal Review
Group. Weighted treatment effects were calculated across trials using the
fixed effects model in RevMan 4.1. The results were expressed as relative
risk (RR and 95% confidence intervals (CI), risk difference (RD with 95%
CI) and number needed to treat (NNT) for dichotomous outcomes.
Five studies on oral immunoglobulin for the prevention of necrotizing enterocolitis were identified of which three met the inclusion criteria. The three studies are published. The details of each of these three studies are given in the table of 'Characteristics of Included Studies' and the two excluded studies are given in the table of 'Characteristics of Excluded Studies'.
Eibl 1988 studied neonates weighing between 800-2000g. Rubaltelli 1991 studied neonates weighing <1500g or <= 34wks gestation and Lawrence 2001 also studied neonates weighing <=1500g. The Eibl 1988 and Rubaltelli 1991 studies did not use a placebo and the Lawrence 2001 used a placebo (albumin). The studies used varying doses and combinations of IgG/IgA. Lawrence 2001 used only IgG, Rubaltelli 1991 used IgG with a trace of IgM and IgA and Eibl 1988 used an IgA-IgG preparation. There were no studies which investigated the use of only IgA. Treatment was commenced in the first twenty four hours following birth in the Eibl 1988 and Rubaltelli 1991 studies, and following commencement of enteral feeding in the Lawrence 2001 study.
All of the studies used formal randomisation. Allocation was adequately concealed in all of the studies. Only one study, Lawrence 2001, reported that the assessment of the primary outcome of necrotizing enterocolitis was blinded. In that study, ten out of 43 cases of definite NEC in the treatment group and 12 out of 41 cases of definite NEC in the control group did not receive any of the trial solutions prior to their illness. The rate of exclusion of neonates after randomisation was high (59%) in the study by Eibl 1988.
Details of the methodologic quality assessments are given in the Table 'Characteristics of Included Studies'.
Although the trials reported outcomes such as definite NEC, suspected NEC, death and need for surgery, the pre-specified outcomes 'length of stay in hospital, hospital readmission, total parenteral nutrition administration, growth and development in childhood, parental emotional and financial costs' were not reported in any of the studies. Death was reported as 'during and after the study period', but not reported as 28 days post-delivery, discharge or by 1 year (as listed in the prespecified outcome measures). It was not anticipated that several outcome measures would be reported 'after the study period'. The decision to report these outcomes was made post-hoc. No data were available for subgroup analysis other than with regard to class of immunoglobulin, IgG/IgA.
In this review of three trials (including a total of 2095 neonates), two of the studies (Rubaltelli 1991, Lawrence 2001) investigated the use of IgG (nil or trace IgA) and one study (Eibl 1988) investigated the use of an IgG/IgA combination. The administration of oral immunoglobulin did not reduce the incidence of definite NEC, suspected NEC, surgery related NEC, or death from NEC, either during or after the study period.
Definite NEC during study period
Three trials reported the incidence of definite NEC during the study period
and there was no reduction in any trial or overall [RR 0.84 (95% CI 0.57,
1.25), RD -0.01 (95% CI -0.03, 0.01)].
Definite NEC after the study period
Two trials reported the incidence of definite NEC after the study period
and there was no reduction in either trial or overall [RR 1.30 (95% CI 0.47,
3.60), RD 0.00 (95% CI -0.01, 0.01)].
Suspected NEC during the study period
One trial reported the incidence of suspected NEC during the study period
and there was no statistically significant reduction [RR 0.84 (95% CI 0.49,
1.46), RD -0.01 (95% CI -0.02, 0.01)].
NEC related surgery during the study period
The two small trials reported the number of neonates requiring surgery during
the study period. There was no statistically significant reduction in either
trial or overall [RR 0.21(95% CI 0.02, 1.75), RD -0.03 (95% CI -0.06, 0.00)]
NEC related deaths during the study period
Three trials reported the incidence of NEC related deaths during the study
period and there was no reduction in any trial or overall [RR 1.10 (95% CI
0.47, 2.59), RD 0.00 (95% CI -0.01, 0.01)].
NEC related deaths after the study period
One trial reported the incidence of NEC related deaths after the study period
and there was no reduction [RR 1.98 (95% CI 0.18, 21.81), RD 0.00 (95% CI
0.00, 0.01)].
There were two studies (Rubaltelli 1991, Lawrence 2001) that investigated the use of oral IgG (nil or trace IgA). The Lawrence 2001 study was large compared to the Rubaltelli 1991 study and thus dominated the results. Oral IgG did not reduce the incidence of definite NEC during the study period [RR 0.95 (95% CI 0.63, 1.42), RD 0.00 (95% CI -0.02, 0.02)], suspected NEC [RR 0.84 (95% CI 0.49, 1.46), RD -0.01 (95% CI -0.02, 0.01)], need for surgery [RR 0.34 (95% CI 0.01, 8.28), RD -0.01 (95% CI -0.06, 0.03)] definite NEC after the study period [RR 1.30 (95% CI 0.47, 3.60), RD 0.00 (95% CI -0.01, 0.01)] or death due to NEC during the study period [RR 1.39 (95% CI 0.55, 3.55), RD 0.00 (95% CI -0.01, 0.01)].
There was only one study (Eibl 1988) that investigated the use of an oral IgA/IgG combination (73% IgA, 26% IgG) . There were trends for this combination to reduce the incidence of definite NEC during the study period [RR 0.08 (95% CI 0.00, 1.39), RD -0.07 (95% CI -0.12, -0.01), NNT 14 (95% CI 8, 100)], death due to NEC during study period [RR 0.21 (95% CI 0.01, 4.25), RD -0.02 (95% CI -0.06, 0.02)] and need for surgery [RR 0.15 (95% CI 0.01, 2.82), RD -0.03 (95% CI -0.08, 0.01)]. None of the results were statistically significant.
One of the studies (Lawrence 2001) reported an increased incidence of Heinz bodies in the experimental group receiving oral immunoglobulin. The proportion of neonates given blood transfusions, however, was similar in the experimental and control groups (62.2% vs. 69.7%) suggesting that clinically important haemolysis did not occur. There were no other reported side effects from the administration of oral immunoglobulin.
Three trials were included in the review. The randomised trials by Rubaltelli 1991 and Eibl 1988 were small and outcome assessment was not blinded. The Eibl 1988 study also had a large number of post randomisation exclusions in both the experimental and control groups (59%). The study by Lawrence 2001 was a large randomised, placebo-controlled and double-blinded study. Rubaltelli 1991 and Eibl 1988 excluded neonates that received breast milk whereas, in the Lawrence 2001 trial, 90% received breast milk. Breast milk has previously been reported to have a protective effect against NEC (Lucas 1990), and this was acknowledged by Lawrence 2001. Rubaltelli 1991 and Eibl 1988 used similar dosages of oral immunoglobulin, 500 mg/day and 600 mg/day, respectively. Lawrence 2001 used a higher dose of 1200 mg/kg/day. The larger dose of oral immunoglobulin does not appear to have produced a greater response.
Eibl 1988 and Rubaltelli 1991 administered the oral immunoglobulin within the first twenty four hours following birth. However, Lawrence 2001 did not administer the oral immunoglobulin until after the commencement of enteral feeding. Thus, in the Lawrence 2001 study, 31% of neonates did not start the treatment until the 5th day or later. The effect of the timing of the administration of immunoglobulin on the incidence of NEC is unknown. In clinical practice, however, it would be difficult to administer oral immunoglobulins to neonates who were unable to tolerate fluids orally.
The trials by Lawrence 2001 and Rubaltelli 1991 used predominately IgG. The study by Eibl 1988 used an immunoglobulin mixture containing 73% IgA and 26% IgG. To date, there is no randomised trial of IgA alone in the prevention of NEC, and the question of whether IgA has a protective effect against NEC is unanswered.
Eibl 1988 studied neonates weighing between 800-2000g. Rubaltelli 1991 studied neonates weighing less than 1500g or less than or equal to 34wks gestation and Lawrence 2001 similarly studied neonates weighing less than or equal to 1500g. The association between prematurity or low birth weight and NEC are well-known. Despite the increasing survival rate of extremely low birth-weight (ELBW) neonates, there are no published randomised studies exclusively targeting ELBW neonates. It would clearly be important to stratify the groups at risk by gestational age and weight.
Based on the available trials, the evidence does not support the administration of oral immunoglobulin for the prevention of NEC. There are no randomised controlled trials of oral IgA alone in the prevention of NEC.
Future trials should examine the effects of oral IgA in extremely low birth-weight neonates <1000g. In addition to examining effect on NEC, consideration should be given to reporting outcomes such as length of stay in hospital, hospital readmissions, need for total parenteral nutrition administration, growth and development in childhood and parenteral emotional and financial costs in any future studies . Given an incidence of NEC in this population of 8%, 1000 patients would be required to show a 50% reduction in NEC at the 5% level (two tailed).
We would like to acknowledge the contribution of Prof. David Henderson-Smart for his valuable advice and supervision.
One of the reviewers of this systematic review is a member of the Australian NEC study group (Lawrence 2001).
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Eibl 1988 | Blinding of randomisation: yes. Blinding of treatment: no Blinding of outcome: no. Completeness of follow-up: no. "Randomly allocated" to group A or group B. 59% loss post-randomisation as breast milk became available and excluded participant from study Complete followup: no |
434 neonates 800-2000gms. Ineligible if breast fed, severe congenital malformations, cardiac malformations and haemorrhage. | Treatment commenced within 24 hours following birth. Exp. group: 600 mg oral IgG/IgA divided into 3 or more doses for 28 days. (N = 211) Control Group: No placebo used. (N = 223) |
NEC assessed by pneumatosis intestinalis (no definition given) or free gas in peritoneum or portal venous tract or by histopathological exam. of tissue obtained during surgery or autopsy. | No sample size estimation. Study was finished at a not prospectively defined point. 59% post randomisation exclusion rate in experimental and control groups. | A |
| Lawrence 2001 | Blinding of randomisation: yes. Blinding of treatment: yes. Blinding of outcome: yes. Completeness of follow-up: yes. Randomisation using a list of random numbers with 5 IgG and placebo subjects in each block of 10 envelopes. Intolerance to feeds, consent withdrawal and protocol errors delayed study treatment. Thus, 26% of neonates who subsequently developed NEC had not received study medication. Complete followup: yes |
1529 neonates 1500gms or less. Ineligible if enterally fed for more than 24 hours prior to enrolment. Eligible if breast fed. | Treatment commenced when enteral feeds commenced. Exp group: 1200 mg/kg/day oral IgG only divided into at least 4 doses for 28 days. (N = 768) Control group: Placebo of oral albumin 2400 mg/kg/day, coloured to look identical to treatment. Albumin was used to simulate the viscosity of the IgG solution. 31% of neonates did not receive the study solution until after the 5th day of life due to a delay in tolerating oral feeds. (N = 761) |
NEC assessed by clinical criteria without radiological or pathological confirmation were a 'history consistent with NEC and presence of a palpable abdominal mass assoc. with overlying abdominal wall cellulitis. Pneumatosis intestinalis, portal vein gas, or presence of a fixed dilated loop of bowel on serial exams. Radiographic diagnosis made by 2 radiologists unaware of treatment or infant identity. Suspect NEC classified as cases with clinical history of NEC but no confirmatory radiological, surgical or pathological results'. |
Sample size estimation done. Ten neonates out of 43 cases of definite NEC in the treatment group and 12 out of 41 cases in control group did not receive any trial solution prior to diagnosis. |
A |
| Rubaltelli 1991 | Blinding of randomisation: yes. Blinding of treatment: no Blinding of outcome: no. Completeness of follow-up: yes. Randomisation by sealed envelopes. Complete followup: yes |
132 neonates less than 1500 gms and/or less than or equal to 34 wks gestation. Ineligible if breast fed during first 15 days, known cardiopathy, congenital malformation or haemorrhagic syndromes. Nil exclusions before or after randomisation. | Treatment commenced within 24 hours following birth. Exp. group: 500 mg oral IgG/trace IgA for 15 days post delivery divided into 5 doses. (N = 65) Control group: No placebo used. (N = 67) |
NEC assessed by abdominal distention, vomitus or biliary gastric residues, and GIT bleeding. Clinical suspicion confirmed by presence of intramural gas and/or gas in portal systems and/or pneumoperitoneum or histological exam. of biopsy specimen obtained during surgery or autopsy. | No sample size estimation. | A |
| Study | Reason for exclusion |
| Fast 1994 | No placebo arm. Oral gentamicin vs an oral IgG/IgA mixture. |
| Richter 1998 | Not a randomized or quasi-randomized trial. This is an historical cohort study. |
Eibl MM, Wolf HM, Furnkranz H, Rosenkranz A. Prevention of necrotizing enterocolitis in low-birth-weight infants by IgA-IgG feeding. N Engl J Med 1988;319:1-7.
Lawrence 2001 {published data only}
* Lawrence G, Tudehope D, Baumann K, Jeffery, H et al. Enteral human IgG for prevention of necrotising enterocolitis: a placebo-controlled, randomised trial. Lancet 2001;357(9274):2090-2094.
Lawrence GW, The Australian NEC Study Group, Baumann K, Swanson C. Controlled double blind trial of oral human IgG in preventing neonatal enterocolitis (NEC). In: Proc Austral N Zealand Perinat Soc. 1996:A80.
Rubaltelli 1991 {published data only}
Rubaltelli FF, Benini F, Sala M. Prevention of necrotizing enterocolitis in neonates at risk by oral administration of monomeric IgG. Dev Pharmacol Ther 1991;17:138-143.
Fast C, Rosegger H. Necrotizing entericolitis prophylaxis: oral antibiotics and lyophilized enterobacteria vs oral immunoglobulins. Acta Paediatr Suppl 1994;396:86-90.
Richter 1998 {published data only}
Richter D, Bartmann P, Pohlandt F. Prevention of necrotizing enterocolitis in extremely low birth weight infants by IgG feeding? Eur J Pediatr 1998;157:924-925.
* indicates the primary reference for the study
Bauer CR. Necrotizing enterocolitis. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992.
Bury RG, Tudehope D. Enteral antibiotics for preventing necrotising enterocolitis in low birthweight or preterm infants. In: The Cochrane Library, Issue 1, 2001. Oxford: Update Software.
Cikrit D, Mastandrea J, West KW, Schreiner RL, Grosfeld JL. Necrotizing enterocolitis: factors affecting mortality in 101 surgical cases. Surgery 1984;96:648-655.
Edelstone DI, Holzman IR. Fetal intestinal oxygen consumption at various levels of oxygenation. Am J Physiol 1982;242:H50-H54.
Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:1519-1523.
Simon NP. Follow-up for infants with necrotizing enterocolitis. Clin Perinatol 1994;21:411-424.
Stoll BJ. Epidemiology of necrotizing enterocolitis. Clin Perinatol 1994;21:205-218.
Stoll BJ, Kliegman RM. Necrotizing enterocolitis. Clin Perinatol 1994;21:xi.
Vasan U, Gotoff SP. Prevention of neonatal necrotizing enterocolitis. Clin Perinatol 1994;21:425-435.
Willoughby RE, Pickering LK. Necrotizing enterocolitis and infection. Clin Perinatol 1994;21:307-315.
Foster J, Cole M. Oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth-weight neonates (Cochrane Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software.
01.01 Definite NEC during study period
01.02 Definite NEC after study period
01.03 Suspected NEC during study period
01.04 NEC related surgery during study period
01.05 NEC related deaths during study period
01.06 NEC related deaths after study period
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Oral Immunoglobulin vs Control | ||||
| 01 Definite NEC during study period | 3 | 1840 | RR (fixed), 95% CI | 0.84 [0.57, 1.25] |
| 02 Definite NEC after study period | 2 | 1661 | RR (fixed), 95% CI | 1.30 [0.47, 3.60] |
| 03 Suspected NEC during study period | 1 | 1529 | RR (fixed), 95% CI | 0.84 [0.49, 1.46] |
| 04 NEC related surgery during study period | 2 | 311 | RR (fixed), 95% CI | 0.21 [0.02, 1.75] |
| 05 NEC related deaths during study period | 3 | 1840 | RR (fixed), 95% CI | 1.10 [0.47, 2.59] |
| 06 NEC related deaths after study period | 1 | 1529 | RR (fixed), 95% CI | 1.98 [0.18, 21.81] |
| This review is published as a Cochrane review in The
Cochrane Library 2004, Issue 1, 2004 (see www.CochraneLibrary.net for information).
Cochrane reviews are regularly updated as new evidence emerges and in response
to comments and criticisms, and The Cochrane Library should be consulted
for the most recent version of the Review. |
