Oral immunoglobulin for the prevention of rotavirus infection in low birth weight infants

Mohan P, Haque K

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

Dates

Date edited: 11/07/2007
Date of last substantive update: 02/04/2002
Date of last minor update: 30/04/2007
Date next stage expected 25/04/2009
Protocol first published: Issue 3, 2002
Review first published: Issue 3, 2003

Contact reviewer

Dr. Pammi Mohan, MD, DCh, MRCPCH
Assistant Professor
Pediatrics, Section of Neonataology
Baylor College of Medicine
6621, Fannin, MC.WT 6-104
Houston
Texas USA
77030
Telephone 1: 001 832 826 1380
Telephone 2: 001-713-795-9230
Facsimile: 001 832 825 2799
E-mail: mohanv@bcm.tmc.edu
Secondary address (home):
2250, Holly Hall street
Apt # 126
Houston
Texas USA
77054
Telephone: 001-713-795-9230

Contribution of reviewers

Pammi Mohan
Literature search and identification of trails for inclusion
Contacting prominent authors in the field for more data and unpublished trials
Abstraction of data from eligible studies
Evaluation of methodological quality of included trials
Verifying and entering data in RevMan
Writing the text of the review

Khalid Haque
Abstraction of data from eligible studies
Evaluation of methodological quality of included trials
Writing the text of the review

Internal sources of support

National Perinatal Epidemiology Unit, Oxford, UK
Epsom & St.Helier NHS trust, UK

External sources of support

None

What's new

This review is an update of the existing review "Oral immunoglobulin for the prevention of rotavirus infection in low birth weight infants", published in The Cochrane Library, Issue 3 2003 (Mohan 2003).

There were no new trials identified with our updated search in April 2007. Two studies (Tam JS unpublished, Ventura 1993) were excluded due to nonavailability of relevant data. Five new references were added to the additional references section. The background and the discussion section have been updated with new references.

Dates

Date review re-formatted: / /
Date new studies sought but none found: 30/04/2007
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Rotavirus infection can cause significant problems including diarrhoea in the newborn. This is particularly true in babies weighing less than 2500 g (low birthweight infants). Rotavirus infection is becoming more common in newborn babies and can spread from one baby to another in the neonatal unit. Administration of antibodies against rotavirus to babies may prevent this infection and its spread in the neonatal unit. In this review, only one small trial was identified. Currently, there is not enough evidence to recommend the use of antibodies against rotavirus to babies exposed to rotavirus infection. More research is needed.

Abstract

Background

Rotavirus is a common neonatal nosocomial viral infection and epidemics with the newer P(6)G9 strains have been reported. Local mucosal immunity in the intestine to rotavirus is important in the resolution of infection and protection against subsequent infections. Oral administration of anti-rotaviral immunoglobulin preparations might be a useful strategy in preventing rotaviral infections, especially in low birth weight babies.

Objectives

To determine the effectiveness and safety of oral immunoglobulin preparations for the prevention of rotavirus infection in hospitalized low birthweight infants (birthweight < 2500 g)

Search strategy

The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007), MEDLINE, EMBASE, CINAHL, biological Abstracts (BIOSIS), Science Citation Index for articles citing Barnes 1982 and the proceedings of the Pediatric Academic Societies from 1991 onwards were searched in April 2007.

Selection criteria

The criteria used to select studies for inclusion were:
1) Design: randomized or quasi-randomized controlled trials
2) Participants: Hospitalized low birthweight infants
3) Intervention: Oral immunoglobulin preparations for prevention of rotavirus infection compared to placebo OR no intervention
4) At least one of the following outcomes were reported: All cause mortality during hospital stay, mortality due to rotavirus infection during hospital stay, rotavirus infection , duration of diarrhoea, need for rehydration, duration of viral excretion, duration of infection control measures, length of hospital stay in days, recurrent diarrhoea or chronic diarrhoea.

Data collection & analysis

The two reviewers independently abstracted data from the included trials.

Main results

One published study (Barnes 1982) was eligible for inclusion in this review. Barnes 1982 found no significant difference in the rates of rotavirus infection after oral gammaglobulin versus placebo in hospitalized low birthweight babies [RR 1.27 (95% CI 0.65-2.37)]. In the subset of infants who became infected with rotavirus after receiving gammaglobulin or placebo for prevention of rotavirus infection, there was no significant difference in the duration of rotavirus excretion between the group who had gammaglobulin (mean 2 days, range 1-4 days) and the group who had placebo (mean 3 days, range 1-6 days). Barnes 1982 reported no adverse effects after administration of oral immunoglobulin preparations.

Reviewers' conclusions

Current evidence does not support the use of oral immunoglobulin preparations to prevent rotavirus infection in low birthweight infants. Researchers are encouraged to conduct well-designed neonatal trials using the newer preparations of anti-rotaviral immunoglobulins (colostrum, egg yolk immunoglobulins) and include cost effectiveness evaluations.

Background

Group A rotavirus infection is a major cause of diarrhoeal morbidity in children. Globally, it is estimated that in children < 5 yrs of age, rotavirus causes 111 million episodes of gastro-enteritis requiring only home care, 25 million clinic visits, two million hospitalizations and 440,000 deaths. 82% of deaths occurred in the poorest countries (Parashar 2003) . It has also been recognized as the most common neonatal nosocomial viral infection (Strodtbeck 1986). Several outbreaks of rotaviral infection in neonatal nurseries in different countries have been reported (Bryden 1982; Shif 1983; Omoigberale 1995; Akinci 1991).

Rotavirus infection epidemics appear to be seasonal, being more common in the colder winter months. Infection rates range from 13% to 78% of neonates in the neonatal unit during epidemics (Widdowson 2000; Tufvesson 1986; Kilgore 1996; Cicirello 1994). The main reservoir of rotavirus infection in neonatal nurseries seems to be the infected neonate (Grillner 1985) and most infection occurs in the first few days of life (Kilgore 1996; Cicirello 1994). Therefore preventive strategies might be useful if administered during this time period. Premature and low birth-weight infants and infants staying in the neonatal unit longer have a greater risk of acquiring the infection (Dennehy 1985; Walther 1984; Dearlove 1983). Rotavirus, especially the newer strains, can cause severe diarrhoea and dehydration in already sick neonates. Rotavirus infection has been shown to be associated with necrotizing enterocolitis (NEC) in premature infants (Mogilner 1983). In another study, 29% of neonates with NEC were stool rotavirus positive. Although these infants had lower Bell's Staging of NEC, the outcome of these infants regarding mortality or complication rates did not differ from rotavirus negative infants who had NEC (Sharma 2004). A significantly higher incidence of bradycardia-apnoea episodes (BAE) has been noticed two days before and two days after the diagnosis of rotavirus infection in infants. These episodes were followed by cyanosis and required intervention more often than did BAE episodes in rotavirus negative infants (Riedel 1996). Rotavirus infected neonates stay in the hospital longer than non-infected neonates, causing increased stress to the family and increased cost to the neonatal unit (Strodtbeck 1986). Strict infection control measures have been advocated including hand protection, hand disinfection, individual nursing sets and cohorting infected babies (Grehn 1990). Closure of neonatal units (Valmari 1984) has been recommended to control and eradicate nosocomial outbreaks of rotavirus infections, placing considerable stress on busy neonatal units.

Newer strains of rotavirus P(6)G9 genotypes which previously have not been known to cause outbreaks of diarrhoea have been identified to cause epidemics in the UK (Cubitt 2000), US (Ramachandran 1998), Bangladesh (Unicomb 1999) and Europe (Widdowson 2000; Widdowson 2002). Unlike previous strains, the new P(6)G9 strains can cause serious outbreaks of diarrhoea in neonatal units and cause severe symptoms in most infected neonates. Most mothers have not been exposed to these new strains and thus a high proportion of neonates lack protective antibodies which could explain high attack rates in the neonatal unit and the severity of symptoms. Predominance of neonatal cases compared to few cases in older children may indicate that neonates have an increased risk of infection by P(6)G9 strains.

Determinants of protective immunity against rotavirus are unclear . It has been suggested (Molyneaux 1995) that local mucosal immunity in the intestine may protect against rotavirus illness. While local antibodies may be important in the resolution of infection and protection from subsequent infections, there is no specific antibody that could be used reliably as a marker of protection (Ward 1996). Breast-fed infants are less susceptible to rotavirus infection and this is probably due to the presence of anti-rotaviral secretory IgA and trypsin inhibitors in the breast milk (McLean 1981; Jayashree 1988). The protective efficacy of breast milk correlates positively with the concentrations of anti-rotaviral secretory IgA in the breast milk (Jayashree 1988). Breast-fed infants tend to excrete fewer viruses than bottle-fed infants after infection with rotavirus (Chrystie 1978).

Oral administration of immunoglobulin containing preparations of bovine colostrum from immunized cows, egg yolk immunoglobulin from immunized hens (Mine 2002) or pooled plasma derived immunoglobulins can provide passive immunity. The highest titers of neutralizing anti-rotaviral antibodies are present in bovine colostrum, then in egg yolk immunoglobulin followed by human pooled plasma derived immunoglobulin (Bogstedt 1996). These preparations may inhibit intestinal viral adherence or viral replication and therefore may have a role in the prevention or treatment of rotavirus infections. Oral immunoglobulin preparations are resistant to proteolytic digestion and retain significant neutralizing activity in the stools of treated infants. The newborn infant's immaturity of proteolytic enzymes or rapid gastrointestinal transit time permits intact or nearly intact Ig to pass throughout the gastrointestinal system (Hilpert 1987; Blum 1981). In a prospective randomized placebo controlled study of oral human plasma immunoglobulin in children (but not neonates) with acute rotaviral gastroenteritis, there was a reduction in total duration of viral diarrhoea and viral excretion, and a faster clinical improvement compared to controls (Guarino 1994). Bovine colostrum from hyperimmunized pregnant cows has been shown to reduce viral excretion, stool output and the need for rehydration when used in the treatment of acute rotaviral gastroenteritis in children other than neonates (Hilpert 1987; Sarker 2001; Mitra 1995). It has also been shown to prevent diarrhoea from rotavirus infection when used as prophylaxis (Ebina 1996; Turner 1993). Antibodies derived from the yolk of rotavirus immunized hens have been tested in acute rotaviral gastroenteritis in children beyond the neonatal period in a randomized placebo controlled trial, and found to cause earlier clearance of virus from the stools and an improvement of diarrhoea (Sarker 1998). Advantages of oral immunoglobulin containing preparations in neonates, especially low birthweight infants, would be a reduction in morbidity, reduction in the need for rehydration, earlier clearance of the virus thereby reducing the duration of infection control measures, and a reduction in hospital stay. Infection control measures are expensive and sometimes involve closure of infected units; oral immunoglobulins could be a cheaper and an easier alternative.

Rotavirus infection in low birthweight infants is a major problem and a systematic review on the efficacy and safety of oral immunoglobulin therapy in low birthweight infants for prevention of rotavirus infection is appropriate.

Objectives

To determine the effectiveness and safety of oral immunoglobulin preparations for the prevention of rotavirus infection in hospitalised low birthweight (birthweight < 2500 g) infants .

Criteria for considering studies for this review

Types of studies

Studies in which hospitalized low birthweight infants are randomized or quasi randomized to receive oral immunoglobulin preparations or either a placebo or no intervention for prevention of rotavirus infection.

Types of participants

Hospitalized low birthweight infants (birth weight < 2500 grams) not known to have rotavirus infection at study entry.

Types of interventions

Oral immunoglobulin preparations, specifically a) pooled plasma, b) colostrum from rotavirus immunized cows or c) egg yolk immunoglobulin from rotavirus immunized hens, used for prevention of rotavirus infection at any dose or duration.

Types of outcome measures

Primary outcome measures:

All cause mortality during hospital stay
Mortality due to rotavirus infection during hospital stay
Rotavirus infection
Duration of diarrhoea
Need for rehydration

Secondary outcome measures:

Duration of viral excretion
Duration of infection control measures
Length of hospital stay in days
Recurrent diarrhoea
Chronic diarrhoea

Definitions:

Rotavirus infection - Detection of rotavirus or antigen in the stools
Rotavirus infection rates - Percentage of infants acquiring rotavirus infection
Diarrhoea - Loose watery stools
Recurrent diarrhoea - Recurrence of diarrhoea after 48 hrs of normal stools
Chronic diarrhoea - Persistence of diarrhoea beyond 14 days
Rehydration for rotavirus diarrhoea - Fluid needed beyond maintenance requirements to maintain normal hydration by any route
Duration of diarrhoea - Time till the last loose watery stools from the onset of diarrhoea measured in days
Duration of viral excretion - Time till two rotavirus negative stools from the time of positive diagnosis measured in days
Mortality due to rotavirus infection during hospital stay - deaths directly attributable to rotavirus infection
Duration of infection control measures - days per infant of extra infection control measures as a result of rotavirus infection above what is normally practiced in that hospital for that infant infected with rotavirus

Search strategy for identification of studies

See: Collaborative Review Group search strategy
The search strategy used to identify studies was devised according to the guidelines of the Cochrane Neonatal Review Group. The search was updated in April 2007.
Relevant trials in any language were identified through
1. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007).
2. Electronic journal reference databases-
MEDLINE (1966-present) and PREMEDLINE
EMBASE (1980-present)
CINAHL (1982-present)
Biological Abstracts (BIOSIS) (1980-present)

3. Science citation index search for all articles, which quoted Barnes 1982 was performed.
4. Abstracts of conferences -proceedings of the Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research) and the European Society for Paediatric Research. The reference list of identified trials and abstracts published in Pediatric Research (1991-present) and Abstracts online (2000-2006) was searched in MEDLINE and EMBASE for full published articles.
5. Communication was made with published authors for more information and other prominent authors in the field for possible unpublished studies, which may or may not have been presented as abstracts.
6. Additional searches were made in reference lists of identified clinical trials and in the reviewers' personal files.

MEDLINE, PREMEDLINE, EMBASE, CINAHL, Biological Abstracts search strategy
#1 Search Rotavirus
#2 Search Infant, newborn
#3 Search Infant, newborn, diseases
#4 Search neonat*
#5 Search Infant, low birth weight
#6 Search Infant, Very Low birth weight
#7 #2 OR #3 OR #4 OR #5 OR #6
#8 Search Immunoglobulin AND Oral
#9 Search Antibodies AND Oral
#10 Search Gammaglobulin AND Oral
#11 #8 OR #9 OR #10
#12 #1 AND #7 AND #11
#13 Limit #12 to (TG = Human) and (PG = Clinical trial)

No language restriction was applied. The reviewers erred on the side of over inclusion and later the articles, which did not meet the eligibility criteria were excluded

Methods of the review

The titles and the abstracts of studies identified by the search strategy were assessed by the two reviewers independently. Differences were resolved by mutual discussion. Full text versions of any eligible studies were obtained for quality assessment. Data extraction was done independently by the authors using paper proforma and compared for any differences, which were then resolved by discussion. Any article for which either person felt that the reference list should be searched was retrieved. Information regarding all infants randomized in the trial by Barnes 1982 was requested and limited information was obtained from the authors. Details of the study by Tam JS (unpublished) including particular details of the participants, interventions and outcomes were requested and obtained from the principal investigator and the sponsor (Numico Research, previously Northfield Laboratories).

The following subgroup analyses were prespecified in the protocol but were not possible
1) Birthweight
Birthweight < 1500 grams
Birthweight from 1500 to 2500 grams

2) Type of preparation
Oral immunoglobulin derived from pooled plasma
Oral immunoglobulin from the colostrum of rotavirus immunized cows
Oral immunoglobulins from egg yolk of rotavirus immunized hens

3) Strains of rotavirus
Newer G(9) strains
Non G(9) strains

Assessment of the Quality of studies

The standardized review methods of the Cochrane Neonatal Review Group (CNRG) were used to assess the methodological quality of the studies. Assessment of the quality of included studies was done by the two reviewers independently using the criteria developed by the CNRG.
Blinding of randomization?
Blinding of intervention?
Blinding of outcome measure assessment?
Completeness of follow-up?
There were three potential answers to these questions - yes, can't tell, no

ANALYSIS
Statistical analyses were performed according to the recommendations of the CNRG. Trials were stratified by quality criteria. The treatment effects in the included trial were analyzed in RevMan 4.1 using, for categorical variables, relative risk (RR) and risk difference (RD). Planned analyses of the subgroups and meta-analyses were not feasible.

Description of studies

Details of the included studies are provided in the table "Characteristics of Included Studies".
The following studies for possible inclusion in this review were identified by our search strategy: Barnes 1982, Tam JS (unpublished), Ventura 1993.

Barnes 1982 was included in this review
Seventy-five infants whose birthweight ranged from 2000 - 2500 g and who were admitted to a special care baby unit where rotavirus infection was endemic were randomized to oral gammaglobulin or placebo within 12 hours of birth. The intervention (gammaglobulin or placebo) was given in a dose of 4 ml, four times a day for seven days. The following outcomes were reported: i) timing of excretion of rotavirus, ii) quantity or grading of rotavirus excreted in the stools, iii) duration of excretion of rotavirus and iv) the incidence of clinically important diarrhoea. The report of this trial analyzed only those 25 infants who were subsequently found to be rotavirus positive; infants who did not excrete rotavirus in the first two weeks of life were excluded from the analysis. As diarrhoea or rotavirus infection were not criteria for entry into the study, we considered this to be a study of prevention of rotavirus infection in low birthweight infants admitted to a neonatal unit, where rotavirus was known to be endemic. In order to conduct analyses based on all infants randomized, we requested and obtained limited information from the authors regarding the outcomes of the infants who were randomized but not infected with rotavirus.

Studies excluded
Tam JS (unpublished)
Two hundred and thirty four infants with birthweight > 1500 g in Hong Kong and Vellore (India) were randomized into three groups to receive: i) colostrum (powder) from rotavirus vaccinated cows, ii) colostrum (powder) from unvaccinated cows and iii) standard infant milk powder (Lactogen) respectively at a dose of 550 mg three times a day during hospital stay and seven days after discharge. Physicians were blinded to the intervention. Outcomes reported were i) rotavirus infection from stools ii) Ig A or IgM seroconversion to rotavirus (defined as a four fold increase in titre in paired samples) and iii) adverse effects. Only 61% (76/234) infants completed the study. The mean age of infants recruited was 16 months and highly unlikely to have any low birthweight infants recruited in the trial. The investigators cannot separately identify the number of low birthweight infants randomized in this trial. There are unresolved discrepancies regarding rotavirus infection status of the participants in the data received from the principal investigator and the sponsor (Numico, previously Northfield Laboratories) and hence the study is excluded.

Ventura 1993
As a part of the prevention arm of a trial that also assessed the efficacy of treatment of acute diarrhoea with oral gammaglobulin or placebo, 16 infants hospitalised during the rotavirus epidemic were randomized to gammaglobulin or no intervention for prevention of rotavirus infection and diarrhoea. Data regarding hospitalized low birthweight infants without known rotavirus infection at study entry who were randomized in the trial are unavailable and hence this study was excluded.

Methodological quality of included studies

Barnes 1982
This is a randomized, placebo controlled study. Randomization was performed in another institution and concealment of allocation (or blinding of randomisation) was noted. Physicians were blinded to the intervention. Assessment of outcomes was also blinded. Fifty enrolled infants who were not diagnosed with rotavirus infection were excluded from analysis in the report of this trial, but have been included in this review in analyzing effect on incidence of rotavirus infection.

Results

i) Rotavirus infection
In the included study (Barnes 1982), there was no significant difference in rotavirus infection rates in infants who received the gammaglobulin compared to infants who received placebo [RR 1.24 (95% CI 0.65- 2.37) RD 0.07 (95% CI -0.14, 0.28)].

ii) Duration of viral excretion
In the subset of infants in Barnes 1982 who developed rotavirus infection after randomization to oral gammaglobulin or placebo, there was no significant difference in the duration of excretion of rotavirus between the gammaglobulin group (mean two days and range 1-4 days) and the placebo group (mean three days and range 1-6 days).

iii) Adverse effects
No adverse effects were reported in the included study (Barnes 1982).

The following outcomes could not be evaluated: all cause mortality during hospital stay, mortality due to rotavirus infection during hospital stay, duration of diarrhoea, need for rehydration, duration of infection control measures, length of hospital stay in days, recurrent diarrhoea and chronic diarrhoea.

Discussion

The single study included in this review (Barnes 1982) is too small to reliably answer the objectives of this review. This study was analyzed in the report as a trial of treatment of rotavirus infection with oral gammaglobulin. Infants were randomized within 12 hours of birth and neither rotavirus infection nor diarrhoea was a criterion for entry into the trial. Twenty-five of the 75 infants randomized were diagnosed to have rotavirus infection. It was assumed that 50 infants who were rotavirus negative were not exposed to rotavirus infection and excluded from analysis. However, it is difficult to assume so in a neonatal unit where rotavirus infection is known to be endemic and hence this study is included as a trial for prevention of rotavirus infection in low birthweight infants. There was no significant difference in the infection rates between the two randomized groups nor was there any significant difference in the duration of rotavirus excretion in the subset of infants who were infected with rotavirus.

Newer immunoglobulin preparations, namely bovine colostrum from rotavirus immunized cows and egg yolk of rotavirus immunized hens (Mine 2002), have been shown to be safe and effective in preventing rotavirus diarrhoea and reducing morbidity when used to treat rotavirus infections in children other than neonates (Ebina 1996; Turner 1993; Hilpert 1987; Sarker 2001; Mitra 1995; Sarker 1998). These preparations have not been tested in neonatal trials for prevention or treatment of rotavirus infection. The obvious advantages are ease of administration, lack of adverse effects and potentially important clinical benefits.

Future investigators should be encouraged to plan large multicenter trials using the newer preparations of anti-rotaviral immunoglobulin for the prevention of rotavirus infection during epidemics of rotavirus infections or in neonatal units where rotavirus is endemic. They would be well advised to use sensitive rotavirus detection methods and include all low birth weight infants, especially the smaller ones who are at a much greater risk of rotavirus infection. These large trials should be planned during the months of the year when rotavirus infections occur. Large multicenter trials would be able to recruit units with different degrees of endemicity for rotavirus infections. In theory, enhancing local mucosal immunity has the potential to reduce rates of rotavirus infections and attenuate symptoms of infection.

Active immunization with rotavirus vaccines can be an effective strategy to prevent rotavirus infections. The initial vaccine licensed was a tetravalent rhesus-human reassortment vaccine (Rotashield). Vaccination with this vaccine was discontinued because of safety concerns, as there was an association with intussuception. Currently available vaccines RotaTeq and RIX4414 (Rotarix) have not been shown to be associated with intussception and are 70% effective against any rotavirus disease and 90 - 100% effective in preventing severe rotavirus disease (Vesikari 2006). The American Academy of Pediatrics has currently recommended a licensed pentavalent human-bovine reassortment rotavirus vaccine (RotaTeq) for routine vaccination in infants, to be given orally for three doses at two, four and six months of age (AAP 2007). However, current rotavirus vaccines do not include the newer P(6)G9 rotavirus strains and immunizations start at two months of age. Therefore, vaccination would not be expected to prevent neonatal rotavirus infection in hospitalized low birthweight infants. Alternate methods of prevention of rotavirus infection therefore become important. Oral immunoglobulin therapy may have the potential to prevent rotavirus infection in hospitalized low birthweight neonates and reduce neonatal morbidity, mortality and health resource utilization.

Reviewers' conclusions

Implications for practice

Current evidence from one small randomized controlled trial does not support the routine use of oral immunoglobulin preparations in the prevention of rotavirus infections in hospitalized low birth weight infants who are exposed to rotavirus.

Implications for research

The efficacy of the newer preparations of anti-rotaviral immunoglobulins, namely colostrum from cows immunized against rotavirus and egg yolk immunoglobulins from hens immunized against rotavirus, have not been assessed for the prevention of rotavirus infections in the newborn. Well designed, large randomized controlled trials are needed to address the effectiveness and safety of these preparations in hospitalized neonates, in the prevention of rotavirus infections. Premature and or low birth weight infants are likely to have a higher mortality and morbidity after infection with the new strains of rotavirus and it will be prudent to test in this group of infants. Such randomized controlled trials should report effects on mortality, morbidity and health resource utilization. Key outcomes to be looked for would be efficacy in the prevention of rotavirus infection, reduction of morbidity and a reduction in the duration of viral excretion which will determine the duration of expensive infection control measures. The design of these randomized controlled trials should also include cost-effectiveness evaluations.

Acknowledgements

We would like to acknowledge the help of
1) Prof. L. Doyle, Dr. G.L. Barnes and R. Bishop for providing us with unpublished information regarding the trial by Barnes 1982.
2) Prof. Davidson for bringing to our notice the trial by Tam JS (unpublished).
3) Prof. Tam and Prof Tai Fok and Mr. Ivan Clarke of Numico Research (previously Northfield Laboratories) for providing us with details of the study Tam JS (unpublished).
4) Nicola Bexon, Information Services Manager, Institute of Health Sciences, Oxford, for developing search strategies of literature conducted in June 2002.
5) Elena Telaro from the Italian Cochrane Center for the translation of an article from Italian to English.
6) Maura Moggia from the Italian Cochrane center for providing us the contact details of A. Ventura, the principal author of the article Ventura 1993.

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Barnes 1982	Single centre, randomised placebo controlled trial Block randomised in blocks of 4 in another institution Blinding of randomisation- yes Clinician blinded to the intervention Blinding of outcome measurement- yes Completeness of follow-up - 50/75 of enrolled infants excluded in the report of this trial, but included in this review.	Low-birthweight infants (2000-2500 gms) Admitted to special care unit, Royal Women's Hospital, Melbourne Period- September 1978 to April 1981 75 infants enrolled 25/75 infants subsequently diagnosed with rotavirus infection	Human gammaglobulin (Commonwealth Serum Laboratories) 16 g/dl preparation-4 ml, 4 times a day for 7 days Placebo-Methyl-cellulose (2% w/v 20 ml); glycerol (20ml); Intravite injection (0.04 ml); water (1 dl) similar dosage to gammaglobulin 38/75 infants had gammaglobulin and 37/75 had placebo	Outcomes were reported for 25 rotavirus positive infants. Outcomes for the 50 rotavirus negative infants were requested from the authors Reported outcomes i) timing of excretion of rotavirus ii) duration of excretion of rotavirus iii) quantification or grading of excretion of rotavirus iv) incidence of clinically important diarrhoea (defined as diarrhoea necessitating change of milk to low lactose feeds)		A

Characteristics of excluded studies

Study	Reason for exclusion
Tam JS (unpublished)	Reliable data regarding low birthweight infants and rotavirus infection in the participants are not available.
Ventura 1993	Data regarding hospitalised low birthweight infants without known rotavirus infection at study entry who were randomised in the trial are not available.

References to studies

References to included studies

Barnes 1982 {published and unpublished data}

Barnes GL, Doyle LW, Hewson PH, Knoches AML, McLellan JA, Kitchen WH, Bishop RF. A randomised trial of oral gammaglobulin in low-birth-weight infants infected with rotavirus. Lancet 1982;1:1371-3.

References to excluded studies

Tam JS (unpublished) {unpublished data only}

Tam JS, Cheng AFB, Fok T, Leung D, Oppenheimer SJ. Passive prevention of rotavirus infection in neonates by oral administration of hyperimmune bovine colostrum containing antibodies to four human rotavirus serotypes.

Ventura 1993 {published data only}

Ventura A, Nassimbeni G, Martelossi S, Bohm P, D'Agro PL. Esperienze con le gammaglobuline per os nella terapia e prevenzione della diarrea infettiva [Experience with gamma globulins per os in the therapy and prevention of infectious diarrhea]. La Pediatria Medica e Chirurgica: Medical and Surgical Pediatrics 1993;15:343-6.

* indicates the primary reference for the study

Other references

Additional references

AAP 2007

American Academy of Pediatrics Committee on Infectious Diseases. Prevention of rotavirus disease. Pediatrics 2007;119:171-82.

Akinci 1991

Akinci A, Tezic T, Gur I, Cetin H, Hatun S. Rotavirus diarrhoea in newborn infants. Turkisk Journal of Pediatrics 1991;33:153-7.

Blum 1981

Blum PM, Phelps DL, Ank BJ, Krantman HJ, Stiehm ER. Survival of oral human serum globulin in the gastrointestinal tract of low birth weight infants. Pediatric Research 1981;15:1256-60.

Bogstedt 1996

Bogstedt AK, Johansen K, Hatta H, Kim M, Casswell T, Svensson L, Hammarstrom L. Passive immunity against diarrhoea. Acta Paediatrica 1996;85:125-8.

Bryden 1982

Bryden AS, Thouless ME, Hall CJ, Flewett TH, Wharton BA, Mathew PM, Craig I. Rotavirus infections in a special-care baby unit. Journal of Infection 1982;4:43-8.

Chrystie 1978

Chrystie IL, Totterdell BM, Banatvala JE. Asymptomatic endemic rotavirus infections in the newborn. Lancet 1978;1:1176-8.

Cicirello 1994

Cicirello HG, Das BK, Gupta A, Bhan MK, Gentsch JR, Kumar R, Glass RI. High prevalence of rotavirus infection among neonates born at hospitals in Delhi, India: predisposition of newborns for infection with unusual rotavirus. Pediatric Infectious Disease Journal 1994;13:720-4.

Cubitt 2000

Cubitt WD, Steele AD, Iturriza M. Characterisation of rotaviruses from children treated at a London hospital during 1996: emergence of strains G9P2A[6] and G3P2A[6]. Journal of Medical Virology 2000;61:150-4.

Dearlove 1983

Dearlove J, Latham P, Dearlove B, Pearl K, Thomson A, Lewis IG. Clinical range of neonatal rotavirus gastroenteritis. British Medical Journal 1983;286:1473-5.

Dennehy 1985

Dennehy PH, Peter G. Risk factors associated with nosocomial rotavirus infection. American Journal of Diseases of Children 1985;139:935-9.

Ebina 1996

Ebina T. Prophylaxis of rotavirus gastroenteritis using immunoglobulin. Archives of Virology Suppl 1996;12:217-23.

Grehn 1990

Grehn M, Kunz J, Sigg P, Slongo R, Zbinden R. Nosocomial rotavirus infections in neonates: means of prevention and control. Journal of Perinatal Medicine 1990;18:369-74.

Grillner 1985

Grillner L, Broberger U, Chrystie I, Ransjo U. Rotavirus infections in newborns: an epidemiological and clinical study. Scandinavian Journal of Infectious Diseases 1985;17:349-55.

Guarino 1994

Guarino A, Canani RB, Russo S, Albano F, Canani MB, Ruggeri FM, Donelli G, Rubino A. Oral immunoglobulins for treatment of acute rotaviral gastroenteritis. Pediatrics 1994;93:12-6.

Hilpert 1987

Hilpert H, Brussow H, Mietens C, Sidoti J, Lerner L, Werchau H. Use of bovine milk concentrate containing antibody to rotavirus to treat rotavirus gastroenteritis in infants. Journal of Infectious Diseases 1987;156:158-66.

Jayashree 1988

Jayashree S, Bhan MK, Kumar R, Bhandari N, Sazawal S. Protection against neonatal rotavirus infection by breast milk antibodies and trypsin inhibitors. Journal of Medical Virology 1988;26:333-8.

Kilgore 1996

Kilgore PE, Unicomb LE, Gentsch JR, Albert MJ, McElroy CA, Glass RI. Neonatal rotavirus infection in Bangladesh: strain characterization and risk factors for nosocomial infection. Pediatric Infectious Disease Journal 1996;15:672-7.

McLean 1981

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Other published versions of this review

Mohan 2003

Mohan P, Haque K. Oral immunoglobulin for the prevention of rotavirus infection in low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 3, 2003.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Oral immunoglobulin vs placebo
01 Rotavirus infection	1	75	RR (fixed), 95% CI	1.24 [0.65, 2.37]

01 Oral immunoglobulin vs placebo

01.01 Rotavirus infection

Contact details for co-reviewers

Dr Khalid N Haque, FRCP(Lond, Edin, Ire), FRCPCH, FPAMS(Pak), MBA
Reader in Neonatal Medicine & Consultant Neonatologist
Epsom & St Helier NHS Trust
Division of Neonatology, Department of Child Health
Queen Mary's Hospital for Children
Wrythe Lane, Carshalton
Surrey UK
SM5 1AA
Telephone 1: +44 208-296-2134
Telephone 2: +44 1932-847-947
Facsimile: 44 208 644 6878
E-mail: KhalidNH99@yahoo.com

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2007 (see http://www.thecochranelibrary.com 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.