Transpyloric versus gastric tube feeding for preterm infants

  • Review
  • Intervention

Authors

  • Julie Watson,

    1. University of York, Maternal and Infant Health and Care, Yorkshire and the Humber Health Innovation and Education Cluster, Department of Health Sciences, York, UK
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  • William McGuire

    Corresponding author
    1. Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, Y010 5DD, UK
    • William McGuire, Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, Y010 5DD, UK. William.McGuire@hyms.ac.uk.

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Abstract

Background

Enteral feeding tubes for preterm infants may be placed in the stomach (gastric tube feeding) or in the upper small bowel (transpyloric tube feeding). There are potential advantages and disadvantages to both routes.

Objectives

To determine the effect of feeding via the transpyloric route versus feeding via the gastric route on feeding tolerance, growth and development, and adverse consequences (death, gastro-intestinal disturbance including necrotising enterocolitis, aspiration pneumonia, chronic lung disease, pyloric stenosis) in preterm infants.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 3), MEDLINE, EMBASE, and CINAHL (to June 2012), conference proceedings, and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials comparing transpyloric with gastric tube feeding in preterm infants.

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. We synthesised data using a fixed-effect model and reported typical risk ratio (RR), risk difference (RD), and mean difference (MD).

Main results

We found nine eligible trials in which a total of 359 preterm infants participated. All of the trials contained methodological weaknesses with lack of allocation concealment, absence of blinding of caregivers or assessors, and incomplete follow-up being the major potential sources of bias. The included trials did not detect any statistically significant effects on feeding tolerance or in-hospital growth rates. Meta-analyses found that infants allocated to receive transpyloric feeding had a higher risk of gastro-intestinal disturbance (typical RR 1.48 (95% confidence interval (CI) 1.05 to 2.09); typical RD 0.09 (95% CI 0.02 to 0.17); number needed to treat for an additional harmful outcome (NNTH) 10 (95% CI 6 to 50); six studies, 245 infants) and all-case mortality (typical RR 2.46 (95% CI 1.36 to 4.46); typical RD 0.16 (95% CI 0.07 to 0.26); NNTH 6 (95% CI 4 to 14); six studies, 217 infants). However, the trial that contributed most weight to these findings was likely to have been affected by selective allocation of the less mature and sicker infants to transpyloric feeding. We did not find any statistically significant differences in the incidence of other adverse events, including necrotising enterocolitis, intestinal perforation, and aspiration pneumonia.

Authors' conclusions

The available data do not provide evidence of any beneficial effect of transpyloric feeding for preterm infants. Some evidence of harm exists, including a higher risk of gastrointestinal disturbance and mortality, but these findings should be interpreted and applied cautiously because of methodological weaknesses in the included trials.

Résumé scientifique

Alimentation entérale transpylorique versus gastrique pour les nourrissons prématurés

Contexte

Les sondes d'alimentation entérale pour les nourrissons prématurés peuvent être placées dans l'estomac (alimentation par sonde gastrique) ou dans la partie supérieure de l'intestin grêle (alimentation par sonde transpylorique). Il existe des avantages et des inconvénients potentiels avec ces deux voies.

Objectifs

Déterminer l'effet de l'alimentation par la voie transpylorique versus l'alimentation par la voie gastrique sur la tolérance à l'alimentation, la croissance et le développement et les conséquences indésirables (décès, troubles gastro-intestinaux, notamment une entérocolite nécrosante, pneumonie par aspiration, maladie pulmonaire chronique, sténose du pylore) chez les nourrissons prématurés.

Stratégie de recherche documentaire

Nous avons utilisé la stratégie de recherche standard du Groupe thématique Cochrane sur la néonatologie. Elle incluait des recherches dans le registre Cochrane des essais contrôlés (The Cochrane Library 2012, numéro 3), MEDLINE, EMBASE et CINAHL (jusqu'à juin 2012), les actes de conférence et les revues antérieures.

Critères de sélection

Les essais contrôlés randomisés ou quasi-randomisés comparant l'alimentation entérale transpylorique versus gastrique chez les nourrissons prématurés.

Recueil et analyse des données

Nous avons extrait les données en utilisant les méthodes standards du Groupe thématique Cochrane sur la néonatologie avec une évaluation de la qualité des essais et une extraction des données séparées par deux auteurs de la revue. Nous avons synthétisé les données en utilisant un modèle à effets fixes et rapporté le risque relatif (RR) typique, la différence de risques (DR) et la différence moyenne (DM).

Résultats principaux

Nous avons trouvé neuf essais éligibles auxquels ont participé un total de 359 nourrissons prématurés. Tous les essais présentaient des faiblesses méthodologiques, une absence d'assignation secrète, une absence de mise en aveugle des soignants ou des évaluateurs et un suivi incomplet représentant les plus grandes sources de biais potentielles. Les essais inclus n'ont détecté aucun effet statistiquement significatif sur la tolérance à l'alimentation ou les taux de croissance à l'hôpital. Les méta-analyses ont révélé que les nourrissons assignés au groupe recevant une alimentation transpylorique présentaient un risque plus élevé de troubles gastro-intestinaux (RR typique 1,48 (intervalle de confiance (IC) à 95 % 1,05 à 2,09) ; DR typique 0,09 (IC à 95 % 0,02 à 0,17) ; nombre de sujets à traiter pour obtenir un effet néfaste supplémentaire (NNTH) 10 (IC à 95 % 6 à 50) ; six études, 245 nourrissons) et mortalité toutes causes confondues (RR typique 2,46 (IC à 95 % 1,36 à 4,46) ; DR typique 0,16 (IC à 95 % 0,07 à 0,26) ; NNTH 6 (IC à 95 % 4 à 14) ; six études, 217 nourrissons). Cependant, l'essai ayant eu le plus de poids dans ces résultats avait de grandes chances d'avoir été affecté par l'assignation sélective des nourrissons moins matures et plus malades à l'alimentation transpylorique. Nous n'avons trouvé aucune différence statistiquement significative en termes d'incidence des autres événements indésirables, notamment l'entérocolite nécrosante, la perforation intestinale et la pneumonie par aspiration.

Conclusions des auteurs

Les données disponibles n'apportent aucune preuve d'un quelconque effet bénéfique de l'alimentation transpylorique pour les nourrissons prématurés. Il existe des preuves d'un effet néfaste, notamment un risque plus élevé de troubles gastro-intestinaux et de mortalité, mais ces résultats doivent être interprétés et appliqués avec prudence en raison des faiblesses méthodologiques des essais inclus.

Plain language summary

Transpyloric versus gastric tube feeding for preterm infants

Preterm infants often have poor co-ordination of sucking and swallowing and this can delay the establishment of safe oral feeding. Enteral feeds may be delivered through a catheter passed via the nose or the mouth into either the stomach (gastric feeding) or beyond the stomach into the next part of the bowel (transpyloric feeding). This review of trials found that babies receiving transpyloric feeding had more adverse events without any evidence of benefit over gastric feeding.

Résumé simplifié

Alimentation entérale transpylorique versus gastrique pour les nourrissons prématurés

Les nourrissons prématurés ont souvent une mauvaise coordination de la succion et de la déglutition et cela peut retarder l'établissement d'une alimentation orale sûre. L'alimentation entérale peut être fournie par un cathéter passant par le nez ou la bouche et débouchant soit dans l'estomac (alimentation gastrique) ou au-delà de l'estomac, dans la portion postérieure de l'intestin (alimentation transpylorique). Cette revue d'essais a découvert que les bébés recevant une alimentation transpylorique avaient plus d'événements indésirables et ne présentaient aucune preuve de bénéfice par rapport à une alimentation gastrique.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Background

Description of the condition

Preterm infants have poor co-ordination of sucking and swallowing and this can delay the establishment of safe oral feeding. Enteral feeds may be delivered through a catheter passed via the nose or the mouth into the stomach or upper small intestine. The gastro-oesophageal valve is more lax and gastric peristalsis and emptying is less effective in preterm than in term infants (Berseth 1989). A further concern with intragastric feeding for preterm infants is that lower oesophageal sphincter laxity results in gastro-oesophageal reflux (GOR) and, putatively, GOR-attributed apnoea or bradycardia and aspiration pneumonia (Misra 2007; Malcolm 2009).

Description of the intervention

Placement of the enteral feeding tube in the duodenum or jejunum (transpyloric feeding) rather than the stomach (gastric feeding) ensures delivery of enteral feeds to the main sites of nutrient absorption and has the theoretical advantage of decreasing the potential for oesophageal reflux, reflux-associated apnoea or bradycardia, and aspiration pneumonia.

Why it is important to do this review

Feeding by the transpyloric route also has potential problems. The gastric phase of the digestion is by-passed and secretion of upper intestinal hormones and growth factors may be impaired (Milner 1981). There is also a risk that potentially pathogenic organisms, which would have been removed in the acidic environment of the stomach, may be delivered directly into upper small bowel (Dellagrammaticas 1983). These factors might contribute to a higher risk of necrotising enterocolitis in infants fed via the transpyloric route as suggested by observational studies (Vazquez 1980; Vinocur 1990). Additionally, transpyloric feeding tubes are difficult to position and, unlike gastric tubes, the position of the transpyloric catheter must be confirmed with imaging. Following placement, the transpyloric tube may still migrate back to the stomach. Serious adverse events including cases of intestinal perforation and of pyloric stenosis have also been reported (Boros 1974; Raine 1982).

Objectives

To determine the effect of feeding via the transpyloric route versus feeding via the gastric route on feeding tolerance, growth and development, and adverse consequences (death, gastro-intestinal disturbance including necrotising enterocolitis, aspiration pneumonia, chronic lung disease, pyloric stenosis) in preterm infants.

Methods

Criteria for considering studies for this review

Types of studies

Controlled trials using either random or quasi-random patient allocation.

Types of participants

Preterm infants who receive enteral tube feeding.

Types of interventions

Trials comparing transpyloric versus gastric tube feeding with catheters passed via the nose or mouth. Trials of gastrostomy, duodenostomy, or jejunostomy feeding were not included. Trials in which parenteral nutritional support was available during the period of advancement of enteral feeds were acceptable, provided that the groups received similar treatment other than the route of enteral feeding.

Types of outcome measures

Primary: feed tolerance and growth
  1. Days from birth to establish full enteral tube feeds independently of parenteral fluids or nutrition.

  2. Growth: rates of change in weight, length, head circumference, or skinfold thickness.

Secondary: adverse effects
  1. Death prior to hospital discharge.

  2. Gastrointestinal disturbance such as diarrhoea or feeding intolerance that results in cessation of enteral feeding.

  3. Necrotising enterocolitis confirmed by at least two of the following features:

    1. abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen;

    2. abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both);

    3. blood in stool;

    4. lethargy, hypotonia, or apnoea (or combination of these); or

    5. a diagnosis confirmed at surgery or autopsy.

  4. Aspiration pneumonia/pneumonitis: clinical or radiological evidence of lower respiratory tract compromise that has been attributed to covert or evident aspiration of gastric contents.

  5. Intestinal perforation.

  6. Pyloric stenosis requiring surgical intervention.

  7. Frequency of episodes of prolonged apnoea (no respiratory effort > 20 seconds) or bradycardia (< 60 beats per minute), or apnoea/bradycardia necessitating stimulation, oxygen administration increase, or positive pressure ventilation.

  8. Chronic lung disease defined as an additional oxygen requirement at 36 weeks post menstrual age.

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group.

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 3), MEDLINE (1966 to June 2012), and EMBASE (1980 to June 2012). The search strategy used the following text words and Medical Subject Headings: [Infant-Newborn/, OR infan*, OR neonat*, OR prematur*, OR preterm], AND [Infant-Nutrition/, OR Feeding-Methods/, OR Intubation, Gastrointestinal/, OR gastric, OR transpyloric, OR nasoduodenal, OR nasojejunal]. We used a search filter in MEDLINE and EMBASE to limit retrieval to clinical trials. We did not apply any language restrictions.

We searched ClinicalTrials.gov, Current Controlled Trials, and WHO Clinical Trials Registry for completed or ongoing trials.

Searching other resources

We examined the references in studies identified as potentially relevant. We also searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2012), the European Society for Pediatric Research (1995 to 2011), the UK Royal College of Paediatrics and Child Health (2000 to 2012), and the Perinatal Society of Australia and New Zealand (2000 to 2012). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

Two review authors screened the title and abstract of all studies identified by the above search strategy. We assessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. We discussed any disagreements until consensus was achieved.

Data extraction and management

We used a data collection form to aid extraction of relevant information from each included study. Two review authors extracted the data separately. We discussed any disagreements until consensus was achieved. We asked the investigators for further information if data from the trial reports were insufficient.

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. Additional information from the trial authors was requested to clarify methodology and results as necessary. We evaluated and reported the following issues in the 'Risk of bias' tables:

  1. Sequence generation: We categorised the method used to generate the allocation sequence as:

    1. low risk: any random process e.g. random number table; computer random number generator;

    2. high risk: any non random process e.g. odd or even date of birth; patient case-record number;

    3. unclear.

  2. Allocation concealment: We categorised the method used to conceal the allocation sequence as:

    1. low risk: e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;

    2. high risk: open random allocation; unsealed or non-opaque envelopes, alternation; date of birth;

    3. unclear.

  3. Blinding: We assessed blinding of participants, clinicians and caregivers, and outcome assessors separately for different outcomes and categorised the methods as:

    1. low risk;

    2. high risk;

    3. unclear.

  4. Incomplete outcome data: We described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised completeness as:

    1. low risk: < 20% missing data;

    2. high risk: > 20% missing data;

    3. unclear.

Measures of treatment effect

We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data with respective 95% confidence intervals (CI). We determined the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) for a statistically significant RD.

Unit of analysis issues

The unit of analysis is the participating infant in individually randomised trials and the neonatal unit for cluster-randomised trials.

Dealing with missing data

We requested missing study data from the trial investigators.

Assessment of heterogeneity

If more than one trial was included in a meta-analysis, we examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We calculated the I² statistic for each analysis to quantify inconsistency across studies and describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error. If substantial (I² > 50%) heterogeneity was detected, we explored the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments) in sensitivity and subgroup analyses.

Assessment of reporting biases

If more than five trials were included in a meta-analysis, we conducted a funnel plot analysis.

Data synthesis

We used a fixed-effect model for meta-analyses.

Subgroup analysis and investigation of heterogeneity

We pre-specified subgroup analysis of trials of routine (non-selective) use of transpyloric feeding versus selective transpyloric feeding for infants with confirmed or suspected GOR or GOR-attributed apnoea or bradycardia.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

We found nine eligible trials (Van Caillie 1975; Wells 1975; Pyati 1976; Roy 1977; Drew 1979; Pereira 1981; Whitfield 1982; Laing 1986; Macdonald 1992; see table Characteristics of included studies).

Included studies

All of the included studies were undertaken in the 1970s or early 1980s. Most recruited very low birth weight infants (birth weight < 1500 g). However, only infants grown appropriately for gestational age were eligible for inclusion in most of the trials. In some trials infants who required respiratory or ventilatory support were not eligible for inclusion. Feeding by the allocated route was usually started within the first few days after birth when enteral feeds were commenced. Feeding tubes used were made of silastic, polyvinyl, or polypropylene. The transpyloric tubes were placed in the second or third part of duodenum or the jejunum with the assistance of positioning of the infant and peristalsis. In all of the trials the position of the tube was confirmed radiologically. All trials reported nutrient (usually energy) intake and short-term growth as the primary outcomes. In most reports, data on adverse events (including death, necrotising enterocolitis, intestinal perforation, and aspiration pneumonia) were available.

Excluded studies

Ten reports were excluded following inspection of the full report (Cheek 1973; Valman 1973; Boros 1974; Chen 1974; Uauy 1975; Wolfsdorf 1975; Avery 1977; Celestin 1978; Price 1978; Agarwal 1980; see table Characteristics of excluded studies).

Risk of bias in included studies

All of the trials were small (total N = 359) and none presented a power or sample size calculation.

Allocation

In most of the trials, allocation was not concealed and the assignment of infants to one or other feeding route could have been predicted.

Blinding

The caregivers or assessors were aware of the intervention to which infants had been allocated in all of the included trials.

Incomplete outcome data

In general, short-term outcome data assessment was complete. However, growth data were often not reported for infants who had failed to complete the study, for example because the enteral tube feeding method was changed (that is, not an intention-to-treat analysis). For adverse outcomes, reporting was generally complete or available indirectly from the text of the report.

Effects of interventions

Primary outcomes: feed tolerance and growth

1. Days from birth to establish full enteral tube feeds independently of parenteral fluids or nutrition

This outcome was reported by Macdonald 1992 and by Pereira 1981. These investigators did not find any statistically significant differences but the data were presented without standard deviations and could not be used in a meta-analysis.

2. Growth

All of the included trials reported short-term (prior to discharge from hospital) growth outcomes. One study provided data on longer-term (following discharge from hospital) growth (Whitfield 1982).

a. Short-term weight gain (Outcome 1.1)

Seven trials reported no statistically significant differences in the rate of weight gain (Pyati 1976; Roy 1977; Drew 1979; Whitfield 1982; Laing 1986; Macdonald 1992). Two trials found statistically significantly higher rates of weight gain in the group allocated to transpyloric feeding (Van Caillie 1975; Wells 1975). Four trials provided data in a form that could be used in a meta-analysis (Roy 1977; Van Caillie 1975; Whitfield 1982; Macdonald 1992). The combined data from these studies did not reveal a statistically significant difference: mean difference (MD) -0.5 (95% confidence interval (CI) -27 to 16) g/week (Figure 1).

Figure 1.

Forest plot of comparison: 1 Transpyloric versus gastric tube feeding for preterm infants: Growth, outcome: 1.1 Change in weight (g/week).

b. Short-term linear growth (Outcome 1.2)

In the five trials that reported linear growth, the investigators did not find any statistically significant difference in the rate of increase in crown heel length (Roy 1977; Drew 1979; Pereira 1981; Laing 1986; Macdonald 1992). Only three studies provided data in a form that could be used in a meta-analysis (Roy 1977; Laing 1986; Macdonald 1992). The combined data from these studies did not reveal a statistically significant difference: MD -0.7 (95% CI -2.4 to 1.0) mm/week (Figure 2).

Figure 2.

Forest plot of comparison: 2 Transpyloric versus gastric tube feeding for preterm infants: Adverse events, outcome: 2.1 Death prior to hospital discharge.

c. Short-term head growth (Outcome 1.3)

In the five trials that reported head growth, the investigators did not find any statistically significant difference in the rate of increase in occipito-frontal head circumference (Roy 1977; Drew 1979; Pereira 1981; Laing 1986; Macdonald 1992). Only two reports provided data in a form that could be used in a meta-analysis (Laing 1986; Macdonald 1992). The combined data from these studies did not demonstrate a statistically significant difference: MD 0.6 (95% CI -0.9 to 2.1) mm/week.

d. Short-term change skinfold thickness (Outcome 1.4)

This was reported in one study (Roy 1977). The investigators did not find a statistically significant difference: MD -0.2 (95% CI -1.2 to 0.8) mm/week.

e. Longer-term growth

Growth following hospital discharge was reported in only one of the trials (Whitfield 1982). At the expected date of delivery, body weight and occipito-frontal head circumference were statistically significantly lower in the nasojejunal group: MD -0.3 (95% CI -0.6 to -0.03) kg, and -1.0 (95% CI -1.7 to -0.3) cm, respectively. At three and six months after the expected date of delivery, there were no statistically significant differences between the groups in body weight or occipito-frontal head circumference. However, there was considerable loss to follow-up, mainly in the transpyloric feeding group where 12 of the recruited 28 infants were not assessed at six months.

Secondary outcomes: adverse effects

Seven of the trials reported adverse events including death, necrotising enterocolitis, gastrointestinal disturbance, aspiration pneumonia, and intestinal perforation. Adverse events were often reported as withdrawal criteria rather than as pre-defined outcome measures. Although there was often incomplete follow-up of recruited infants with regard to growth data, in the majority of the reports we have been able to determine the incidence of adverse events for the complete or near complete cohort.

1. Death before discharge from hospital (Outcome 2.1)

Six trials reported this outcome (Wells 1975; Van Caillie 1975; Drew 1979; Whitfield 1982; Laing 1986; Macdonald 1992). Only Laing 1986 found that nasojejunal feeding was associated with a statistically significantly higher mortality rate. The other trials did not find any statistically significant difference. Meta-analysis found a statistically significantly higher rate of death in the infants who were fed via the transpyloric route: typical risk ratio (RR) 2.5 (95% CI 1.4 to 4.5); typical risk difference (RD) 0.16 (95% CI 0.07 to 0.26); number needed to treat for an additional harmful outcome (NNTH) 6 (95% CI 4 to 14) (Figure 2). There was not any evidence of heterogeneity (I² = 0%) or funnel plot asymmetry (Figure 3).

Figure 3.

Funnel plot of comparison: 2 Transpyloric versus gastric tube feeding for preterm infants: Adverse events, outcome: 2.1 Death prior to hospital discharge.

In a sensitivity analysis (Outcome 2.2), Laing 1986 was excluded because of the differences in the baseline characteristics of the feeding groups. When only the remaining five studies were included in the meta-analysis, the difference was not statistically significant: typical RR 2.2 (95% CI 0.9 to 5.4); typical RD 0.1 (95% CI 0.00 to 0.2).

2. Gastrointestinal disturbance such as diarrhoea or feeding intolerance (Outcome 2.3)

Seven trials reported this outcome (Van Caillie 1975; Roy 1977; Drew 1979; Pereira 1981; Whitfield 1982; Laing 1986; Macdonald 1992). None of the individual trials found any statistically significant difference in the incidence of gastrointestinal disturbance. Meta-analysis found a statistically significantly higher risk of gastrointestinal disturbance in the infants fed via the transpyloric route: typical RR 1.48 (95% CI 1.05 to 2.09); typical RD 0.09 (95% CI 0.02 to 0.17); NNTH 10 (95% CI 6 to 50) (Figure 4). There was not any evidence of heterogeneity (I² = 0%) but funnel plot inspection suggested asymmetry and over-representation of smaller trials with large effect sizes (Figure 5).

Figure 4.

Forest plot of comparison: 2 Transpyloric versus gastric tube feeding for preterm infants: Adverse events, outcome: 2.3 Gastrointestinal disturbance (including diarrhoea) prior to hospital discharge.

Figure 5.

Funnel plot of comparison: 2 Transpyloric versus gastric tube feeding for preterm infants: Adverse events, outcome: 2.3 Gastrointestinal disturbance (including diarrhoea) prior to hospital discharge.

In a sensitivity analysis (Outcome 2.4), removing Laing 1986, there remained a statistically significant difference in the incidence of gastrointestinal disturbance: typical RR 1.4 (95% CI 1.02 to 2.0); typical RD 0.1 (95% CI 0.01 to 0.21); NNTH 10 (95% CI 5 to 100).

3. Necrotising enterocolitis (Outcome 2.5)

Seven trials (Van Caillie 1975; Wells 1975; Drew 1979; Pereira 1981; Whitfield 1982; Laing 1986; Macdonald 1992 ) reported this outcome. None of the individual trials, nor a meta-analysis of the studies, found any statistically significant difference in the incidence of necrotising enterocolitis: typical RR 0.6 (95% CI 0.3 to 1.5); typical RD -0.03 (95% CI -0.09 to 0.03).

In a sensitivity analysis (Outcome 2.6), removing Laing 1986, there was not any statistically significant difference in the incidence of necrotising enterocolitis: typical RR 0.9 (95% CI 0.3 to 2.6); typical RD -0.01 (95% CI -0.08 to 0.06).

4. Aspiration pneumonia/pneumonitis (Outcome 2.7)

Four trials (Van Caillie 1975; Pyati 1976; Drew 1979; Pereira 1981; Macdonald 1992) reported this outcome. None of the individual trials, nor a meta-analysis of the studies, found any statistically significant difference in the incidence of aspiration pneumonia/pneumonitis. Meta-analysis: typical RR 1.35 (95% CI 0.44 to 4.14); typical RD 0.02 (95% CI -0.06 to 0.1).

5. Intestinal perforation (Outcome 2.8)

Four trials (Van Caillie 1975; Roy 1977; Pereira 1981; Whitfield 1982) reported this outcome. Of the 129 infants studied, there was only one reported case of intestinal perforation. None of the individual trials, nor a meta-analysis of the studies, found any statistically significant difference in the incidence of aspiration pneumonia. Meta-analysis: typical RR 2.3 (95% CI 0.1 to 50.1); typical RD: 0.01 (95% CI -0.05 to 0.08).

6. Pyloric stenosis

This outcome was not reported in any of the trials.

7. Frequency of apnoea/bradycardia

This outcome was not reported in any of the trials.

8. Chronic lung disease

This outcome was not reported in any of the trials.

Discussion

Summary of main results

We did not find any evidence of benefit of transpyloric compared with gastric feeding in preterm infants. We found some evidence that transpyloric feeding increases the risk of gastrointestinal disturbance and mortality. However, many of the studies included in the review had a variety of methodological weaknesses and these findings need to be interpreted and applied with caution (Figure 6).

Figure 6.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Overall completeness and applicability of evidence

Only two of the included trials assessed the effect of transpyloric versus gastric tube feeding on measures of 'feed tolerance' such as the time taken to establish enteral feeding. With regard to growth parameters, in many of the trials the growth data from infants who developed complications during the study period, or in whom enteral tube placement was unsuccessful, were not reported. In the largest included trial only 41 of the 80 infants who entered the study were included in the growth data analysis (Laing 1986). In Drew 1979, of the 66 infants allocated to a feeding route, there were outcome data for only 44 infants. Given these levels of loss to follow-up, the findings should be regarded with caution. For example, it may be that the repeated failed attempts to position the transpyloric tube introduces a delay in starting or establishing nutritional input. Since it is plausible that such delay may affect growth, the findings may have been different in a true intention-to-treat analysis.

Gastro-oesophageal reflux (GOR), aspiration, and apnoea/bradycardia

Observational studies have suggested that transpyloric feeding may reduce the frequency or degree of GOR and GOR-related apnoea/bradycardia and prevent pulmonary aspiration of intestinal contents (Misra 2007; Malcolm 2009). This review did not find any evidence that transpyloric feeding affected the risk of aspiration pneumonia but a modest yet important effect size has not been excluded. However, none of the included trials assessed the effect of transpyloric versus gastric tube feeding on the incidence of GOR-related apnoea/bradycardia, and none of the trials specifically recruited infants with confirmed or suspected GOR or GOR-attributed problems. Although uncertainty exists as to whether GOR is an important cause of apnoea/bradycardia in preterm infants (Peter 2002; Di Fiore 2005; Corvaglia 2009), it has been proposed that clinical trials are warranted to evaluate whether transpyloric feeding is an effective prevention or treatment option in preterm infants with clinical problems attributed to GOR (Misra 2007; Malcolm 2009).

Quality of the evidence

The finding that transpyloric feeding increased the risk of mortality should also be interpreted carefully since it is possible that the pooled estimate in the meta-analysis is over-inflated by allocation bias in several of the trials. In particular, the outcomes for Laing 1986 (which contributes > 50% of the weight to the pooled risk ratio) may have been affected by preferential allocation of less mature or sicker infants to the transpyloric feeding group. When this study was excluded from the meta-analysis the increase in mortality in the transpyloric group was not statistically significant.

Similarly, the increase in the risk of gastrointestinal disturbance in infants who received transpyloric feeding may have been inflated by allocation bias as well as by ascertainment or surveillance biases since caregivers and clinicians were aware of the allocated intervention in all of the trials. We did not detect any statistically significant differences in the incidences of necrotising enterocolitis or intestinal perforation between the feeding groups. Additionally, although it may be pragmatic to compare continuous transpyloric feeding with intermittent or bolus gastric feeding, as was the case in seven of the included trials, this co-intervention may also have affected the outcomes. The Cochrane review that compared continuous nasogastric tube feeding versus intermittent bolus feeding for preterm infants concluded that the clinical benefits and harms could not be reliably discerned from the available data from randomised trials (Premji 2011).

Authors' conclusions

Implications for practice

The available trial data do not provide evidence that transpyloric feeding has benefits for preterm infants but do raise concerns about a higher risk of adverse affects including gastrointestinal disturbance and mortality. However, these findings need to be interpreted and applied cautiously because of methodological weaknesses in the included trials.

Implications for research

Even if the concerns regarding an effect on mortality are discounted, the lack of evidence of an effect on growth and the finding of an higher risk of gastrointestinal disturbance suggest that a randomised controlled trial of routine transpyloric versus gastric tube feeding in preterm infants is not a priority. The lack of trial data on the effect of transpyloric feeding on preventing or treating gastro-oesophageal reflux-attributed apnoea/bradycardia means that a randomised controlled trial in this select population may be considered appropriate by clinicians and families.

Acknowledgements

We are grateful to Dr P. Gupta, Editor, Indian Paediatrics.

We would like to acknowledge the significant contributions of Dr. Peter McEwan to previous versions of this review.

Data and analyses

Download statistical data

Comparison 1. Transpyloric versus gastric tube feeding for preterm infants: growth
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in weight (g/week)493Mean Difference (IV, Fixed, 95% CI)-5.50 [-26.88, 15.89]
2 Change in crown heel length (mm/week)393Mean Difference (IV, Fixed, 95% CI)-0.67 [-2.36, 1.02]
3 Change in occipito-frontal head circumference (mm/week)275Mean Difference (IV, Fixed, 95% CI)0.56 [-0.95, 2.08]
4 Change in subscapular skinfold thickness (mm/week)118Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.18, 0.78]
Analysis 1.1.

Comparison 1 Transpyloric versus gastric tube feeding for preterm infants: growth, Outcome 1 Change in weight (g/week).

Analysis 1.2.

Comparison 1 Transpyloric versus gastric tube feeding for preterm infants: growth, Outcome 2 Change in crown heel length (mm/week).

Analysis 1.3.

Comparison 1 Transpyloric versus gastric tube feeding for preterm infants: growth, Outcome 3 Change in occipito-frontal head circumference (mm/week).

Analysis 1.4.

Comparison 1 Transpyloric versus gastric tube feeding for preterm infants: growth, Outcome 4 Change in subscapular skinfold thickness (mm/week).

Comparison 2. Transpyloric versus gastric tube feeding for preterm infants: adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death prior to hospital discharge6245Risk Ratio (M-H, Fixed, 95% CI)2.46 [1.36, 4.46]
2 Death prior to hospital discharge (excluding Laing 1986)5165Risk Ratio (M-H, Fixed, 95% CI)2.19 [0.89, 5.35]
3 Gastrointestinal disturbance (including diarrhoea) prior to hospital discharge7297Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.05, 2.09]
4 Gastrointestinal disturbance (including diarrhoea) prior to hospital discharge (excluding Laing 1986)6217Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.02, 2.01]
5 Necrotising enterocolitis prior to hospital discharge7298Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.26, 1.53]
6 Necrotising enterocolitis prior to hospital discharge (excluding Laing 1986)6218Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.32, 2.58]
7 Aspiration pneumonia prior to hospital discharge5171Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.44, 4.14]
8 Intestinal perforation prior to hospital discharge4129Risk Ratio (M-H, Fixed, 95% CI)2.31 [0.10, 50.85]
Analysis 2.1.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 1 Death prior to hospital discharge.

Analysis 2.2.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 2 Death prior to hospital discharge (excluding Laing 1986).

Analysis 2.3.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 3 Gastrointestinal disturbance (including diarrhoea) prior to hospital discharge.

Analysis 2.4.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 4 Gastrointestinal disturbance (including diarrhoea) prior to hospital discharge (excluding Laing 1986).

Analysis 2.5.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 5 Necrotising enterocolitis prior to hospital discharge.

Analysis 2.6.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 6 Necrotising enterocolitis prior to hospital discharge (excluding Laing 1986).

Analysis 2.7.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 7 Aspiration pneumonia prior to hospital discharge.

Analysis 2.8.

Comparison 2 Transpyloric versus gastric tube feeding for preterm infants: adverse events, Outcome 8 Intestinal perforation prior to hospital discharge.

What's new

Last assessed as up-to-date: 30 June 2012.

DateEventDescription
18 July 2012New search has been performed

This updates the review 'Transpyloric versus gastric tube feeding for preterm infants' (McGuire 2007).

Search updated in June 2012. No new trials identified.

The 'Background' and 'Discussion' sections have been updated to include discussion of the possible role of transpyloric feeding in preventing gastro-oesophageal reflux-attributed apnoea/bradycardia.

18 July 2012New citation required but conclusions have not changed

New author added - Dr Julie Watson.

No change to conclusions of review.

History

Protocol first published: Issue 1, 2002
Review first published: Issue 3, 2002

DateEventDescription
20 March 2007New search has been performedThis review updates 'Transpyloric versus gastric tube feeding for preterm infants', published in the Cochrane Database of Systematic Reviews, The Cochrane Library, Issue 3, 2002 (McGuire 2002).

Our electronic search was updated in June 2012. No new trials were eligible for this updated search.

We re-classified one study that was reported as an abstract only from 'excluded' to 'included', as it is clear that this trial was randomised. Inclusion of this small trial did not change any of the conclusions of the review.
20 March 2007New citation required but conclusions have not changedSubstantive amendment

Contributions of authors

Julie Watson, Peter McEwan, and William McGuire revised the protocol, undertook the electronic and handsearches, and screened the title and abstract of identified studies, and the full text of potentially relevant reports. Two authors independently assessed the methodological quality of the included trials, extracted the relevant information and data, and completed the final review.

2012 update completed by Julie Watson and William McGuire.

Declarations of interest

None

Sources of support

Internal sources

  • Tayside Institute of Child Health, Ninewells Hospital and Medical School, Dundee, UK.

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Drew 1979

MethodsQuasi-randomised controlled trial
Participants

66 appropriate for gestational age infants of birth weight < 1500 g

Infants who were receiving assisted ventilation were not included

InterventionsNasojejunal (N = 32) versus nasogastric feeding (N = 34) until achieving an enteral intake of 200 ml/kg/day
OutcomesGain in weight, length, and head circumference prior to hospital discharge, calorie intake, and adverse events (including death, necrotising enterocolitis, intestinal perforation, and aspiration pneumonia)
NotesSetting: University of Melbourne, Australia, 1974-1977
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAlternate allocation
Allocation concealment (selection bias)High riskAlternate allocation
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
High risk

Nasojejunal group: 11 infants withdrawn after allocation; 1 required assisted ventilation, 10 because of failure to pass the feeding tube

Nasogastric group: 11 infants withdrawn after allocation; 5 required assisted ventilation, 4 died within 24 hours, 2 had "insufficient data to compute"

Laing 1986

MethodsQuasi-randomised controlled trial
Participants100 infants allocated, of whom 80 were included. These were infants of birth weight < 1500 g (and appropriate for gestational age - between the 10th and the 90th centile for birth weight)
InterventionsContinuous nasoduodenal (N = 45) versus intermittent nasogastric tube feeding (N = 35) for 7 weeks
OutcomesWeight and length gain, head growth prior to hospital discharge, and adverse events (including death, necrotising enterocolitis, intestinal perforation, and aspiration pneumonia)
Notes

Setting: University of Edinburgh, 1982-1984

There were statistically significant differences in the baseline characteristics of the 2 cohorts that may have affected clinical outcomes. The group of infants who were allocated to nasoduodenal feeding were of statistically significantly lower gestational age, and had statistically significantly lower Apgar scores at 1 minute and at 5 minutes. It seems unlikely that these differences were due to chance. We consider that because of the lack of allocation concealment it is likely that some of the less mature and sicker infants were allocated preferentially to nasoduodenal feeding

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAlternate allocation
Allocation concealment (selection bias)High riskAlternate allocation
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
High risk

Growth data were reported only for infants who had successfully tolerated the allocated feeding route: 16 of the 45 infants allocated to the nasoduodenal route, and 25 of the 35 infants allocated to the nasogastric route.

In this review, the data on adverse events on all 80 infants included have been extracted from the report

Macdonald 1992

MethodsRandomised controlled trial
Participants

43 infants of birth weight < 1400 g

Infants fed with expressed human breast milk were excluded from the trial

InterventionsContinuous nasoduodenal tube feeding (N = 15) versus bolus nasogastric (N = 15) or continuous nasogastric (N = 13) tube feeding until a weight of 1600 g was attained
OutcomesGain in weight, head circumference, and length in surviving infants until 36 weeks gestation, calorie intake, time to achieve enteral feeding, plasma albumin, transferrin, urea, and alkaline phosphatase levels, and adverse events (including necrotising enterocolitis, intestinal perforation, and aspiration pneumonia)
Notes

Setting: University of Glasgow, late 1980s

The data from the bolus nasogastric and continuous nasogastric feeding groups have been combined in this review

The number of infants who died in each group is reported. Growth data are reported only for those infants who survived to the end of the study period

Transpyloric group: 15 infants allocated
- 10 infants completed study - growth data available
- 3 infants died before milk feeding established - no growth data available
- 1 infant transferred to another hospital - no growth data available
- 1 infant failure to position tube - no growth data available
Nasogastric group: 28 infants (13 in the continuous NG feed group, 15 in the bolus NG feed group)
- 24 "completed study" - growth data available
- 3 infants died before milk feeding established - no growth data available
- 1 infant transferred to another hospital - no growth data available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Low riskSealed envelopes containing random sequence
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up; see notes above

Pereira 1981

MethodsRandomised controlled trial
Participants53 infants of birth weight < 1700 g or gestational age < 33 completed weeks
InterventionsContinuous nasojejunal (N = 26) versus intermittent nasogastric tube feeding (N = 27) until breast feeding was established
OutcomesWeight gain and head growth prior to hospital discharge, calorie intake, and adverse events (including death, necrotising enterocolitis, intestinal perforation, and aspiration pneumonia)
Notes

Setting: University of Colorado, late 1970s

There were not any standard deviations reported with the growth velocity data

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up

Pyati 1976

MethodsRandomised controlled trial
Participants19 infants of birth weight < 1500 g. All participants were of birth weight "appropriate for gestational age"
InterventionsContinuous nasojejunal (N = 8) versus nasogastric feeding (N = 11) with standard-calorie formula milk started within 30 hours after birth and continued until 3 weeks after birth
OutcomesCalorie intake and weight gain until 3 weeks after birth
Notes

Setting: Chicago Medical School, early 1970s

There were limited numerical data reported. We have not been able to contact the investigators to obtain any unpublished data

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up

Roy 1977

MethodsRandomised controlled trial
Participants21 infants of birth weight < 1500 g and appropriate for gestational age
Infants who required assisted ventilation or phototherapy were excluded
InterventionsContinuous nasojejunal (N = 12) versus intermittent nasogastric tube feeding (N = 9) for 7 days
OutcomesGain in weight, length, and skinfold thickness prior to hospital discharge, and stool frequency
Notes

Setting: University of Toronto, early 1970s

3 infants in the nasojejunal tube feeding group who developed complications were withdrawn, and not included in the growth comparison
1 infant was withdrawn because of persistent displacement of the tube back to the stomach. A second infant developed "transitory but extensive abdominal distention". Since it is unclear whether this complication resulted in cessation of enteral feeding, we have not classified this as an adverse event. The third infant developed peritonitis following duodenal perforation (confirmed at laparotomy)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up; see notes above

Van Caillie 1975

MethodsQuasi-randomised controlled trial
Participants11 preterm infants of birthweight < 1300 g
InterventionsAllocated alternately to continuous nasoduodenal (N = 6) versus continuous nasogastric tube feeding (N = 5) for 40 days
OutcomesWeight gain prior to hospital discharge, calorie intake, adverse events (including death, necrotising enterocolitis, intestinal perforation, and aspiration pneumonia)
Notes

Setting: University of Texas, USA. Early 1970s

The report gives outcome data on all infants who entered the study. However, one of the infants who had been allocated to nasoduodenal feeding died at aged 30 hours. This infant was included in the analysis of adverse outcomes, but not included in the calculations of short-term growth parameters presented by the investigators

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAlternate allocation
Allocation concealment (selection bias)High riskAlternate allocation
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up; see notes above

Wells 1975

MethodsQuasi-randomised controlled trial
Participants22 infants of birth weight < 500 g and of gestational age < 32 completed weeks
InterventionsContinuous nasojejunal (N = 11) versus intermittent nasogastric tube feeding (N = 11) for 21 days
OutcomesWeight gain for the 21-day study period, calorie intake, and adverse events (death, necrotising enterocolitis)
Notes

Setting: Wisconsin Perinatal Center, early 1970s

3 of the infants who had been allocated to the nasogastric feeding group were switched during the study to nasojejunal feeding because of concern about the level of calorie intake. These infants were not included in the analysis of growth rates. There were insufficient data for 1 other infant, who had been allocated to nasojejunal feeding, to be included in the analysis of growth outcomes presented in the report

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAlternate allocation
Allocation concealment (selection bias)High riskAlternate allocation
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up; see notes above

Whitfield 1982

  1. a

    EDD: expected date of delivery
    NG: nasogastric

MethodsQuasi-randomised controlled trial (alternate months)
Participants44 appropriate for gestational age preterm infants of birth weight 1000 to 1500 g
InterventionsContinuous nasojejunal (N = 28) versus intermittent nasogastric tube feeding (N = 16) until attaining a weight of 1500 g
OutcomesWeight gain and head growth until 6 months old, and adverse events (death, necrotising enterocolitis, intestinal perforation)
Notes

Setting: University of Sheffield. Late 1970s

1. Short-term weight gain data are presented for only those infants with birth weight less than 1.4 kg - i.e. these data are not presented for infants of birth weight 1.4 to 1.5 kg
- Transpyloric group: 20 infants
- NG group: 10 infants

2. Longer-term growth data: presented for infants for whom a weight at the expected data of delivery was available:

At EDD:
- Transpyloric group: 21 infants available for follow-up (4 infants had died, 2 infants had been transferred to another hospital, 1 infant had been "withdrawn" because of "intractable abdominal distension", and the reason for the non-availability of the unaccounted for infant is unclear from the report)
- NG group: 15 infants available for follow-up (1 infant had been transferred to another hospital)

At EDD +3 months - further loss to follow-up occurred, leaving:
- Transpyloric group: 18 infants available for evaluation
- NG group: 15 infants available for evaluation

At EDD + 6 months - further loss to follow-up occurred, leaving:
- Transpyloric group: 16 infants available for evaluation
- NG group: 15 infants available for evaluation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAlternate monthly allocation
Allocation concealment (selection bias)High riskAlternate monthly allocation
Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNear-complete follow-up; see notes above

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Agarwal 1980Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Avery 1977Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Boros 1974Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Celestin 1978Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Cheek 1973Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Chen 1974Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Price 1978Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Uauy 1975Reported as an abstract only, this is described as a "controlled study", but is unlikely to represent a report of a randomised or quasi-randomised trial
Valman 1973Although not apparent from the title, this is not a report of either a randomised or quasi-randomised trial
Wolfsdorf 1975Although not apparent from the title or abstract, this is not a report of a randomised or quasi-randomised trial