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Cochrane Database of Systematic Reviews Protocol - Intervention

Exposure to the smell and taste of milk to accelerate feeding in preterm infants

Authors' declarations of interest

Version published: 29 May 2018 Version history

https://doi.org/10.1002/14651858.CD013038

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine whether exposure to the taste or smell (or both) of milk administered with tube feedings can accelerate progress to full sucking feeds without adverse effects in preterm infants. We will also assess these effects in subgroups with different modes of administration, gestational age, birthweight, and type of milk.

Background

Description of the condition

Because of immaturity of neurologic and digestive systems, preterm infants (born before 37 weeks’ gestation) are often unable to co‐ordinate sucking, swallowing, and breathing in order to feed. Initial nutrition is usually provided intravenously and via a tube which goes through the nose or mouthinto the stomach, with a gradual transition to sucking feeds as co‐ordination improves (Toce 1987). Usually, enteral feeds (feeds provided via the gut) start at small volumes and are increased slowly until full enteral feeds are tolerated.

Feeding intolerance is defined as the inability to digest enteral feedings in association with increased gastric residuals (fluid remaining in the stomach after tube feeds), abdominal distension or vomiting, or both (Moore 2011). It often leads to a delay in attainment of full enteral feeds and prolonged intravenous nutrition (Fanaro 2013). Prolonged intravenous nutrition can increase the risk of: infection; cholestasis (impaired bile flow) (Gargasz 2012); impaired development of the gut mucosa;necrotising enterocolitis (severe intestinal inflamation) (Fanaro 2013); and increased morbidity and mortality (The SIFT Investigators Group 2013).

Taste and smell are important for the appreciation of food but also have a significant role in nutrition. In response to sensory cues, a sequence of pre‐absorptive physiological responses is triggered by the brain, collectively referred to as cephalic phase responses (Smeets 2010).

The cephalic phase response plays an important role in the activation of physiological processes at multiple sites to optimise digestion, including increased salivation, increased peristaltic movements, and increased secretion of digestive enzymes and digestive‐related hormones, all of which are active in the newborn (Lipchock 2011; Mattes 1997; Zolotukhin 2013).

The pathways underlining the cephalic phase response to taste and smell stimulation are diverse and stimulate different parts of the digestive system. First, the increase in salivation starts the process of digestion as a result of the presence of salivary enzymes (such as α‐amylase and lingual lipase), salivary insulin, and the moistening of the digestive bolus to assist swallowing. Further down the gastrointestinal tract, the cephalic phase response initiates the release of gastric secretions containing gastrin, gastric acid, trypsin and gut peptides. It also initiates the release of hormones such as ghrelin, glucagon‐like peptide‐1, leptin and somatostatin, as well as increasing gut motility. Smell and taste also are known to stimulate gastric emptying by increasing contraction of segments of the gastrointestinal tract. Lastly, the release of pancreatic secretions that are rich in digestive enzymes such as lipase, amylase and cholecystokinin assist further digestion of nutrients. In addition to the pancreatic secretions released in the gut, the pancreas also releases insulin and glucagon into the bloodstream in response to sensory stimulation.

All of the responses described above contribute to food digestion and absorption (Mattes 1997; Zolotukhin 2013). However, little is known about the effects of taste and smell stimulation in preterm infants, despite the presence of functional taste receptors from 18 weeks’ gestation and flavour perception from around 24 weeks’ gestation (Lipchock 2011).

Fetal swallowing of amniotic fluid starts by the end of the first trimester and reaches up to 750 mL/day by 34 weeks' gestation (Dasgupta 2016). Thus, fetal smell and taste receptors are exposed to the components of amniotic fluid for many weeks before birth and at equivalent gestations to those of infants born preterm (Bloomfield 2017), suggesting that the first sensory experiences happen in utero.

Distinct olfactory reflexes have been demonstrated in neonates after 32 weeks of gestation, with infants presenting different responses to the smell of substances such amniotic fluid, colostrum or peppermint oil, varying from sucking response alone to a combination of sucking and arousal‐withdrawal reflex (Bingham 2003; Marlier 1998; Sarnat 1978). These findings suggest that the olfactory system is fully functional in preterm infants after 32 weeks of gestational age.

Tube feedings bypass the oral and nasal cavities, so tube‐fed infants have limited exposure to the taste and smell of their feeds. Therefore, there is little stimulation of the cephalic phase response of digestion, which is important for digestion and tolerance of feeds.

The provision of smell and taste exposure to preterm infants receiving tube feedings is currently being applied in the care of some preterm infants based on the assumption that there is biological plausibility for a possible benefit, despite lack of evidence to support this practice. More importantly, potential adverse effects have not been assessed; these could include risks such as aspiration, gagging or choking, bradycardia, desaturations or increase in oxygen requirement.

Description of the intervention

The intervention consists of placing a few drops of the milk with which the infant is being fed on the infant’s lips and tongue in order to provide the taste of milk, and placing a cotton bud or gauze soaked with a few drops of milk close to the infant’s nostril to provide the smell of milk. The exposure should be done before starting the tube feed in order stimulate the cephalic phase response of digestion.

How the intervention might work

Preterm infants being fed via gastric tube have limited exposure to the taste and smell stimulation which trigger the cephalic phase response of digestion, and this might contribute to feeding intolerance and prolonged intravenous nutrition.

Exposure to the taste and smell of milk before tube feeding may stimulate the cephalic phase response of digestion and assist digestion by increasing salivation, triggering peristaltic movements of gut, secretion of digestive enzymes and release of digestion‐related hormones such as ghrelin, leptin, gastrin, insulin and others (Power 2008).

Why it is important to do this review

Prolonged exposure to intravenous nutrition increases the risk of late‐onset sepsis, prolonging hospital stay and increasing health costs. In addition, delayed enteral feeding can result in degeneration of gastrointestinal mucosa and increase the risk of necrotising enterocolitis once the tube feedings start, impacting significantly on infant survival and hospital costs (Johnson 2014). Thus any interventions that accelerate transition to enteral feedings, and then to sucking feedings, would be of considerable potential benefit to infants, their families and the healthcare system.

It is increasingly common for staff in neonatal nurseries to include exposure to the smell or taste (or both) of milk in the process for tube feeding preterm infants. This is largely based on the belief that this must be beneficial , which could lead to performance bias when assessing the effects of the intervention. Furthermore, this additional intervention requires staff time (and therefore cost), and there is also the potential for adverse effects such as choking or aspiration. Reliable evidence is required on the benefits as well as possible risks of this intervention.

Objectives

To determine whether exposure to the taste or smell (or both) of milk administered with tube feedings can accelerate progress to full sucking feeds without adverse effects in preterm infants. We will also assess these effects in subgroups with different modes of administration, gestational age, birthweight, and type of milk.

Methods

Criteria for considering studies for this review

Types of studies

We will include any published or unpublished randomised or quasi‐randomised trials where the unit of randomisation is the infant, or cluster‐randomised trials where the neonatal unit or hospital is the unit of randomisation. We will exclude cross‐over trials and non‐randomised trials such as controlled before‐and‐after studies.

Types of participants

Preterm infants (born before 37 weeks’ gestation) of both sexes and all ethnicities who are receiving any enteral feeds and have not yet reached full sucking feeds.

Types of interventions

We will include studies that report the exposure to the taste or smell (or both) of breast milk or formula milk, immediately before or at the time of tube feedings.

For smell stimulation, we will include in this review interventions that consist of delivering the smell of milk to preterm infants using a gauze with a few drops of milk placed in the cot/incubator close to the infants’ nose, or using a cotton bud soaked with milk or other forms of administration of the smell of milk (eg. using an olfactometer adapted to a pacifier).

For taste stimulation, we will include in this review studies that report placing a few drops of milk on the infant’s lips or tongue using a syringe, or other forms of oral administration of a small amount of milk (eg. using a pacifier dipped in milk).

We will explore the following comparisons.

  1. Exposure to the smell and taste of milk with tube feeds versus no exposure

  2. Exposure to the smell of milk with tube feeds versus no exposure

  3. Exposure to the taste of milk with tube feeds versus no exposure

Types of outcome measures

Primary outcomes

  1. Time to reach full sucking feeds (defined as the removal of the feeding tube), measured in days.

  2. Adverse effects related to the intervention, such as aspiration, gagging/choking, bradycardia, desaturations or increase in oxygen requirement during the intervention period.

Secondary outcomes

  1. Duration of parenteral nutrition (defined as the removal of intravenous nutrition line), measured in days.

  2. Time to reach full enteral feedings (150 ml/Kg/day, or as defined by the trialists), measured in days.

  3. Feed intolerance (resulting in cessation or reduction in enteral feeding), during the period of hospitalisation.

  4. Necrotising enterocolitis (Bell’s stage 2 or more) (Walsh 1986), during the period of hospitalisation.

  5. Late infection (bacterial or fungal infection confirmed by presence of blood or cerebrospinal fluid infection with initiation of symptoms beyond 48 hours after birth) (ANZNN 2015), during the period of hospitalisation..

  6. Growth from birth to discharge (weight, height/length, head circumference and z‐scores; gain in these parameters from birth to 36 weeks’ postmenstrual age or to term equivalent age; body composition).

  7. Exclusive breastfeeding at time of discharge (WHO 2008).

  8. Time to first discharge home, measured in days.

Search methods for identification of studies

We will use the criteria and standard methods of Cochrane and Cochrane Neonatal (see the Cochrane Neonatal search strategy for specialized register). We will search for errata or retractions from included studies published in full‐text on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was done within the review. We will not limit the search to any particular geographical region, language or timing of publication.

Electronic searches

We will conduct a comprehensive search of databases, including: Cochrane Central Register of Controlled Trials (CENTRAL, current issue) in the Cochrane Library; MEDLINE via PubMed (1996 to current); Embase (1980 to current); and CINAHL (1982 to current), using search terms unique to the review topic, plus database‐specific limiters for randomised controlled trials (RCTs) and neonates (see Appendix 1 for the full search strategies for each database). We will search clinical trials registries for protocols of ongoing or recently completed trials (clinicaltrials.gov; ICTRP; ANZCTR and the ISRCTN Registry). We will search using both English and American spelling. We will not apply language restrictions.

Searching other resources

Additionally, we will review the reference lists of all identified articles for relevant articles not identified in the primary search. We will also approach well‐known researchers in this area to identify any unpublished or ongoing research.

Data collection and analysis

We will follow the standard data collection methods of the Cochrane Neonatal Group.

Selection of studies

Two authors will independently evaluate and appraise the retrieved studies, following the steps below.

  1. Screen titles and abstracts to select relevant reports and exclude studies not relevant for this review

  2. Access the full text of potentially relevant reports

  3. Use a reference software management to combine search results and remove duplicate records of the same report and combine multiple reports of the same study

  4. Examine full‐text studies for compliance with the eligibility criteria determined for this review

  5. Where appropriate, corresponded with study authors in order to elucidate any issue regarding selected studies, such as request for missing results or complementary information

  6. Make final decisions on study inclusion and proceed to data collection

We will resolve disagreements by discussion and if necessary, a third review author will mediate for differences in interpretation.

We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009), and 'Characteristics of excluded studies' table.

Data extraction and management

We will develop a data extraction form to extract data from eligible studies. Two review authors will independently extract data from each eligible study. Information extracted will include, but not be limited to: source details, eligibility assessment, methodological details, characteristics of participants, details of intervention and outcomes reported. Any disagreement will be resolved by discussion and if necessary in discussion with a third review author. We will enter details from the data extraction form into Review Manager 5 (Review Manager 2014). Where review authors are authors of an included trial, we will ensure that those authors are excluded from any decision‐making regarding inclusion of the trial in this review, and they will not be involved in data extraction or quality assessment relating to that trial.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool (Higgins 2017). We will assess the risk of bias the following domains.

  1. Sequence generation (selection bias)

  2. Allocation concealment (selection bias)

  3. Blinding of participants and personnel (performance bias)

  4. Blinding of outcome assessment (detection bias)

  5. Incomplete outcome data (attrition bias)

  6. Selective reporting (reporting bias)

  7. Any other bias

Any disagreements will be resolved by discussion or by a third assessor. See Appendix 2 for a more detailed description of risk of bias for each domain. We will enter the assessed risk of bias into Review Manager 5 (Review Manager 2014).

Measures of treatment effect

We will use the numbers of events in the control and intervention groups of each study to calculate risk ratios (RRs) for dichotomous data. We will calculate mean differences (MDs) between treatment groups where outcomes are measured in the same way for continuous data. Where outcomes are measured differently we will report data as standardised mean differences (SMDs). We will report risk differences (RDs), and where a significant effect is found we will calculate the numbers needed to treat to benefit (NNTB) or the numbers needed to treat to harm (NNTH). We will report 95% confidence intervals (CIs) for all outcomes.

Unit of analysis issues

The unit of analysis will be the participating infant in individually randomised trials and an infant will be considered only once in the analysis. The participating neonatal unit or section of a neonatal unit or hospital will be the unit of analysis in cluster randomised trials. We will analyse them using an estimate of the intra‐cluster correlation coefficient (ICC) derived from the trial (if possible), or from a similar trial or from a study with a similar population as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If we use ICCs from a similar trial or from a study with a similar population we will report this and conduct a sensitivity analysis to investigate the effect of variation in the ICC.

If we identify both cluster‐randomised trials and individually randomised trials, we will only combine the results from both if there is little heterogeneity between the study designs, and the interaction between the effect of the intervention and the choice of randomisation unit is considered to be unlikely.

Any possible heterogeneity in the randomisation unit will be acknowledged and a sensitivity analysis will be performed to investigate possible effects of the randomisation unit.

Dealing with missing data

We intend to carry out analysis on an intention‐to‐treat basis for all outcomes, where feasible. We will analyse all participants in the treatment group to which they were randomised, regardless of the actual treatment received, whenever possible. If important missing data (in the outcomes) or unclear data are identified, we will request the missing data by contacting the original investigators. We will make explicit the assumptions of any methods used to deal with missing data. We may perform sensitivity analyses to assess how sensitive results are to reasonable changes in the assumptions that are made. We will address the potential impact of missing data on the findings of the review in the 'Discussion' section.

Assessment of heterogeneity

We will observe the clinical and methodological characteristics of the included studies in order to assess if the studies are sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We will do this by inspecting the forest plots and assessing statistical heterogeneity using the Chi2 test and the I2 statistic, considering the guidelines recommended by the Cochrane Neonatal Group for interpretation of results. We will consider an I2 value of less than 25% to represent no heterogeneity; 25% to 49% to represent low heterogeneity; 50% to 74% to represent moderate heterogeneity; and more than 75% to represent high heterogeneity.

We will consider an I2 value greater than 50% and a low P value (less than 0.10) in the Chi2 test for heterogeneity to indicate substantial heterogeneity (Deeks, 2017). If we detect substantial heterogeneity, we will explore possible explanations in sensitivity/subgroup analyses. We will take statistical heterogeneity into account when interpreting the results, especially if there is any variation in the direction of effect.

Assessment of reporting biases

We intend to conduct a comprehensive search for eligible studies and we will be alert for duplication of data. If 10 or more trials are identified for meta‐analysis, we will assess possible publication bias by inspection of a funnel plot. If we uncover reporting bias that could, in the opinion of the authors, introduce serious bias, we plan to conduct a sensitivity analysis to determine the effect of including and excluding these studies in the analysis.

Data synthesis

We will evaluate studies for potential clinical diversity and restrict meta‐analysis to situations where clinical consistency is apparent. Where substantial heterogeneity is detected, we will test the potential causes in subgroup and sensitivity analysis. We will use a fixed‐effect model to combine data where it is reasonable to assume that studies were estimating the same underlying treatment effect. If there is evidence of clinical heterogeneity we will try to explain this based on the different study characteristics and subgroup analyses.

Quality of evidence

We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes.

  1. Time to reach full sucking feeds (defined as the removal of the feeding tube), measured in days

  2. Time to reach full enteral feedings (150 ml/Kg/day, or as defined by the trialists), measured in days

  3. Feed intolerance (resulting in cessation or reduction in enteral feeding)

  4. Duration of parenteral nutrition (defined as the removal of the intravenous nutrition line), measured in days

  5. Necrotising enterocolitis (Bell’s stage 2 or more) (Walsh 1986)

  6. Late infection (bacterial or fungal infection confirmed by presence of blood or cerebrospinal fluid infection with initiation of symptoms beyond 48 hours after birth) (ANZNN 2015)

  7. Adverse effects related to intervention such as aspiration, gagging/choking, bradycardia, desaturations or increase in oxygen requirement

Two review authors will independently assess the quality of the evidence for each of the outcomes above. We will consider evidence from randomised controlled trials as high quality, but downgrade the evidence by one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We will use GRADEpro GDT to create a ‘Summary of findings’ table to report the quality of the evidence for these specified outcomes.

The GRADE approach results in an assessment of the quality of a body of evidence in one of the four following grades.

  1. High: we are very confident that the true effect lies close to that of the estimate of the effect.

  2. Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

  3. Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

  4. Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

Where we identify sufficient data, we plan to carry out the following subgroup analyses using a fixed‐effect model.

  1. Type of administration of smell exposure (cotton swab or similar soaked with milk placed close to infants’ nostril versus placed by the infant’s side)

  2. Type of administration of taste (cotton swab or similar soaked with milk placed on infant’s lips and tongue versus syringe administration of milk directly onto the infant’s lips and tongue versus use of pacifier to deliver taste of milk)

  3. Type of exposure (provision of smell and taste versus provision of taste only versus provision of smell only)

  4. Gestational age (less than 28 weeks' versus 28 to less than 32 weeks' versus 32 to less than 37 weeks' postmenstrual age)

  5. Type of diet (exclusively human milk versus formula versus human milk + formula)

  6. Intrauterine growth restricted or small for gestational age (less than 10th centile or as defined by the trialists) versus appropriately grown at birth

We will investigate whether the results of subgroup analyses are significantly different by examining the overlap of confidence intervals and performing the test for subgroup differences available in Review Manager 5 software (Review Manager 2014).

Sensitivity analysis

Where we identify substantial heterogeneity, we will conduct sensitivity analysis to determine if the findings are affected by inclusion of only those trials considered of adequate methodology with a low risk of selection and performance bias. We will report results of sensitivity analyses for primary outcomes only.