Abstract
Introduction:
Infants born very prematurely usually are initially feeding by orogastric or nasogastric tube. These infants lack the maternal milk smell and taste, both of which initiate the cephalic phase of nutrition. Offering the olfactory and gustatory experience of breast milk could enhance weight growth and expedite discharge, which are the primary advantageous outcomes for extremely premature infants.
Purpose:
To evaluate the potential of exposing very preterm newborns to the smell and taste of breast milk to expedite weight growth and facilitate early discharge.
Methods:
This study is a double-blind, randomized, superiority clinical trial. A study was conducted on infants born very prematurely (less than 32 weeks gestation) who were receiving tube feeding. Prior to tube feeding, the interventional group was exposed to the smell and taste of breast milk. The primary outcomes were an increase in weight and a shorter length of hospital stay.
Results:
A total of 63 children born very prematurely were randomly assigned and completed the research. The intervention and control groups did not exhibit any significant difference in terms of weight increase and time to discharge. The weight gain was 715 g (95% CI: 544 to 876 g) in the intervention group and 657 g (95% CI: 510 to 804 g) in the control group, with a p value of 0.60. The time to discharge was 39 days (95% CI: 30 to 48) in the intervention group and 37 days (95% CI: 28 to 54) in the control group, with a p value of 0.735.
Conclusion:
The smell and taste of breast milk right before tube feeding did not speed up weight growth or lead to early discharge in extremely premature newborns.
Introduction
In 2020, around 13.4 million infants were delivered prematurely, accounting for 4–16% of all births globally. Prematurity is the leading cause of death among children under the age of 5.1,2 Preterm neonates, particularly those born before 32 gestational weeks, experience challenges with sucking, swallowing, and breathing due to the underdeveloped state of their neurological and digestive systems. 3 Therefore, the majority of extremely premature neonates necessitate the use of nasogastric or orogastric tube feeding or maybe even parenteral nourishment. These dietary approaches elevate the likelihood of contracting infections, liver illness, necrotizing enterocolitis, and spontaneous intestinal perforation.4,5 Therefore, further research is required to expedite the process of achieving complete enteral nutrition, which is a crucial milestone in the management of extremely premature children.
Olfactory and gustatory sensations are formed throughout early stages of development. The primary processing of these signals occurs in the olfactory and gustatory cortex, after which they are integrated with higher cognitive functions. 6 This stimulus induces the cephalic phase responses, which are the physiological changes that prepare the body for food intake. These changes include the secretion of enzymes and hormones such as insulin, glucagon-like peptide-1, ghrelin, leptin, cholecystokinin, and pancreatic polypeptide. It also increases gastro-intestinal motility, leading to improved digestion and metabolic control. 7 These factors are particularly important in addressing the nutritional needs of very preterm infants.8,9 Administering milk through a nasal or stomach tube does not include the sense of smell or taste.
According to a recent Cochrane systematic review, 10 the presence of milk smell and taste in tube feeds has minimal to no impact on the duration it takes to achieve complete sucking feeds. Nevertheless, only seven studies were incorporated, characterized by limited sample numbers and methodological constraints. In addition, the authors stated that three papers that have not yet been categorized may potentially impact the findings of this study. A prior Cochrane systematic review, 10 which examined only two studies and had low-quality evidence, did not find any meaningful effect on the time it took to achieve complete suckle feeding. However, a different recent systematic review 11 also incorporated seven randomized or quasi-experimental studies and found that preterm infants had a decrease in the duration required to achieve full enteral feeds when compared with standard care. These systematic studies did not consider weight gain, which is the primary factor for determining the release of premature infants, since it indicates their nutritional status and the lack of any health issues that could hinder their growth.
Our objective was to confirm the increase in weight and the duration till discharge in extremely premature newborns who were fed through a tube, with the stimulation of smell and taste of breast milk.
Methods
This is a clinical, double-blinded, randomized superiority trial. This trial investigated the smell and taste of breast milk in extremely premature infants who were tube-fed. This study was conducted at the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Brazil, between April, 2023, and March, 2024. This study was previously approved by IMIP Ethical Committee (CAAE n°: 65635922.0.0000.5201) and written informed consent was obtained from all parents before enrollment. This study followed the CONSORT reporting guidelines. This trial was registered at the Clinical Trials under ID NCT06305052.
Eligibility criteria were infants born with gestational age between 28 and 32 weeks, birth weight of less than 1,500 g, and not yet fed orally. Newborns were ineligible if they had a syndromic diagnosis, were twins, or had any congenital or acquired conditions leading to impaired growth.
Randomization
Eligible infants were randomly assigned to the treatment or control group. A random allocation sequence of intervention or control was generated using the “package” randomizer do software R (R: A Language and Environment for Statistical Computing, Vienna, Austria. https://www.R-project.org/ software RANDOMIZATION). Sequentially numbered, sealed, and opaque envelopes containing the intervention assignment were opened once eligibility criteria were met.
Intervention
An infant in the intervention group received the smell and taste of breast milk with every tube feed. The smell was provided by a drop of breast milk on a cotton swab placed as close as possible to the infant’s nose without touching the infant. Taste was provided with a drop of breast milk on the infant’s tongue. If the infant was asleep, the smell was given by a drop of milk on a gauze swab placed as close as possible to the infant’s nose. The breast milk used to provide the smell and taste was the same breast milk the infant received as a tube feed (i.e., expressed breast milk or donor breast milk). In the control group, an infant received routine care and exposure to the smell and taste of double distilled water.
To ensure double blinding, all study personnel (assistant researcher that followed up with infants and sponsor teams) and study patients as well as their families were blinded to the treatment allocation. Another assistant researcher conducted the intervention (breast milk or water), confidentially and independently.
Outcomes
The primary outcomes were the weight gain and time to hospital discharge. Secondary outcomes included height and head circumference growth from birth to discharge, respiratory syndrome distress, retinopathy of prematurity, intraventricular hemorrhage, or necrotizing enterocolitis, the for invasive mechanical ventilation, and wheter the child was exclusively breastfeeding at discharge.
Statistical analysis
To calculate the sample size, it was assumed that the standard deviation of weight gain in each group would be equal to 350 g. Adopting a significance level of 5% and a power of 90%, it appears that samples from at least 30 children in each group would be sufficient to detect an increase above 300 g in the weight gain of the treated group in relation to the weight gain of the control group.
Categorical data were summarized using absolute and percentage frequencies; continuous data, using the usual measurements of location (mean or median) and dispersion (standard deviation or interquartile ranges). Comparisons of proportions were performed using the chi-square test or Fisher’s exact test. Comparisons of means between two groups were performed using the Student’s t test when the variables presented distributions compatible with a normal distribution. For variables with asymmetrical distribution, comparisons were made between medians using the bootstrap resampling method. In all tests, a significance level of 5% was adopted.
Results
A total of 63 preterm infants were studied, 36 male and 27 female (Figure 1). There were no differences between the intervention and control groups regarding biological and maternal variables (Table 1).
Flowchart.
Biological and Maternal Characteristics of the Two Groups Studied, Intervention and Control
p value calculated by chi-square test.
p value calculated by the Student’s t test.
The weight gain until hospital discharge was similar between the intervention and control groups, respectively 715 g (95% CI: 544 to 876) versus 657 g (95% CI: 510 to 804); p = 0.60. The time for hospital discharge also did not show difference between intervention and control group, respectively 39 days (95% CI: 30 to 48) versus 37 days (95% CI: 28 to 54); p = 0.735.
Regarding secondary outcomes, height and head circumference growth showed no differences between the intervention and control groups, respectively 4.5 cm (±0.9) versus 3.6 cm (±1.1); p = 0.351 and 3.0 cm (±1.4) versus 3.9 cm (±0.6); p = 0.954. The others studied variables also did not show differences between the intervention and control groups (Table 2).
Secondary Outcomes Between Intervention and Control Groups
Discussion
This study was a double-blind randomized controlled trial that examined the impact of olfactory and gustatory stimulation using breast milk on the weight gain and hospital discharge of extremely premature infants who were receiving tube feeding. The findings of our study indicate that the olfactory and gustatory properties of breast milk during tube feeding did not result in increased weight gain or earlier discharge in the extremely preterm infants that were examined.
The results of our study are consistent with previous research conducted by Becker 12 and a study conducted in Iran, which found that non-nutritive sucking with breast milk odor did not have any impact on daily weight gain or weight at the time of discharge. 13 Alemdar et al. also reported no statistically significant disparity in weight, height, and head circumference among infants who were exposed to the scent of breast milk upon their discharge. 14 In a recent randomized research conducted by Alexander et al., it was discovered that the duration of full enteral feeding was comparable between infants who were exposed to taste and smell and those who were not. 15 A recent systematic analysis conducted by Cochrane in 2024 indicates that the introduction of milk in tube feeds for preterm infants does not significantly impact the time it takes for them to achieve full sucking feeds. 10
However, other investigations, such as the one conducted by Abd-Elgawad et al., have documented a noteworthy enhancement in weight gain. 16 Davidson and colleagues discovered that premature children born before 31 weeks’ gestational age, who were exposed to the scent of their mothers’ own milk, exhibited faster learning of feeding compared with a group of infants who did not get this olfactory stimulation. 17 Nevertheless, this observation was not evident in newborns delivered prior to or after 31 weeks of gestational age, indicating a certain period of development that is most conducive to the impact of olfactory stimulus. In a nonrandomized research conducted by Yildiz et al. in Turkey, it was shown that preterm infants who were exposed to the scent of breast milk during gavage feeding showed a transition to oral eating 3 days earlier compared with the control group. 18
Our hypothesis was that exposing premature infants to the smell and taste of breast milk would trigger the cephalic phase response, which would help improve their gastrointestinal function and metabolic reaction to food. This, in turn, would lead to a shorter time required to achieve full enteral feeding. The findings of our study corroborate the conclusions of a Cochrane review, 10 which suggested that there are no evident benefits in terms of the length of hospital discharge for patients. The absence of noticeable effects on olfactory and gustatory perception in this study may be attributed to the abundance of stimuli present in a neonatal intensive-care setting, including many smells, which may have overshadowed any potential influence of the smell and taste of milk. Nevertheless, the source of cephalic phase responses remains unknown, whether it is an innate characteristic or acquired progressively over time. 19
Nevertheless, a recent meta-analysis 11 aimed to identify randomized controlled trials investigating the impact of olfactory and/or gustatory stimulation on preterm infants, involved 871 participants in 7 randomized controlled trials and showed a decrease in the duration required for preterm infants to reach full enteral feeds compared with standard care. There was no significant evidence found to suggest that olfactory and gustatory stimulation have an impact on the length of time a stomach tube is in place, the duration of hospital stay, the occurrence of necrotizing enterocolitis, or the likelihood of spontaneous bowel rupture in premature infants.
Strengths and limitations
This trial is conducted using a double-blind method. During our literature search, we were unable to locate any other study that utilized a double-blind strategy to investigate the effects of smell and taste stimulation on premature newborns receiving tube feeding. The two main outcomes examined, namely weight gain and early hospital discharge, are widely utilized in the current standard of care for preterm newborns. One disadvantage of our study is that we only examined a small cohort of youngsters, despite conducting a prior sample calculation.
Conclusions
This study, which followed a double-blind randomized clinical trial design, found no evidence to support the idea that exposing very preterm infants who were being tube-fed to the smell and taste of breast milk resulted in increased weight growth or earlier discharge from the hospital. No negative effects were observed with the olfactory and gustatory intervention. This simple and inexpensive technique requires further investigations to validate our findings.
Footnotes
Authors’ Contributions
L.G.R.d.F.: Investigation, methodology, project administration, validation, visualization, writing—review and editing. C.A.L.: Investigation, methodology, project administration, resources, supervision, validation, visualization, writing—review and editing. J.N.F.: Data curation, formal analysis, methodology; validation, roles/writing—original draft, writing—review and editing. J.G.B.A.: Conceptualization, formal analysis, funding acquisition, methodology, resources, supervision, roles/writing—original draft, writing—review and editing.
Disclosure Statement
The authors have no conflicts of interest to declare.
Funding Information
This study was not supported by any sponsor or funder.