Olfactory stimulation for promoting development and preventing morbidity in preterm infants.

rationalePreterm infants, often gavage-fed due to immaturity, may benefit from interventions that hasten the move to breastfeeding. Olfactory stimulation may increase appetite and speed up the transition to full oral feeding, potentially shortening hospital stay and improving outcomes for both infants and families.

objectivesTo evaluate the benefits and harms of olfactory stimulation for reducing morbidity and promoting development in hospitalized preterm infants. SEARCH

methodsWe searched MEDLINE, Embase, CENTRAL, CINAHL, Epistemonikos, two trial registries, and conference abstracts up to 2 April 2025. We checked the reference lists of included studies and systematic reviews on olfactory or sensory stimulation. ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs evaluating olfactory stimulation with different odorants (maternal breast milk, food-associated odors, or non-food-associated odors) in preterm infants (born before 37 weeks' gestation). Eligible controls were no intervention, placebo, or standard care (considered together) or another odorant. We excluded studies combining olfactory stimulation with taste, as another review will focus on combined sensory stimulation. OUTCOMES: Our critical outcomes were apnea, intermittent hypoxemia, duration of hospital stay, time to full oral feeding, and exclusive breastfeeding. Our important outcomes included blindness and sensorineural deafness requiring amplification. RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 2) to assess risk of bias in the included studies. SYNTHESIS

methodsWe conducted meta-analyses using fixed-effect models to calculate risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, each with its 95% confidence interval (CI). We assessed the certainty of evidence using GRADE. INCLUDED STUDIES: We included 14 trials enrolling 1087 neonates. The types of olfactory stimulation under investigation were maternal breast milk (9 studies); food-associated odors such as cinnamon, vanilla, or anise (5 studies); and non-food-associated odors such as rose or parents' scent (3 studies). Three studies evaluated two different odorants. Gestational age and bodyweight varied widely. The comparators were placebo, no intervention, and standard care. Eleven studies aimed to assess the effect of olfactory stimulation on infant feeding outcomes such as time to full oral feeding, weight gain, length of hospital stay, or a combination of these outcomes. Three studies aimed to assess the effect of olfactory stimulation on apnea prevention, oxygen saturation, or both. We identified five ongoing trials. SYNTHESIS OF

resultsNo studies reported apnea as a dichotomous outcome, intermittent hypoxemia, exclusive breastfeeding, or major neurodevelopmental disability for any of the comparisons. We downgraded the certainty of evidence for limitations in study design, imprecision, and indirectness. Olfactory stimulation with maternal breast milk versus no intervention, placebo, or standard care The evidence is very uncertain about the effect of olfactory stimulation with maternal breast milk on the mean number of daily apnea episodes (MD -0.50, 95% CI -1.27 to 0.27; 1 study, 26 participants; very low-certainty evidence) and duration of hospital stay in days (MD -0.18, 95% CI -0.64 to 0.27; I² = 0%; 4 studies, 270 participants; very low-certainty evidence). Olfactory stimulation with maternal breast milk may result in a slight reduction in time to full oral feeding in days (MD -1.68, 95% CI -3.25 to -0.11; I² = 30%; 3 studies, 204 participants; low-certainty evidence). Olfactory stimulation with food-associated odors versus no intervention, placebo, or standard care Olfactory stimulation with food-associated odors may result in a slight reduction in the mean number of daily apnea episodes (MD -1.99, 95% CI -2.69 to -1.29; I² = 58%; 2 studies, 62 participants; low-certainty evidence). The evidence is very uncertain about the effect of olfactory stimulation with food-associated odors on duration of hospital stay in days (MD -2.65, 95% CI -6.18 to 0.89; I² = 20%; 3 studies, 185 participants; very low-certainty evidence) and time to full oral feeding in days (MD -2.06, 95% CI -5.16 to 1.04; I² = 36%; 3 studies, 185 participants; very low-certainty evidence). Olfactory stimulation with non-food-associated odors versus no intervention, placebo, or standard care Olfactory stimulation with non-food-associated odors may result in a slight reduction in duration of hospital stay in days (MD -3.23, 95% CI -5.50 to -0.97; I² = 0%; 2 studies, 94 participants; low-certainty evidence). The evidence is very uncertain about the effect of olfactory stimulation with non-food-associated odor on the mean number of daily apnea episodes (MD -2.13, 95% CI -2.28 to -1.98; 1 study, 60 participants; very low-certainty evidence) and time to full oral feeding (mean 21 (standard deviation 3.1) days in the intervention group and mean 21 (standard deviation 15.6) days in the control group; 1 study, 27 participants; very low-certainty evidence). AUTHORS'

conclusionsOlfactory stimulation with maternal breast milk compared to no intervention, placebo, or standard care may result in a slight reduction in time to full oral feeding, but the evidence is very uncertain about its effect on frequency of apnea episodes and duration of hospital stay. Olfactory stimulation with food-associated odors compared to no intervention, placebo, or standard care may result in a slight reduction in frequency of apnea episodes, but the evidence is very uncertain about its effect on duration of hospital stay and time to full oral feeding. Olfactory stimulation with non-food-associated odors compared to no intervention, placebo, or standard care may result in a slight reduction in duration of hospital stay, but the evidence is very uncertain about its effect on frequency of apnea episodes and time to full oral feeding. Future studies should be more rigorous in their design, report using TIDieR (Template for Intervention Description and Replication) checklists, have larger sample sizes, and measure outcomes such as apnea (number of infants with ≥ 1 episode), intermittent hypoxemia (number of infants with ≥ 1 episode), exclusive breastfeeding, and major neurodevelopmental disabilities.

fundingDedicated funding for this review can be found in the 'Sources of support' section. REGISTRATION: Protocol: https://doi.org/10.1002/14651858.CD016074.