Review identifies odorants used in neonatal clinical care but identifies need for further research

Olfactory cues play a crucial role in early development,1 but the natural olfactory environment is fundamentally disturbed in hospitalised term and preterm infants. Physical and olfactory contact with their mother is limited and food odours may be disturbed by artificial nutrition, respiratory support and disinfectants. Newborn preterm infants are in contact with airborne stimuli, instead of water-soluble stimuli from the amniotic fluid. It is largely unknown whether the lack of natural smells affects a neonate's physical and mental development or their relationships with their parents. Smells trigger memories and have been associated with positive and negative emotions. Even though the olfactory system is still developing in the womb, a fetus can discriminate smells2 and learn from them.3 Smell seems to play an important role in neonatal mother–child bonding and establishing breastfeeding. Humans infants seem to be particularly receptive to olfactory learning directly after birth, like animals.4 This suggests that early olfactory experiences play an essential role in neonatal development. We reviewed whether smells influenced the clinical outcomes of hospitalised term and preterm infants. PubMed was searched for peer-review studies that demonstrated successful clinical applications of olfactory stimulation to neonates and were published in English up to 28th February 2023. We reviewed titles and abstracts and identified 1874 papers, plus 26 found on Google. Duplicates and studies on model organisms or older children were removed and 849 studies were analysed more closely. We identified 21 papers that demonstrated the potential use of olfactory stimulation in neonatal intensive care units (Table 1). The effects of olfactory stimulation on term and preterm infants had mainly been studied in relation to feeding, pain and stress management and preventing apnoea. Positive effects had been reported. Olfactory stimulation enhanced sucking behaviour or food intake and resulted in better weight gain. Pain responses and crying behaviour during painful procedures were reduced and olfactory stimulation decreased the frequency of premature apnoea. The most frequently investigated substance was breastmilk, which improved feeding and reduced pain and stress management, especially when it is was from the infant's own mother. Breastmilk odours did not prevent apnoea. Vanilla was effective in improving feeding, reducing pain and stress and preventing apnoea. Other odorants were infrequently tested, but did have some positive effects. Anise and cinnamon were associated with higher weight gain in preterm infants and amniotic fluid or lavender reduced pain scores in preterm infants during venipuncture. Neonates responded better to vanilla when they were already familiar with it. Familiarisation and pleasant experiences triggered positive associations and may generally play an important role in individual responses to any olfactory stimulus. This could explain the positive effects of maternal breastmilk on improving feeding and reducing pain and stress, as familiarity was probably beneficial and enhanced the appetising and relaxing effects. However, stimulation might be more appropriate than soothing for apnoea, as positive effects were not reported. Overall knowledge in the field is still incomplete, apart from the positive effects already mentioned. There have been large inconsistencies in study methods and the outcomes assessed. This brief report provides positive examples of olfactory stimulation, but other studies have failed to show such effects. Only a few volatile substances have been tested and there is no standard protocol on how odours should be presented for the best effect. Detailed knowledge about the effects of concentrations, familiarity with the stimulus, individual preferences and optimal frequency of odour presentation, to prevent habituation effects, are needed to optimise experiments. We also need to explore how preterm birth affects the general development of the olfactory system, as even short-term odour deprivation alters olfactory function in adults.5 It is also important to understand the effects that olfactory deprivation during artificial ventilation have on infants, as the olfactory system is still developing. Future studies on the role of olfaction during infancy are warranted and there is growing evidence of the positive effects that olfactory stimulation has on term and preterm infants in relation to improving feeding, reducing pain and stress and preventing apnoea. Cornelia Hinz: Writing – original draft; conceptualization; investigation; methodology. Axel Heep: Writing – review and editing; project administration; supervision. Torsten Plösch: Writing – review and editing. Julia Huber: Writing – review and editing. Matthias Lange: Conceptualization; investigation; writing – review and editing. None. Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.