Olfactive stimulation interventions for managing procedural pain in preterm and full-term neonates: a systematic review protocol
De Clifford-Faugère et al. Systematic Reviews
Olfactive stimulation interventions for managing procedural pain in preterm and full-term neonates: a systematic review protocol
Gwenaëlle De Clifford-Faugère 0 1 3
Andréane Lavallée 0 1 3
Marilyn Aita 0 1 2 3
0 CHU Sainte-Justine Research Center , Montreal , Canada
1 Faculty of Nursing, Université de Montréal, C.P. 6128 Succ. Centre-ville , Montreal H3C 3J7 , Canada
2 Quebec Network of Nursing Intervention Research (RRISIQ) , Montreal , Canada
3 Faculty of Nursing, Université de Montréal, C.P. 6128 Succ. Centre-ville , Montreal H3C 3J7 , Canada
Background: While hospitalized in the NICU, preterm neonates undergo many painful procedures. This may be the same for full-term neonates when longer hospitalization is required. Untreated and repeated pain has short-term as well as long-term consequences for these neonates. Pharmacological pain management methods have many limitations in their applications for both preterm and full-term neonates. A combination of different non-pharmacological methods is recommended for pain management. The effect of olfactive stimulation as a non-pharmacological pain management method was investigated by a few studies in the past years with premature and term neonates, but no systematic review has been conducted. The objective of this systematic review is to evaluate the effect of olfactive stimulation intervention on the pain response of preterm and full-term neonates during painful procedures. Methods: An electronic search will be conducted in various databases such as PubMed (1946 to date), MEDLINE (1946 to date), CINAHL (1981 to date), Embase (1947 to date), PsycINFO (1806 to date), Web of Science (1945 to date), CENTRAL and Scopus (1960 to date), and Proquest, without restriction for the year of publication. Only studies published in English or French will be included. The search will be conducted using the following three concepts: pain, odors, and neonates. Selection of articles, data extraction, and assessment of risk of bias will be conducted by two independent researchers. A third researcher will intervene in case of disagreement. According to the availability of studies and data homogeneity, the results will be combined to perform a meta-analysis, or they will be described by a narrative synthesis. Discussion: This systematic review will provide light on the current state of knowledge on the effectiveness of olfactive stimulation interventions for managing pain in preterm and full-term neonates. This review will guide clinical practice as well as research to improve preterm and full-term neonates' pain management and prevent short-term and long-term complications caused by pain. Systematic review registration: PROSPERO CRD42017058021
Pain; Odors; Non-pharmacological intervention; Preterm; Full-term neonate; Systematic review
It has been known, for several decades, that neonates feel
]. Almost 8% of births are premature in North
]. Full-term and preterm neonates are subject
to painful procedures during their hospitalization in the
neonatal unit. These procedures are quite frequent,
varying from 7.5 to 17.3 per week, depending on the unit and
the neonate’s health status [
]. The preterm neonates are
especially vulnerable to pain [
] due to the immaturity of
their neurological system. According to a study conducted
in 2011 by Johnston, Barrington [
], the frequency of
painful procedures experienced by preterm neonates reach 33
per week during their hospitalization in the neonatal unit.
For full-term and preterm neonates, only half of these
painful procedures are accompanied by a pharmacological
or non-pharmacological pain management intervention
3, 5, 6
]. Moreover, untreated pain has short-term
consequences such as physiological and behavioral changes in
]. Furthermore, untreated and repeated pain
could cause sensory disorders associated with the number
of painful procedures received during the hospitalization,
for full-term and preterm neonates [
], as well as lower
mental and psychomotor indices of development in
preterm neonates [
]. So, to improve health outcomes, it
appears essential to effectively relieve pain in preterm and
term neonates. This paper presents the protocol for a
systematic review considering the effectiveness of olfactive
stimulation interventions as a pain management
intervention during the ten most frequent painful procedures [
to which full-term and preterm neonates are exposed
throughout neonatal hospitalization.
Despite advances in this area of knowledge, there is
still little evidence supporting pain management
interventions for full-term and preterm neonates [
]. A lack
of knowledge still persists about the long-term impact of
pharmacological pain management methods, limiting
their application [
]. Systematic reviews have found
that effective non-pharmacological interventions for
fullterm neonates are sucrose administration, which could
be combined to non-nutritive sucking [
breastfeeding, and skin-to-skin contact . For preterm
neonates, only sucrose, with or without non-nutritive
], or skin-to-skin contact [
] is considered
to be effective interventions. However, these
interventions are not always applicable depending on the
circumstances as breastfeeding requires the mothers’
presence, and skin-to-skin contact requires one of the
two parents. In addition, it is recommended by the
American Academy of Pediatrics [
] to combine several
non-pharmacological methods in order to effectively
relieve pain in preterm and full-term neonates. Olfactive
stimulation interventions could be easily combined with
other interventions as it uses the olfactive sphere which
is little stimulated by the above cited interventions.
How the intervention might work
During embryogenesis, the olfactory system is growing
rapidly since as early as 11 weeks of gestation, the first
functional cells are present [
]. Full-term and
preterm neonates have acquired the necessary skills
allowing them to detect, distinguish, and recognize a smell as
soon as 28 weeks of gestation . Furthermore, they
may express preferences when they are exposed to
different smells [
]. For neonates, olfactive stimulation
interventions seem to be particularly interesting to
investigate. To our knowledge, the effectiveness of this
type of intervention has never been evaluated by a
Several other elements, let us hypothesize that an
olfactive intervention could contribute to pain
management in neonates. The skin-to-skin contact where the
neonate smells his own mother’s odor helps decrease
]. Breastfeeding is also an effective intervention
for neonates, where they can smell their mother’s milk
]. Olfactive stimulation intervention could also act as
a distraction. By linking pain with olfaction physiology,
we hypothesize that olfactive stimulation could have an
impact on the emotional and affective pain components.
Importance of doing the review
To our knowledge, no systematic review has evaluated
the effectiveness of olfactive stimulation interventions
on full-term and preterm neonates’ pain response.
Considering short-term and long-term consequences of
repeated and untreated pain, as well as the lack of
knowledge about the other pain management
interventions, it is essential to evaluate the effectiveness of this
type of intervention. If possible, we will also evaluate the
combined effect of olfactive stimulation intervention
with another pain management intervention, in
accordance with the recommendations of the American
Academy of Pediatrics [
]. A better knowledge of effective
pain management interventions for neonates will guide
the clinical practice and future research. The purpose of
this systematic review is to assess the effectiveness of
olfactive stimulation interventions on full-term and
preterm neonates’ pain response.
The objective of this systematic review is to answer the
following question: What is the effectiveness of olfactive
stimulation interventions on full-term and preterm
neonates’ pain response during a painful procedure
compared to standard of care?
We followed the Preferred Reporting Items for
Systematic review and Meta-Analysis Protocols (PRISMA-P)
recommendations for the development of this protocol
[see Additional file 1] [
Types of studies
Randomized controlled trials will be included in the
systematic review. Quasi-experimental studies will only be
included in the descriptive synthesis and excluded from
the meta-analysis of this review. There will be no
restrictions in regard to the clinical settings where the olfactive
stimulation interventions have been evaluated.
Types of participants
Participants will be full-term neonates (> 37 weeks of
gestation) and preterm neonates (< than 37 weeks of
gestation) undergoing a painful procedure. The ten most
frequent painful procedures in full-term and preterm
neonates documented will be considered in this review [
(1) nasal aspiration, (2) tracheal aspiration, (3) heel
prick, (4) adhesive removal, (5) gastric tube insertion, (6)
venipuncture, (7) arterial puncture, (8) installation of
peripheral intravenous cannula, (9) chest physiotherapy,
and (10) removal of peripheral intravenous line.
Types of interventions
The olfactive stimulation interventions that will be
included in this systematic review include all types of
odors that neonates may have been exposed to during
the intervention, whether natural (e.g., milk) or artificial
(e.g., vanilla). All methods of odor administration to the
neonates will be considered (e.g., gauze, cotton). Studies
examining the effectiveness of multisensory
interventions will not be considered in this systematic review,
because it will not be possible to isolate the effect of the
olfactive stimulation intervention on pain response.
Comparators include placebo, standard of care, or
different odors. Standard care can be defined as any care or
intervention carried out in the clinical setting in order to
manage procedural pain in neonates. Standard care must
have been received by the two groups in the selected
studies. For ethical considerations, the control group
may be an active group, where the evaluation will focus
on the combined effect of the olfactive stimulation
intervention with, for example, sucrose or swaddling
(considered in some areas as standard care) compared to
sucrose alone or to the swaddling alone.
Full-term and preterm neonates’ pain response is the
primary outcome of this systematic review. Pain has different
components that evaluate, among other things, behavioral
and physiological indicators [
]. Pain response could be
measured by behavioral indicators (i.e., crying, facial
reactions), physiological indicators (i.e., cortisol levels, heart
rate, respiratory rate, oxygen saturation), and contextual
indicators (i.e., gestational age). Procedural pain
assessment tools are different for full-term and preterm
neonates. Pain response should be measured in studies by
valid and reliable scales for the two populations in order
to be included in the meta-analysis of this review, such as
the premature infant pain profile (PIPP) adapted to
measure pain in neonates from 28 to 40 weeks of gestation
(WG), the neonatal infant pain scale (NIPS) from 26 to 47
WG, the neonatal facial coding system (NFCS) from 26 to
47 WG, and the Douleur aigue du nouveau-né [acute pain
of the newborn] (DAN) from 24 to 41 WG.
Adverse events of olfactive stimulation interventions will
be considered as a secondary outcome. Secondary
outcome will only be considered if the study’s primary
outcome is pain management. Adverse events will be
evaluated as follows: (1) adverse events reported by
authors, (2) none adverse events reported by authors, and
(3) adverse events not mention by authors.
A search by Mesh terms and keywords will be
performed with the three central concepts: pain, odors, and
neonates (term and preterm). The search strategy has
been designed in collaboration with an experienced
librarian using these three concepts [see Additional file 2].
The research strategy will be adapted to each specific
database. No year of publication restrictions will be
applied because olfactive stimulation interventions have
never been evaluated by a systematic review. Only
studies published in English or French will be considered in
Research will be conducted in different electronic
PubMed, 1946 to date
MEDLINE (OVID), 1946 to date
CINAHL (EBSCOHost), 1981 to date
EMBASE (OVID), 1947 to date
PsycINFO (OVID), 1806 to date
Web of Science, 1945 to date
Cochrane Central Register of Controlled Trials
(CENTRAL), The Cochrane Library
Scopus, 1960 to date
ProQuest Dissertation and Theses Global British
Searching other resources
Journals focused on neonatology, neonates, and pain will
be consulted. Conference abstracts will be searched
(BIOSIS, Biological abstract). References of the included
studies will be screened for other potential studies. If
data is missing, the authors will be contacted to provide
additional data, as well as to identify unpublished
studies. We will also seek the ClinicalTrials.gov website, the
World Health Organization International Clinical Trials
Registry Platform, and metaRegister of controlled trials
for ongoing or unpublished randomized clinical trials.
Data collection and analysis
The process of study selection will be illustrated by a
PRISMA diagram [
] and will be made according to
the steps described by Pai et al. [
]. Duplicates of
studies will first be eliminated from the studies identified
through the database searches. Study references will be
saved in a bibliographic management software
(EndNote© X7). Study selection will be performed in two
steps. The first step will be a selection of studies from
their titles and abstracts, by two independent
researchers. In case of disagreement, consensus will be
sought by discussion, and if necessary, a third expert
intervention will be sought. In the second step, full
studies selected previously will be read by two independent
researchers in order to decide on the inclusion or
exclusion of each study according to our selection criteria.
Additional data could be requested to the study authors,
if necessary to make a decision about its inclusion in the
systematic review. Disagreements will be solved by
consensus or by a third expert if necessary. Reasons for
study exclusion will be documented. Each included study
will have a unique identification number.
Data extraction and management
Two independent researchers will extract the data of ten
studies and then compared to ensure consistency
between the two researchers. A third researcher will be
requested in case of disagreement. For each study,
extracted data will be:
– Characteristics of the study: authors, year, country
of publication, title of the study, and trial number;
– Methodology: design, purpose of the study, type of
randomization, control group, sample size, study
setting, method of data collection, and instruments
used (i.e., video.);
– Participants: sociodemographic characteristics
(gestational age at birth, age at the time of the
intervention, birth weight, breastfeeding, mode
of delivery, respiratory support during the
intervention) and exclusion and inclusion criteria;
– Painful procedure: painful procedure type, frequency,
– Intervention: description (duration, type of odors,
exposure time to the odors, frequency, distance of
the odor to the neonates’ head, comparator); and
– Results of the study.
These data will be extracted for each study and
entered into a data extraction form. Then, data will be
entered in the software review manager (RevMan 5.1). If
several papers of the same study are found, the paper
containing the most comprehensive information will be
included. Others will be excluded, unless they report
additional data that are not exactly the same and that
are also related to pain or pain components, in which
case they will also be included.
Dealing with missing data
When data are missing in studies, authors will be
contacted. If data cannot be obtained, an imputation
method will be used [
] and then a sensitivity analysis
will be performed to assess the impact of imputing data
in the studies’ data synthesis. Otherwise, a descriptive
synthesis will be carried out.
Assessment of risk of bias
Risk of bias of each selected study will be assessed by
two independent researchers. In case of disagreement, a
third expert will be consulted. We will use the Cochrane
Risk of Bias Assessment Tool [
] to assess the risk of
bias according to the following items: (1) random
sequence generation (selection bias); (2) allocation
concealment (selection bias); (3) blinding of participants,
staff, and outcome assessment (detection and
performance bias); (4) incomplete outcome data (attrition bias);
(5) selective outcome reporting (presence reporting
bias); (6) other sources of bias (other bias has not been
addressed in other sections); and (7) overall risk of bias.
Authors of included studies will be contacted in case of
doubts during the evaluation of a bias. Each of these
biases will be classified in terms of uncertain risk, low
risk, and high risk. In the review, this information will
be presented in a table done by the RevMan 5.1
software. Risk of bias will be taken in consideration for the
analysis and the interpretation of the results.
A descriptive synthesis will summarize data from different
studies. Furthermore, a meta-analysis will be conducted
according to the number of included studies and their
data homogeneity. For continuous data, we will report the
average as well as the mean difference (MD) for outcomes
measured by the same scale and standardized mean
difference (SMD) for outcomes measured by different scales,
both with a 95% confidence interval. For dichotomous
data, we will use a risk ratio with a 95% confidence
interval. Heterogeneity will be statistically verified by a
chisquare test, with a p value < 0.1 for statistical significance,
as well as report the I2. I2 will be interpreted as the
]: 0–40%: heterogeneity might not be important,
30–60%: may represent moderate heterogeneity, 50–90%:
may represent substantial heterogeneity, and 75–100%:
considerable heterogeneity. If a I2 > 50% is found, a
subgroup analysis will be carried out in order to try to explain
it. The RevMan 5.1 software will be used to combine
studies. First, we will choose a fixed effect model; then, we will
change to the random effect model if the data are not
sufficiently homogenous. Otherwise, a descriptive synthesis,
taking into account the design, the randomization, the
intervention, and how pain response was measured, as
well as the results, will be conducted [
If possible, full-term and preterm neonates will be
separated into subgroups for analysis. Moreover, if
possible, subgroup analysis will be conducted by
considering different types of odors used in studies and
the different pain components in the instruments (i.e.,
If more than ten studies meet the inclusion criteria,
publication bias will be assessed graphically through a Funnel
plot done by the RevMan software as well as statistically
by a regression of Egger test [
Quality of evidence
Assessment of data quality will be performed by the
Grading of Recommendations Assessment, Development and
Evaluation working group methodology (GRADE),
including five considerations: limitations, effect consistency,
imprecision, indirectness, and publication bias [
Depending on the GRADE score, quality of the evidence will
be ranked high, medium, low, or very low, by two
independent experts and will be taken into account in the
recommendations based on data analysis. In addition, studies
may be excluded based on the quality of evidence.
Given consequences of repeated and untreated pain, it is
important to evaluate the effectiveness of interventions
for pain management in preterm and full-term neonates
during painful procedures. This systematic review will
contribute to the advancement of knowledge on pain
management in preterm and full-term neonates to guide
clinical practice and research.
Additional file 1: PRISMA-P 2015 checklist (DOCX 29 kb)
Additional file 2: PubMed search strategy. (DOCX 13 kb)
DAN: Douleur aigue du nouveau-né; GRADE: Grading of recommendations
assessment, development, and evaluation working group methodology;
NFCS: Neonatal facial coding system; NICU: Neonatal intensive care unit;
NIPS: Neonatal infant pain scale; PIPP: Premature infant pain profile;
PRISMAP: Preferred reporting items for systematic review and meta-analysis
protocols; WG: Weeks of gestation
Thank you to Assia Mourid, librarian at the Faculty of Nursing of the University
of Montreal, and Josianne Dupuis, librarian. AL thanks TD Bank in collaboration
with the Comité pour le Développement de la recherche infimière (DÉRI) of the
CHU Sainte-Justine for financial support.
This systematic review is not supported by funding. This review is conducted
as part of the doctoral studies of GD.
Availability of data and materials
GD is the guarantor of the review. The systematic review will be written by
GD, MA, and AL. Disagreement resolution will be done by MA who will also
act as a consultant. Selection of studies and databases, gray literature, and
authors’ contacts will be done by GD. Selection, data extraction, and evaluation
of the quality of evidence of the studies will be carried out by GD, MA, and AL.
The data will be entered in RevMan by GD. Data analysis will be done by GD in
collaboration with a statistician and then interpreted by GD, MA, and AL. All
authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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