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Abstract
Objective The objective of this review was to determine the efficacy of non-pharmacological interventions for pain management during retinopathy of prematurity (ROP) screening.
Methods and analysis Electronic search of Ovid MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature, Google Scholar and ClinicalTrials.gov (USA) was conducted. Search terms from the research question and inclusion criteria were used to select randomised control trials (RCT) published from January 2000 to May 2023. Relevant data were extracted, and risk of bias was assessed using the Cochrane Risk of Bias tool V.2. Critical appraisal and grading of the quality of evidence were done using the Critical Appraisal Skills Programme tool for RCTs and the Grading of Recommendations Assessment, Development and Evaluation, respectively.
Results Twenty-one RCTs were included; 14 used sweet taste, while 7 used modified developmental care, touch or positioning, multisensory stimulation, non-nutritive sucking or music. Six studies on sweet taste and all seven latter studies showed a difference in the pain scores in favour of the interventions. The quality of evidence was however judged low and moderate due to some concerns in the randomisation process, measurement of outcome assessment and selection of reported results domains.
Conclusion The use of gentle touch, nesting, positioning, music, multisensory stimulation and developmental care in reducing pain during ROP screening is promising, however, larger studies designed to eliminate the identified concerns are needed. More evidence is also needed before sweet taste interventions can be recommended in routine practice.
- Child health (paediatrics)
- Retina
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Retinopathy of prematurity screening is a painful procedure and topical anaesthesia which is recommended for pain management does not completely alleviate pain during the procedure, thereby exposing the neonates to the adverse short-term and long-term effects of pain.
WHAT THIS STUDY ADDS
Evidence from this review shows that non-pharmacological interventions such as modified developmental care, touch, positioning with or without non-nutritive sucking and music can help alleviate pain during retinopathy of prematurity (ROP) screening, although the quality of evidence was moderate-low. However, effectiveness of sweet taste interventions in reducing pain reduction during ROP screening appears to vary across studies and lacks consistency.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study shows that non-pharmacological interventions such as modified developmental care, music, touch or positioning alleviate pain during ROP screening and may be added as adjunct therapy to topical analgesia for pain management.
More robust studies with protocols reflecting the blinding of assessors and inclusion of precision estimates on these non-pharmacological interventions including sweet taste are needed to provide high-quality evidence to justify their inclusion in routine practice and policy.
Introduction
Retinopathy of prematurity (ROP) is a potentially blinding condition that affects preterm neonates. It may regress spontaneously or progress to retinal detachment and visual loss if not treated promptly.1 Screening for ROP is recommended for preterm infants for early detection, monitoring and prompt treatment. However, the specific gestational ages and weights for screening may vary slightly depending on the country’s guideline.2–4
Until recently, most extremely and early preterm neonates in low and middle-income countries did not survive the neonatal period, however, with improvement in neonatal care, more of these infants are surviving.5 This, coupled with the high number of preterm births in Asia and sub-Saharan Africa,6 has increased the population exposed to risk factors such as supplemental oxygen without adequate monitoring, thus increasing those at risk of ROP.7 Ophthalmologists and neonatologists caring for these infants are therefore encouraged to optimise care to reduce the risk factors, screen for ROP and treat when needed to avoid visual loss.8
The ROP screening procedure involves pupillary dilatation, inserting of a speculum to keep the eyes open and examining of the retina using indirect ophthalmoscopy. These are all distressing and painful to the neonate.9 10 Follow-up eye examinations may be required depending on the retinal findings,2 further exposing the preterm neonate to repeated pain during the eye examinations. The UK screening of retinopathy of prematurity guideline recommends topical anaesthesia and ‘comfort care’ for pain during ROP screening.11 The American Academy of Pediatrics’ policy statement on ROP screening also recommends topical anaesthesia and considers non-pharmacological interventions.12
Preterm infants with low birth weight and low gestational age, have the highest risk of ROP,13 and are also prone to complications resulting in poor outcomes.14–16 These neonates are usually sick and they undergo many painful procedures as part of their care during their neonatal intensive care unit (NICU) stay.17 Repeated exposure to procedural pain in preterm neonates has been associated with short-term and long-term poor outcomes such as poor postnatal growth, poor cognitive and motor development and cortical changes.18–21 It is therefore morally and ethically necessary to adequately manage pain in these neonates in keeping with the ethical principle of doing no harm (non-maleficence) in health research.22
A Cochrane review by Dempsey et al, concluded that topical anaesthesia, which is recommended for pain management during ROP screening, does not completely alleviate the pain.23 Hence, it is important to study other interventions that may be beneficial and safe.
Pharmacological agents such as morphine have been associated with side effects such as hypotension and apnoea.19 24 Many non-pharmacological interventions including oral sucrose, oral dextrose, non-nutritive sucking (NNS), swaddling and skin-to-skin position have been shown to be beneficial in pain management in neonates.25–27 Non-pharmacological methods of pain relief are relatively easy to use, apparently safe, feasible and easy to learn and will be easy for universal implementation.28 However, some of these methods such as skin-to-skin care may not be suitable for procedures requiring a particular position like ROP screening or in very sick neonates. On the other hand, the reverse kangaroo mother care position was reported to reduce stress in babies undergoing ROP in a pilot study.29 Procedures such as acupuncture may not be readily acceptable due to concerns about infection, the inability of the infant to cooperate and the skill required for the procedure.30
It is important that the available evidence for or against these non-pharmacological interventions for pain relief during ROP screening should be critically appraised before the decision to apply these interventions to routine practice is made. Therefore, the objective of this systematic review was to determine the efficacy of non-pharmacological interventions for pain management during ROP screening.
Materials and methods
Study design
A literature search was conducted using a systematic review approach which ranks high on the hierarchy of evidence table,31 32 to appraise and summarise available evidence from well-designed randomised studies on the efficacy of non-pharmacological pain relief interventions for ROP screening.
Research question
To keep the review focused, the main concepts of this research were identified to formulate a research question using the PICO (Population; Intervention; Comparison and Outcome) framework.33 The research question was ‘In preterm neonates undergoing ROP screening (Population), are non-pharmacological pain management interventions used alone or in combination with topical anaesthesia (Intervention) compared with placebo or topical analgesics (Comparison) efficacious for pain relief assessed by preterm pain scores (Outcome)?’.
Search strategy
A systematic electronic search of large databases Ovid MEDLINE, PubMed, EMBASE, Cochrane Database of systematic reviews, Cumulative Index to Nursing and Allied Health Literature, Google Scholar, Web of Science, and ClinicalTrials.gov (USA) (for completed clinical trials) was conducted to identify available studies on the topic. An initial quick search of the topic revealed two meta-analyses published in 2018,34 and 2022,35 respectively. The search for the studies included in the 2018 study ended in 2017, while the 2022 meta-analysis included only six studies. The search for this review was done from January 2000 to May 2023 to ensure all relevant available studies are included for a robust review.
The search terms derived from the research question, keywords (synonyms, abbreviations and truncations) used for the search were preterm (premature; prematurity); retinopathy of prematurity (ROP); screening; non-pharmacologic (breastmilk, breast milk, sucrose, glucose, ‘non-nutritive sucking’, swaddling, nesting, ‘facilitated tucking’, touch, ‘developmental care’); ‘pain management’ (‘pain relief’, ‘pain treatment’, ‘pain scores’, reduc*; prevent*).
The search terms for the comparison, ‘placebo OR topical anaesthetics’ were excluded from the search.
Inclusion and exclusion criteria
The inclusion criteria were randomised controlled studies written in English and studies that used non-pharmacological interventions to treat or prevent pain during ROP screening. For objectivity of pain assessment and ease of comparison, only studies with objective outcome measures of pain scores using the premature infant pain profile (PIPP) or PIPP-revised which are the most frequently used and validated pain scales in preterm infants, were included.36
Exclusion criteria were articles on pharmacological interventions, pain management during ROP treatment and on interventions with the possibility of non-acceptance such as acupuncture and those where performing the eye examination may be difficult such as during breast feeding and skin-to-skin position. These may make the result not to be easily generalisable. Other exclusion criteria were non-English articles, non-peer-reviewed articles, abstracts and conference proceedings.
Study selection and analysis
The initial search was done by IBF and IOFD, BNE also performed an independent search for additional papers. The title/abstract screening, full-text screening and data abstraction were done using the Covidence tool independently by IBF and IOFD and consensus was agreed on by both authors. In case of disagreement, VCE acted as a tiebreaker. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram was used to describe the study selection process.37 To determine how much value to place on the studies in clinical practice, the included randomised control trials (RCTs) were assessed for risk of bias using the Cochrane Risk of Bias tool V.2 (ROB 2).38–41 The risk of bias was judged as ‘high’, ‘low’ or ‘some concerns’ for each of five domains (Randomisation process, Deviations from the intended interventions, Missing outcome data, Measurement of the outcome and Selection of the reported result). The ROB 2 for crossover studies had an additional domain (bias arising from period and carryover effects).41 The data extracted from the articles were critically appraised using the Critical Appraisal Skills Programme (CASP) tool for RCTs to determine the reliability of the results of included studies.42 43
Trial registry databases (ClinicalTrials.gov, International Standard Randomised Controlled Trial Number and WHO International Clinical Trials Registry Platform) were also searched for registration of the protocols for these RCTs to improve the critical analysis and risk of bias assessment process.44 Other aspects of the studies such as ethical consideration and reporting format were also appraised. The Grading of Recommendations Assessment, Development and Evaluation approach was also used to assess the overall quality of the evidence for the primary outcome.45 The review was registered on PROSPERO (ID - CRD42023432500)
Results
The search of databases identified 2152 references, after removing 693 duplicates and screening the abstracts for eligibility, 23 full articles were excluded for various reasons and 21 articles were finally included in the review as shown in figure 1. The details of the excluded studies are shown in online supplemental appendix A.
Supplemental material
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for the search. CINAHL, Cumulative Index to Nursing and Allied Health Literature, RCT, randomised control trial.
Study design and data extraction
All the included studies were prospective RCTs,46–66 of these, two were crossover RCTs,48 58 while the others were parallel-group RCTs. All the studies were done in Asia except three in North America,46–48 and two in Europe.49 50 The included studies were divided into two groups, A and B. Group A included the 14 studies utilising sweet taste (dextrose, sucrose, glucose and breast milk),46–57 61 63 while the remaining 7 using touch, position, multisensory stimulation, environmental modification, music and NNS made up Group B.58–60 62 64–66 A study which compared sucrose with pacifier was categorised under Group A,49 while another compared multisensory stimulation with breast milk and was categorised in Group B.64 The summary of the included studies in the two groups is shown in table 1.
Summary of included studies
Sample size and participants
The sample size was calculated in 12 studies to achieve the conventional alpha of 0.05 and power of 80–90%.46 48–50 52 53 56–58 61 62 64 One study stated a power of 90% without the alpha level,54 while five other studies used a power of 95 or 97%.51 55 59 65 66 There was no information on the sample size power calculation in three studies,47 60 63 however, Liao et al,60 acknowledged the small sample size as a limitation. Eight of the studies enrolled infants who were undergoing their first ROP examination,49 51 56 57 60 63–65 while others provided no information on this. Exclusion criteria varied among the studies, although the use of sedatives and analgesic drugs were common to most of the studies. The study by Liao et al did not state any exclusion criteria.60
A total of 1966 preterm infants were included in all the studies, 11 studies had sample size of 60 or more with a range of 60–120,51 54–56 59 60 62–66 while the remaining had less than 60 with range of 14–45.46–50 52 53 57 58 61
Ethical considerations
All the included studies obtained ethical approval from their review boards, and informed consent from the parents of the infants. In addition to the study or control interventions, all the studies used topical anaesthesia, which is recommended for pain relief during ROP screening,11 12 except Olsson and Eriksson.50 One study gave no form of analgesia to the babies when they served as their own control during the second eye examination.53
Side effects
Only five studies monitored for adverse effects,48 51–53 56 and all reported no adverse effects. The other studies did not report on adverse effects of the intervention used.
Statistical analysis
Six group A studies compared two non-pharmacological interventions; three compared sucrose with breast milk,54 55 57 one compared dextrose and breast milk,61 another one compared a single high dose with repeated low dose of 24% sucrose,56 while the last compared pacifier and sucrose.49 All the six studies had a control arm of distilled water or sterile water. Only four of these studies analysed the data comparing each arm with the control group,49 55–57 while the remaining two did a global analysis of all the three arms together with no multiplicity adjustment.54 61 Two of the group B studies also had three arms comparing two non-pharmacological interventions with a control arm, both compared the two interventions with each other as well as with the control arm separately.64 66 All the included studies reported only the p values except Boyle et al49 and Chuang et al,58 that reported 95% CI. This limits the precision and strength of evidence that can be attached to the results of studies without precision estimates.
Outcome
All the studies included in this review used the premature infant pain profile or the revised premature infant pain profile pain scoring tools as the measure of primary outcome, both tools have been validated in preterm infants.67–69 The PIPP demonstrated good construct validity and excellent inter-rater and intra-rater reliability coefficients of 0.93–0.96 and 0.94–0.98, respectively.69 This is similar to the >0.09 intraclass correlation coefficient for the level of agreement,59 and 0.90–1.00 inter-observer consistency in this review.62 Another primary outcome assessed was behavioural score (colour, respiration and alertness).58
Benzer et al studied two different doses of sucrose, 0.2 mL repeated three times and a single dose of 0.6 mL with a single dose of distilled water.56 Pain scores were recorded at baseline, 30 s, 60 s and 2 min after insertion of the speculum into each eye and at 4 min after insertion of speculum into the eye that was examined last. They reported lower median pain scores in both intervention groups compared with control (p=0.015), 30 min after examination of the first eye. The crying duration and severity were also reduced in the intervention groups compared with the control (p=0.028 and p=0.009 respectively) also after the first eye examination. All the other measurements were similar between the groups (p>0.05).
All group B studies, reported lower mean pain scores in the experimental groups compared with the control groups and these differences were statistically significant.58–60 62 64–66 The outcome assessors were not blinded in five of the studies,58–60 62 65 however, there were at least two assessors to reduce bias in outcome measurements.
The secondary outcomes assessed varied between the studies. The crying time was shorter in the intervention compared with the control groups (p=0.028, 0.01 and 0.001),56 59 60 and the crying severity was also lower in the sucrose group compared with placebo (p=0.009).56 The mean recovery time was shorter for the developmental compared with the standard care group (8.6±11.5 min vs 25.5±20.8 min, p=0.003).58 The reduction in regional cerebral oxygen saturation measured with near-infrared spectrophotometer from baseline for controls (−9.94+8.98) was greater than (−4.61±5.23) for the experimental group.62
Critical appraisal
The ROB 2,40 was used to assess the risk of bias for the parallel-group RCTs,46 47 49–57 59–66 while the ROB 2 for cross-over studies,41 was used for the two crossover studies.48 58 Three group A studies,51 53 63 had some concerns with the randomisation process and or allocation concealment, while all the others had a low risk of bias. There was also a low risk of bias in the deviation from intended interventions, missing outcome data and selection of reported results domains in the parallel-group RCTs in group B.59 60 62 64–66 The four parallel group RCTs in group B that used interventions in which blinding of outcome assessors was difficult, had ‘some concerns’ in the measurement of outcome domain.59 60 62 65 However, there were at least two outcome assessors with good interobserver reliability. The group A crossover RCT also had some concerns about the selection of reported results.48 The group B crossover study, had some concerns regarding risk of bias in the randomisation process, measurement of outcome and selection of reported results domain.58 The information provided was not detailed enough to show whether the results of both periods or only those of the first period were analysed.
Only four of the studies had their protocols registered in the trial registries that were searched, though the details were scanty.56 62 64 65 This was considered when assessing the risk of selective reporting to answer the question on whether the statistical analysis methods used were decided before the unblinded outcome results (where applicable), were made available. This domain was however judged as low-risk for all the parallel-group RCTs as the answers to the other questions did not suggest a problem with reporting bias. The result for the risk of bias for the parallel-group RCTs is shown in figure 2.
Risk of bias judgement for included parallel-group randomised control trials using Cochrane Risk of Bias tool V.2.
The included studies were further critically appraised for quality using the CASP checklist,42 as summarised in table 2.
Summary of the critical appraisal of the included studies using the Critical Appraisal Skills Programmes (CASP) for randomised control trials checklist
The quality of evidence from an RCT in the hierarchy of evidence is high,31 however, some issues with risk of bias/limitations, inconsistency, indirectness, imprecision or publication bias may require that the level of evidence of the RCT be downgraded.70 The quality for two of the group A studies was downgraded from high to low,51 63 while the remaining were downgraded from high to moderate. All the parallel group RCTs where there was no blinding of outcome assessors except the study by Chuang et al,58 were downgraded from high to low on account of concerns with risk of bias and imprecision (table 3).
Assessment of quality of evidence of included RCTs using the GRADE approach
Discussion
The objective of this review paper was to identify and judge the quality of available evidence to support the routine use of non-pharmacological interventions for pain relief during ROP screening. The evidence identified from this review shows that non-pharmacological interventions using position and environmental modification, multisensory stimulation, NNS and music are beneficial in reducing pain in neonates undergoing ROP screening. All the group B studies showed significant differences in pain scores in favour of the interventions,58–60 62 64–66 however, only one reported the effect estimates which provide information on the strength and direction of the effect.58 Therefore, the strength of the evidence could not be weighted, in addition, a forest plot could not be done to summarise and compare the weight of the results obtained from these studies.
Furthermore, five of the studies had some concerns regarding outcome measurement bias due to the non-blinding of the assessors which is attributed to the nature of the interventions being tested,58–60 62 65 and these could affect the results and internal validity of the studies.71 However, the use of pain scales and the dual or triple assessors for outcome assessment in these studies, could reduce this bias in outcome.
The result of the studies using sweet taste in this review are inconsistent. Only 6 of the 14 studies on sweet taste were favourable for the intervention,46 48 51 52 55 63 while the remaining 8 showed no significant changes in the pain scores between the intervention and the control arms in the group. Contrary to the findings in this current review, the two recent meta-analyses earlier identified,34 35 reported that sweet taste was beneficial. Disher et al reported that sweet taste combined with topical anaesthesia and an adjunct intervention such as non-nutritive sucking had the highest probability of being the optimal intervention for pain management during ROP screening. The pain score difference was −3.67 (95% CI −5.86 to −1.47) and surface under the curve was 0.86.34 The reason for the difference between these studies and the current one is however not clear.
There were some variations in the patient population regarding the number of ROP examinations, the timing of the pain score assessment and when the study ended. Some studies recruited preterm infants undergoing their first ROP examination,49 51 56 57 60 63–65 while others did not add this in their inclusion criteria. This could influence the results as repeated pain has been shown to modulate pain response in preterm infants.72 Therefore, infants having their second or third ROP examination may show reduced pain compared with those having their first examination.72 73 The timing of pain scores assessment varied across studies, some assessed before, during and after the eye examination, some had specific timing such as 30 s after insertion of speculum, some were at insertion of speculum, while others were not specific.54 62 The study ended after examination of the first eye in some of the studies,46 49 51 60 61 some ended after examination of the second eye,47 48 54 56 57 59 62 64 66 while others were not specific.50 52 53 55 58 63 65 These variations could be sources of type 1 errors and may affect the internal validity of the studies.
Implementation of findings
The interventions that consistently showed reduction in pain scores in this review appear to be low-cost as no equipment or drug were involved in their use. However, interventions like ROP position, gentle touch and developmental care require training and additional personnel which all come with added costs and expertise. Interventions such as developmental care programme are also time consuming and may overstretch the already overworked staff in NICUs in low-resource countries. This may reduce the widespread use of these interventions even when there is high-level of evidence in support of their use.
Another challenge to implementation is the fact that preterm infants with the exclusion criteria in the included studies such as presence of stage 3 or 4 intraventricular haemorrhage, use of mechanical ventilator and asphyxia are also at risk of ROP, thus, the reproducibility of the findings of these studies in these excluded populations is not certain.
Strengths and limitations
The rigorous process for conducting systematic reviews which was employed in this review is a major strength for this study. The limitations of this study include the exclusion of non-English publications which could create bias during the study selection, data extraction and analysis process. Performing a meta-analysis may have improved precision and quality of evidence of this review,74 however, the heterogeneity within the studies was a major constraint.
Conclusion
Non-pharmacological pain management interventions during ROP screening using touch, position, multisensory interventions, music, NNS and environmental modification appear to be beneficial, however, the quality of the level of evidence for these studies is low to moderate. Considering the negative consequences of untreated pain in preterm neonates, interventions such as music, nesting and NNS, which are easy to administer and require little or no funds may be added as adjunct to topical anaesthesia for pain management during ROP screening. Larger and better-designed studies with a low-risk of bias (outcome assessment and selection reporting bias), that consider the feasibility of these interventions in more settings are needed before these interventions can be recommended for routine use.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Acknowledgments
This was originally an MSc dissertation by IBF and was later expanded and contributed to by other authors. We appreciate Dr Michael Hall and Susan Smith of the Faculty of Health Sciences, University of Southampton, and Rami Subhi of University of Melbourne for their immense and valuable contributions to shaping this work.
References
Supplementary material
Supplementary Data
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Footnotes
Contributors Conception or design of the study: IBF. Acquisition of data: IBF, IOFD and BNE. Analysis and interpretation of data: IBF, IOFD and VCE. Drafting the manuscript: IBF. Revising it critically for important intellectual content: IOFD, BNE and VCE. Final approval of the version to be published: IBF, IOFD, BNE and VCE. Agreement to be accountable for all aspects of the work: IBF, IOFD, BNE and VCE. Guarantor: IBF.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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