The Comparative Efficacy and Safety of Sweet Solutions to Reduce Preterm Infants’ Pain Level: A Systematic Review and Network Meta-analysis

The Comparative Efficacy and Safety of Sweet Solutions to Reduce Preterm Infants’ Pain Level: A Systematic Review and Network Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Comparative Efficacy and Safety of Sweet Solutions to Reduce Preterm Infants’ Pain Level: A Systematic Review and Network Meta-analysis Defi Efendi, Yi-No Kang, Regina Natalia, Ariesta Milanti, Putri M.T. Marsubin, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4935843/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Jan, 2026 Read the published version in Systematic Reviews → Version 1 posted 4 You are reading this latest preprint version Abstract Background: The efficacy of sweet solutions in alleviating pain for preterm infants has been extensively investigated, yet the most efficacious sweet solutions remain unknown. Methods: We conducted a search in the CINAHL, MEDLINE, EMBASE, CENTRAL, Scopus, and ProQuest databases for studies. Randomized controlledtrials (RCTs) utilizing glucose, sucrose, or expressed breast milk for managing pain in preterm infants were included in this study. A random-effects frequentist network meta-analysis was conducted to evaluate outcomes in three pain measurement time points. The primary outcome was the pain level in the reactivity phase. The secondary outcomes were pain in the regulation and recovery phases, as well as heart rate, oxygen saturation, respiratory rate, crying time, and adverse events. P-scores and beading plot were utilized to rank the efficacy of the sweet solutions. Results: Of 10,043 references, 42 RCTs (2,733 newborns) were analyzed. Compared to the controls alone, glucose (standardized mean difference [SMD], -0.72; 95% confidence interval [CI], -1.19 to -0.25]) and sucrose (SMD, -0.56; 95% CI, -1.04 to -0.07]) were associated with lower pain responses in reaction phase. In the regulation and recovery phases, pain reduction was consistently linked to glucose, sucrose, and expressed breast milk. Those interventions were supported by results of P-scores that ranged from 0.877 to 0.917 showing glucose's superiority in the three phases. Glucose was associated with a higher risk of adverse events. Half of the 38 trials had a low risk of bias. Meanwhile, the certainty of the evidence was high to very low. Conclusions: Our findings indicate that glucose was ranked best for lowering pain in preterm infants, followed by sucrose and expressed breast milk. Future RCTs are expected to investigate the efficacy of sweet solutions, both alone and combined with other pain management methods, as well as the effects of repeated applications. Systematic review registration: PROSPERO CRD42023389288. sweetener pain management calming effect physiological stability low birth weight newborn network meta-analysis meta-regression Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Compared to healthy-term neonates, preterm newborns are more likely to experience prolonged and repetitive painful procedures (Anand, 2001 ; Obeidat et al., 2021 ). These unpleasant stimuli were reported to have negative clinical, physiological, and psychological consequences (Efendi, Rustina, et al., 2018; Gao et al., 2016 ; Li et al., 2022 ). Previous studies showed the impacts of painful exposures on brain development (Duerden et al., 2018 ; Ranger et al., 2015 ), cognitive delays (Campbell-Yeo et al., 2022 ; Vinall & Grunau, 2014 ; Walker, 2019 ), and persistent internalizing behavioral problems across toddlerhood to age 8 years (McLean et al., 2022 ). Furthermore, premature infants experiencing pain are more likely to develop non-communicable diseases (Greer, 2017 ; Huang et al., 2016 ; Williams & Lascelles, 2020 ). Thus, measures to reduce pain sensations in this vulnerable population are urgently needed. As a simple non-invasive method (Harrison et al., 2017 ; Kassab et al., 2012 ; Stevens et al., 2016 ), the utilization of sweet solutions to reduce acute discomfort in neonates has garnered significant attention and investigation (Harrison et al., 2017 ). Previous systematic reviews and meta-analyses extensively examined the efficacy of glucose, sucrose, and breast milk (Bueno et al., 2013 ; Disher et al., 2018 ; Gao et al., 2016 ; Harrison et al., 2017 ; Li et al., 2022 ; Liu et al., 2017 ; Shah et al., 2012 ; Stevens et al., 2013 ; Stevens et al., 2016 ), and these sweet solutions can reduce pain or crying times during various procedures such as heel lances, venipuncture, intramuscular injections, and eye examinations. However, the most effective sweet solutions intervention has yet to be definitively ascertained, and there is a notable absence of a comprehensive approach for evaluating the efficacy of diverse sweet solutions interventions within the contemporary scientific domain. Comparing more than two interventions using multiple pairwise meta-analyses may lead to incoherent estimates of the relative effects of every intervention compared to every other one (Dias & Caldwell, 2019 ). In addition, several significant findings in previous syntheses relied on a fixed-effect model despite statistical heterogeneity concerns, whereas other syntheses aggregated data using a random-effects model. Comparing the effects of various sweet solutions interventions across these syntheses is inappropriate, especially given differences in analytical assumptions and statistical models. A network meta-analysis (NMA) is a reliable method for synthesizing data from multiple treatment comparisons across trials (Dias & Caldwell, 2019 ; Salanti, 2012 ; Salanti et al., 2008 ). For each outcome, it provides estimates of the effect for all possible pairwise comparisons and offers a comprehensive overview of the impact of sweet solution interventions on pain alleviation in preterm infants. This study aimed to rank sweet solution interventions for preterm infants undergoing painful procedures based on their efficacy and safety, using a consistent model through network meta-analysis (Rücker & Schwarzer, 2015 ). Methods Study design A frequentist framework was used in this NMA. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) with an NMA extension to report this study (Hutton et al., 2015). The protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (PROSPERO CRD42023389288). Search Strategy and Study Selection We searched relevant randomized controlled trials (RCTs) to compare different kinds of sweet solutions to reduce pain for various procedures in hospitals from six databases (CINAHL, MEDLINE, EMBASE, CENTRAL, Scopus, and ProQuest Dissertation and Thesis) starting from their inception to 26 December 2022. In addition, we use the automatic alert function of the database to track whether there are newly published studies until July 2024. Reference lists of published systematic reviews were also searched. Details of the search strategy sample are provided in Supplemental eTable 1. Preterm infants who were less than 28 days old and experiencing procedural pain such as heel pricking, suctioning, orogastric/nasogastric insertion, or intravenous line cannulation were the target population in this study (Supplemental eTable 2) (Hall & Anand, 2014; Shen et al., 2021). Infants who were critically ill with altered consciousness or who had received analgesics were excluded from the study. Two researchers (OO and OO) independently screened titles and abstracts using Endnote 20 and assessed the full text for potential inclusion in the study. Any disagreement was resolved through a discussion moderated by the first author (OO). Intervention This review incorporated three different sweet solutions. The following solutions containing sugar were defined as (1) glucose or dextrose as a single sugar sweetness from the monosaccharide class; (2) sucrose as a single sugar’s sweetness from the disaccharide class; (3) fructose as a single sugar’s sweetness from the monosaccharide class; and (4) expressed breast milk as a natural sweetener that contains sugar in the form of lactose and belongs to the disaccharide class (Assary & Curtiss, 2012; Eggleston et al., 2018; Engelking, 2015). Finally, we defined the control group as a placebo, no intervention, or other active intervention given above. Primary and secondary outcomes We included pain as the primary outcome which was measured by validated instruments as described in Supplemental eTable 3. We modified previous definitions to categorize the pain level time measurement (De Clifford-Faugere et al., 2020; Disher et al., 2018; Efendi, Caswini, et al., 2018), comprised of pain reactivity (during a procedure), pain regulation (immediately after a procedure), and pain recovery (more than 2 minutes after a procedure). Secondary outcomes comprising heart rate, respiratory rate, and oxygen saturation in the reactivity, regulation, and recovery phases were analyzed. In addition, we assessed the impacts of interventions on the total crying time and adverse events (AEs). Data extraction OO and OO independently extracted data from the reviewed studies. Any discrepancies were resolved through discussion. We extracted characteristics of study participants such as gestational age, birth weight, gender, and other required data. We further extracted arm-level data including the sample size, mean, median, standard deviation, interquartile range, and other types of data for all of the given time measurements. Ten different scenarios were used to calculate missing data as described in a previous study (Chi et al., 2023). Quality of evidence and risk of bias Two independent researchers (OO and OO) evaluated the risk of bias (RoB) among studies using the Cochrane risk of bias 2.0 (JPT et al., 2022; Sterne et al., 2019). Additionally, confidence in the NMA (CINeMA) framework covering within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence was used to assess the certainty of the evidence (CoE) (Nikolakopoulou et al., 2020). This approach relies on the methodology proposed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group for pairwise meta-analyses (PMAs) (Salanti et al., 2014). Data synthesis and statistical analysis Transitivity assumptions were evaluated by checking distributions of potential confounding variables nested in the infants’ characteristics as described in Supplemental eTable 4. The DerSimonian-Laird random-effects model was used to calculate the contrast-based model meta-analysis (DerSimonian & Laird, 2015; George & Aban, 2016). Cohen’s D was used to estimate and classify mean differences (MDs), standardized mean differences (SMDs), and risk ratios (RRs) between groups (Durlak, 2009). Some empirical studies have suggested that there may be minimal practical differences between Frequentist and Bayesian approaches to network meta-analysis (Lázaro et al., 2020; Seide et al., 2020). Given that our confidence ratings are derived from CINeMA, which is grounded in Frequentist principles (Nikolakopoulou et al., 2020), we opted to estimate relative treatment effects and rankings using a Frequentist framework (Watt et al., 2019). To illustrate treatment comparisons based on direct evidence, the network plot geometry was used for each outcome of interest (Tonin et al., 2019). The sizes of nodes in the plots corresponded to sample sizes, and the width of the edges was proportional to the total studies involved in the comparisons. Statistical analyses were performed in R, version 4.2.2 using the “netmeta” package (Rücker et al., 2023; van Valkenhoef et al., 2012). To summarize the findings with treatment rankings, we used P score that analogue to the surface under the cumulative ranking curve (SUCRA) (Harrer et al., 2021; Rücker & Schwarzer, 2015; Salanti et al., 2011). Then, we employed beading plot to visually summarize the ranking probabilities for all outcomes of interest using the "rankinma" package (Chen et al., 2023). This innovative graphic technique provides a concise representation of complex NMA rankings with multiple outcomes in a single linear plot. Each line corresponds to a specific outcome, and the position of the dots along the line indicates the relative ranking of treatments. In our meta-analysis, treatments positioned further to the right are considered more effective (Chen et al., 2024). Heterogeneity, incoherence, and outliers within network models were evaluated. We assessed heterogeneity using t 2 by estimating the variance caused by the true effect size (Higgins, 2008). Values of t 2 of 0.04, 0.09, and 0.16 are respectively defined as low, moderate, and high heterogeneity (Borenstein et al., 2008). Alternatively, I 2 > 50% was also considered an attribute of higher between-study heterogeneity by assessing the amount of variance observed (Higgins et al., 2019; Higgins et al., 2003). We also examined the mean path length to estimate the degree of indirectness of an estimate (Papakonstantinou et al., 2020) with a threshold of > 2 which indicated a less-reliable NMA estimate (Konig et al., 2013). We used split direct and indirect evidence to detect the local consistency. Global inconsistency and a design-by-treatment interaction model were considered to detect inconsistencies within the entire NMA using Cochrane’s Q statistic with a significant level of p < 0.1 (Higgins et al., 2012). Meanwhile, Egger's test and visual inspection of the comparison-adjusted funnel plots were used to evaluate publication bias and small study effect (Chaimani & Salanti, 2012; Egger et al., 1997). Forward search algorithm was used to detect extreme study effects through “NMAoutlier” package (Petropoulou et al., 2021). Cook's distance and the variance ratio were used to detect potential outliers. Furthermore, we created a forward plot with z-values to visually demonstrate whether the results were significantly impacted by each individual study, considering both direct and indirect evidence. To explore the source of heterogeneity, we performed a sensitivity analysis and network meta-regression. Sensitivity analysis in this study was carried by removing single trial with a high risk of bias and an extremely high dose of sweet solutions (Dehghani et al., 2019). In addition, a meta-regression was further performed to assess the impact of risk of bias and type of procedure on relative effect of treatment comparisons using R package “rjags” and “gemtc” with 10,000 simulation iterations. We explored whether the overall evidence differs from results based on low-bias studies, and whether a single painful procedure, such as heel sticking, affects the overall outcomes. Results Study characteristics The literature searches from six databases identified 10,043 potential references. After screening for duplicates and excluded studies, 52 full-text articles were assessed for eligibility. Six studies were excluded for reasons listed in Supplemental eTable 5. After adding from the previous review's reference list, 42 RCTs were eligible for the current synthesis (Figure 1). The total sample included in this review consisted of 2,733 preterm infants with a mean gestational age of 32.16 weeks and a birth weight of 1643.12 g. Our NMA was produced from three oral sweeteners consisting of dextrose, sucrose, and expressed breast milk. Most of the comparisons were constructed from direct evidence with a mean path length of < 2 (Supplemental eFigure 1), indicating the high reliability of the NMA estimate (Konig et al., 2013). Characteristics of the included trials are described in Table 1. Half of the 38 trials revealed a low risk of overall bias. Ten studies (26.3%) demonstrated a moderate, and the last nine studies (23.7%) were categorized as having a high RoB. Details of the RoB are reported in supplementary eFigure 2. Primary outcome: Pain Pain levels were assessed using several pain measurement instruments including the Premature Infant Pain Profile (PIPP), PIPP-R (Premature Infant Pain Profile-Revised), Douleur Aiguë Nouveau-né (DAN; Newborn Acute Pain) Scale, Neonatal/Infant Pain Scale (NIPS), and Neonatal Facial Coding Scale (NFCS). In the reactivity phase, glucose and sucrose mostly showed better clinical outcomes as depicted in Figure 2. Figures 3 and 4 show network and forest plots of direct comparisons of sweet solutions as analgesia. A total of 23 studies involving 1,553 infants were investigated for pain reactions (Supplemental eTable 6). Compared to the controls alone, glucose (standardized mean difference [SMD], -0.72; 95% confidence interval [CI], -1.19 to -0.25) and sucrose (SMD, -0.56; 95% CI, -1.04 to -0.07) were associated with lower pain responses in reaction phase. In the regulation phase, glucose (SMD, -1.09; 95% CI, -1.43 to -0.75), sucrose (SMD, -0.80; 95% CI, -1.30 to -0.29), and expressed breast milk SMD, -0.80; 95% CI, -1.30 to -0.29) were likely to reduce pain compared to the controls. Thirdly, compared to the controls, glucose (SMD, -0.76; 95% CI, -1.06 to -0.47), sucrose (SMD, -0.62; 95% CI, -0.94 to -0.30), and expressed breast milk (SMD, -0.57; 95% CI, -0.91 to -0.22) were likely to reduce pain during recovery phase. A summary of the NMA is given in Table 2. These interventions were further supported by P-scores that ranged from 0.877 to 0.917 showing glucose's superiority in the three phases (Supplemental eTable 7). Table 2. Summary of Network Meta-analysis for Comparative Efficacy and Safety of Glucose, Sucrose, and Expressed Breast Milk (EBM) Outcomes Glucose vs. controls Sucrose vs. controls EBM vs. controls Glucose vs. sucrose Glucose vs. EBM Sucrose vs. EBM Pain Reaction ‡ -0.72 [-1.19; -0.25] -0.56 [-1.04; -0.07] -0.22 [-0.80; 0.36] -0.16 [-0.78; 0.47] -0.50 [-1.13; 0.13] -0.34 [-1.00; 0.32] Regulation ‡ -1.09 [-1.43; -0.75] -0.80 [-1.30; -0.29] -0.80 [-1.30; -0.29] -0.30 [-0.82; 0.23] -0.30 [-0.79; 0.19] -0.00 [-0.68; 0.67] Recovery ‡ -0.76 [-1.06; -0.47] -0.62 [-0.94; -0.30] -0.57 [-0.91; -0.22] -0.20 [-0.56; 0.17] -0.14 [-0.47; 0.19] 0.06 [0.47; -0.36] Crying time -12.31 [-21.32; -3.31] -19.53 [-30.76; -8.30] -6.60 [-32.75; 19.55] 7.22 [20.46; -6.03] -5.71 [-31.25; 19.84] -12.92 [-40.99; 15.15] Heart rate Reaction ¥ -0.99 [-6.10; 4.12] -0.16 [-1.98; 1.67] -0.15 [-6.56; 6.25] -0.83 [-6.08; 4.42] -0.84 [-9.02; 7.34] -0.01 [-6.61; 6.60] Regulation ¥ -6.56 [-14.90; 1.77] -3.10 [ -7.67; 1.46] -6.50 [-14.45; 1.45] -3.46 [-11.58; 4.66] -0.06 [-11.58; 11.45] 3.40 [12.57; -5.77] Recovery ¥ -2.07 [ -7.14; 2.99] -1.64 [ -6.53; 3.26] -5.23 [-10.23; -0.23] -0.44 [ -6.57; 5.69] 3.16 [ 9.35; -3.04] 3.59 [ 9.76; -2.57] Oxygen saturation Reaction ¥ 0.40 [-1.50; 2.30] 0.41 [-1.16; 1.99] 0.05 [-2.61; 2.70] 0.01 [-2.31; 2.34] 0.35 [-2.90; 3.61] 0.37 [-2.60; 3.34] Regulation ¥ 0.24 [-2.54; 3.03] -0.75 [2.00; -3.49] 1.50 [-2.60; 5.60] 0.99 [-2.39; 4.37] -1.26 [3.70; -6.21] -2.25 [2.69; -7.18] Recovery ¥ 0.16 [-1.00; 1.32] -0.94 [0.48; -2.36] 1.72 [ 0.45; 2.99] 1.11 [-0.58; 2.79] -1.56 [0.04; -3.15] -2.66 [-0.81; -4.52] Respiratory rate Reaction ¥ 1.98 [8.62; -4.65] 0.81 [7.46; -5.84] NA 1.17 [9.30; -6.96] NA NA Recovery ¥ -1.33 [-4.88; 2.22] -0.22 [-5.91; 5.47] -2.93 [-8.15; 2.29] -1.10 [-7.06; 4.85] 1.60 [6.25; -3.05] 2.71 [9.97; -4.55] Adverse events $ 1.55 [1.09; 2.19] 0.83 [0.36; 1.92] 1.47 [0.44; 4.89] 1.86 [0.76; 4.54] 1.05 [0.33; 3.35] 0.56 [0.13; 2.42] Note: For pain, a negative standardised mean difference (SMD) indicates that the intervention favoured reducing pain compared to the control. Similarly, for crying time, heart rate, respiratory rate, and adverse events, a negative mean difference (MD) or risk ratio (RR) indicates that the intervention was beneficial. Conversely, for oxygen saturation, a positive MD reflects a favourable outcome for the intervention.. NA, not available. ‡, standardised mean difference (SMD). ¥, mean difference (MD). $, risk ratio (RR). Secondary outcomes 3.1 Crying time Crying times were reported in 13 trials involving 731 preterm infants, across four treatment groups (Supplemental eFigure 3, eTable 6). Among groups, both glucose (SMD, -12.31; 95% CI, -21.32 to -3.31) and sucrose (SMD, -19.53; 95% CI, -30.76 to -8.30) showed significantly lower total crying times (Supplemental eFigure 4). Meanwhile expressed breast milk did not show a statistically significant effect of reducing crying times compared to the controls (SMD, -6.60; 95% CI, -32.75 to 19.55). P-scores indicated that sucrose and glucose were superior to the other groups (Supplemental eTable 7). 3.2 Heart rate Fifteen studies reported heart rate in the three phases. Most of the comparisons showed that there was no evidence of efficacy. Compared to the controls, only expressed breast milk in the recovery state (number of studies = 3, n = 186) was associated with a statistically significant HR reduction (SMD, -5.23; 95% CI, -10.23 to -0.23) (Table 2; Supplemental eTable 6). P-scores also revealed the highest probability for expressed breast milk among the others at 0.8981 (Supplemental eTable 7). 3.3 Respiratory rate Table 2 shows that there was no efficacy of the interventions in reducing the respiratory rate in the reaction and recovery stages. The NMA was not performed in the regulation stage due to an inadequate number of studies. 3.4 Oxygen saturation Most of the treatment comparisons did not show a statistically significant effect on oxygen saturation in any phase. Compared to the controls (13, n = 741), expressed breast milk and sucrose were associated with higher oxygen saturation levels (SMD, 1.72; 95% CI, 0.45 to 2.99) and (SMD, 2.66; 95% CI, 0.81 to 4.52). P-scores indicated that expressed breast milk was the most effective treatment (0.9886; Supplemental eTable 7). 3.5 Adverse events (AEs) Fifteen studies ( n = 1107) reported one or more AEs through all phases, consisting of desaturation, bradycardia, regurgitation, or vomiting. Compared to the controls, only glucose showed a risk of having higher AEs (RR, 1.55; 95% CI, 1.09 to 2.19). Evaluation of Heterogeneity, Inconsistency, Outlier, and Small-study effect Heterogeneity varied across different pain-related outcomes (Supplemental eTable 8). Our NMA showed no local inconsistencies (Supplemental eTable 9). Some inconsistencies were detected in the global assessment and design-by-treatment, but most of them were resolved after removing studies in the sensitivity analysis (Supplemental eTables 10, 11). Furthermore, Cook’s distance (Supplemental eFigure 5) and ratio of variance (Supplemental eFigure 6) concurrently indicated four outliers in the model of primary outcome. However, these extreme values did not seriously affect the findings. They were only weakly linked to the differences between direct and indirect evidence without statistical significance (absolute z-values < 2; Supplemental eFigure 7), and the treatment rankings based on global metrics remained largely stable (Supplemental eFigure 8). Comparison-adjusted funnel plots did not show obvious asymmetric (Supplementary eFigure 9). Sensitivity Analyses and Meta-regression Glucose maintained its superiority in relieving pain in the sensitivity analysis. A summary of the sensitivity analysis is presented in Supplemental eTable 12. The meta-regression analysis showed that high risk of bias was a source of heterogeneity in the consistency model of pain during reaction phase ( β = -1.87, CrI: -3.35 to -0.46), but trends and treatment rands were not affected by the risk of bias (Supplemental eFigure 10). On the other hand, painful procedure (i.e. heel sticking) seemed to be not critical source of heterogeneity on pain during reaction phase ( β = -0.716, CrI: -1.88 to 0.454; Supplemental eFigure 11). Quality-of-Evidence Assessment Table 3 presents the certainty of the evidence as assessed using the CINeMA. Confidence ratings ranged from moderate to very low for the primary outcome. Meanwhile, other secondary outcomes revealed high to very low confidence ratings. Discussion To our knowledge, this is the first NMA to systematically examine the comparative effectiveness of various sweet solutions for optimal pain management in preterm infants. This review included 42 studies of three kinds of sweet solutions involving 2,733 preterm infants to reduce pain responses in the reaction, regulation, and recovery stages. All of the sweet solutions provided better effects of reducing pain than the control groups, with glucose showing the greatest reduction in pain. However, the secondary outcomes revealed differences in the efficacy of the interventions. Our study proved the efficacy of sucrose, glucose, and expressed breast milk in reducing procedural pain in preterm infants. In line with this study, a former PMA proved the analgesic effects of sucrose (Gao et al., 2016; Li et al., 2022; Liu et al., 2017; Stevens et al., 2013; Stevens et al., 2016) and glucose (Bueno et al., 2013) in relieving procedural pain in neonates. As a natural sweet-tasting solution, expressed breast milk was also proven to be an effective analgesic (Benoit et al., 2017; Shah et al., 2007; Shah et al., 2006; Shah et al., 2012). Additionally, some studies examined the composite effects of those solutions aggregated into a single category which showed procedural pain reduction in newborns (Disher et al., 2018; Harrison et al., 2017). Hence, based on those previous reviews, the optimal treatment among them remained inconclusive. Our study contributes to providing a ranking of the treatment efficacies, and showed that glucose, sucrose, and expressed breast milk were the most effective in reducing pain intensity. These findings are consistent with the sensitivity analysis model. The mean path length for the pain reduction outcome was below the threshold, suggesting sufficient direct evidence across all comparisons, which should contribute to the robustness of our model. Moreover, this present review elaborated large of included studies and sample sizes, with very specific criteria and rigorous methods. Thus, these findings should be considered credible. The mechanism of analgesia induced by oral sweet solutions in humans is still not well understood (Bembich et al., 2018; Gradin & Schollin, 2005; Oliveira et al., 2021). It was postulated that endogenous opioids may be involved in the underlying mechanism (Oliveira et al., 2021). Intraoral sucrose activates two key brainstem sites which are critically involved in modulating descending pain: neurons in the periaqueductal gray matter and in the nucleus raphe magnus (Carbajal, 2020). This process should be mediated by the sweet sensation from the solutions (Bembich et al., 2018). Glucose is the only monosaccharide among the sweeteners examined (Eggleston et al., 2018; Engelking, 2015), which may make it easier to absorb (Herman & Birnbaum, 2021). Meanwhile, although both expressed breast milk and sucrose are in the disaccharide group (Eggleston et al., 2018), due to high concentrations of tryptophan as a precursor of melatonin (Heine, 1999), they may induce an increase in beta-endorphin concentrations (Fitri et al., 2020). A former Cochrane review and a PMA depicted no effect of sucrose use on heart rate, respiration rate, or oxygen saturation during or after painful procedures (Li et al., 2022; Stevens et al., 2013; Stevens et al., 2016). Another MA also showed no effect of expressed breast milk administration on heart range changes (Shah et al., 2012). Due to an inadequate number of studies, the effects of glucose or other sweeteners on those given outcomes remain inconclusive (Bueno et al., 2013; Disher et al., 2018). Our current review provides additional evidence of expressed breast milk's superiority in reducing heart and respiratory rates in the recovery stage. Several PMAs proposed glucose, sucrose, or expressed breast milk to reduce the total crying time of neonates undergoing painful procedures (Bueno et al., 2013; Harrison et al., 2017; Liu et al., 2017; Stevens et al., 2013; Stevens et al., 2016). This current review supported the efficacies of glucose and sucrose in reducing crying times. However, our NMA estimate did not prove the efficacy of expressed breast milk. Although current and former meta-analyses did not depict signs of inconsistency, the contrasting results may have been induced by the different populations. This NMA only focused on preterm infants, while a preceding PMA also included healthy term infants (Shah et al., 2012). We found a review that reported similar AEs between sweet solutions and topical anesthesia (Disher et al., 2018). However, this NMA had insufficient studies to produce estimates to systematically compare AEs among treatments. Our results provide additional evidence which indicates potential AEs for preterm infants consuming glucose as oral analgesia. This finding was congruent with a previous report which showed higher AEs in infants receiving glucose, compared to those who received water (Bueno et al., 2013). Nevertheless, AEs self-recovered with no requirement for professional interventions (Bueno et al., 2012; Kumari et al., 2017). AEs more likely occur in preterm infant subjects on which our study focused (Li et al., 2022; Stevens et al., 2016). Meanwhile, previous meta-analyses incorporated healthy newborns in their studies (Liu et al., 2017; Stevens et al., 2016). Moreover, using the inverse variance to estimate effect of rare events in an NMA may potentially cause biases (Evrenoglou et al., 2022). Limitations This study has several limitations. Given the reflection of the heterogeneity in the synthesis, preterm newborns may have different stages of illness severity, which the study did not differentiate or account for. This stratification could potentially have introduced variability in the study's outcomes. Regrettably, a notable dearth of data impeded any in-depth exploration of how the varying health statuses of preterm infants may have impacted the aggregated results. Second, there was a vast difference in how the sweet solutions were administered, such as the frequency, concentration, and tools used for administration. This practical heterogeneity added a layer of complexity when attempting to draw universal conclusions regarding optimal parameters for sweet solutions administration. Third, some evidence produced in this study relied on weak certainty of evidence. Particularly for glucose vs breast milk which suffers from very low certainty of evidence. Most treatment comparisons in heart rate recovery outcomes are also based on very low certainty. Notably, our review lacked direct evidence comparing EBM and Sucrose for pain reactivity and adverse events. The limitations of this study, such as heterogeneity in sweet solution administration, population differences, and uncertainty in evidence quality, necessitate cautious interpretation of the findings in clinical settings. Finally, the effects of repeated sweet solutions administration could not be evaluated in the current synthesis due to a paucity of data. Conclusions In this study, based on the evidence with low-to-moderate certainty, sweet solutions effectively reduced pain in preterm infants undergoing painful procedures, and glucose seemed to be the most effective sweet solutions intervention because it was more likely to have a greater analgesic effect across all phases, with a moderate to low CR. Given the potential for adverse effects, glucose administration should be carefully monitored and implemented by experienced healthcare professionals. In cases where glucose is not appropriate, expressed breast milk or sucrose may be considered as alternative options. Among the various types of sweet solutions, the evidence from expressed breast milk is graded as having low certainty. Therefore, any comparisons involving expressed breast milk should be interpreted with caution. For a more comprehensive understanding and to improve clinical practice, further RCTs should investigate the efficacy and safety of sweet solutions, both as standalone interventions and in combination with other pain management methods, especially in extremely premature infants. Additionally, future studies should explore the effects of repeated applications of sweet solutions, across different doses as this is often necessary in clinical practice. Abbreviations AEs adverse events CINeMA Confidence in Network Meta-Analysis CoE certainty of the evidence CI confidence interval DAN Douleur Aiguë Nouveau-né (Newborn Acute Pain) Scale GRADE Grading of Recommendations Assessment, Development and Evaluation MDs mean differences NFCS Neonatal Facial Coding Scale NIPS Neonate/Infant Pain Scale NMA network meta-analysis PIPP Premature Infant Pain Profile PIPP-R Premature Infant Pain Profile-Revised PMAs pairwise meta-analyses PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analysis RCTs Randomized clinical trials RoB risk of bias RRs risk ratios SMD standardized mean difference SUCRA surface under the cumulative ranking curve References Anand, K. J. S. (2001). Concensus statement for the prefention of and management of pain in the newborn. American Medical Association , 155 , 172-180. Assary, R. S., & Curtiss, L. A. (2012). 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Marsubin","email":"","orcid":"","institution":"University of Indonesia: Universitas Indonesia","correspondingAuthor":false,"prefix":"","firstName":"Putri","middleName":"M.T.","lastName":"Marsubin","suffix":""},{"id":390661661,"identity":"634a4619-0afb-4cfe-9f81-5c1c7fb05aa1","order_by":5,"name":"Christina Yeni Kustanti","email":"","orcid":"","institution":"Sekolah Tinggi Ilmu Kesehatan Indonesia Maju","correspondingAuthor":false,"prefix":"","firstName":"Christina","middleName":"Yeni","lastName":"Kustanti","suffix":""},{"id":390661662,"identity":"c4a71af9-3b97-4422-bfeb-5e59e2729103","order_by":6,"name":"Kee-Hsin Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYBACCQYGNgYGAwY5CJeNBC3GPDAtPMRpYWBI7CFai2R787GHPwrupO8XO2PA8KHsMIO9RAJ+LdI8x9KNeQye5fZI5xgwzjh3mIGHkBY5iRwzaQaDw2AtzLxtQC3ShLTIv/8m+cPgcDoPSMtfYrRIS/CwSfAYHE4Aa2EkRotkT5qZNFCLYc/ttIKDPefSeXjuP8CvReL44WeSP/4clmefnbzxwY8yazn2ngP4taAAkFqC0TIKRsEoGAWjgAgAAPU6OlpRBqVDAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9772-482X","institution":"Taipei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Kee-Hsin","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-08-19 04:44:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4935843/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4935843/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13643-025-03043-3","type":"published","date":"2026-01-10T15:58:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71683483,"identity":"22071284-eea1-4c9e-8622-8e22af43f985","added_by":"auto","created_at":"2024-12-17 16:54:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5713,"visible":true,"origin":"","legend":"\u003cp\u003eThis image is not available with this version.\u003c/p\u003e","description":"","filename":"placeholderimage.png","url":"https://assets-eu.researchsquare.com/files/rs-4935843/v1/1507e7c5f56d7f3d84fa861c.png"},{"id":71682447,"identity":"be0e9164-87c4-45ee-b244-053b7d81b7a3","added_by":"auto","created_at":"2024-12-17 16:46:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5713,"visible":true,"origin":"","legend":"\u003cp\u003eThis image is not available with this version.\u003c/p\u003e","description":"","filename":"placeholderimageCopy.png","url":"https://assets-eu.researchsquare.com/files/rs-4935843/v1/44ba21ca18979d271798c9cf.png"},{"id":71684168,"identity":"5d2daad1-fd94-40d6-a896-541b2ab5a377","added_by":"auto","created_at":"2024-12-17 17:02:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":120515,"visible":true,"origin":"","legend":"\u003cp\u003ePictures A to C depict the network geometry of pain interventions in the reaction (23 studies, 4 nodes with 1,533 participants), regulation (28 studies, 4 nodes with 1,669 participants), and recovery stages (17 studies, 4 nodes with 1,563 participants). The size of each node corresponds to the number of participants, and the node colour indicates the risk of bias (RoB). The thickness of the connecting lines represents the total number of studies in the direct comparisons.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4935843/v1/1f6717c30bbe5d395ba2a738.png"},{"id":71684163,"identity":"e0052016-4ab0-4ef2-8b7a-3aea31a44110","added_by":"auto","created_at":"2024-12-17 17:02:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":115886,"visible":true,"origin":"","legend":"\u003cp\u003eThe figure illustrates the comparative efficacy of glucose, sucrose, and EBM in managing pain, relative to a control group. A random-effects meta-analysis was conducted to estimate treatment effects. Glucose demonstrated the most significant reduction in pain regulation (SMD = -1.09, 95% CI: -1.43 to -0.75), followed by sucrose and EBM (both SMD = -0.80, 95% CI: -1.30 to -0.29). For pain recovery, glucose (SMD = -0.76, 95% CI: -1.06 to -0.47) and EBM (SMD = -0.62, 95% CI: -0.94 to -0.30) were more effective than control. These findings highlight the superior efficacy of glucose in managing pain across all domains, with sucrose and EBM offering additional benefits, particularly for pain recovery and regulation.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4935843/v1/e0bc0dcaf413e93db9df6102.png"},{"id":100069310,"identity":"2e1a9917-9d6f-47c2-a491-698a2763494d","added_by":"auto","created_at":"2026-01-12 16:12:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1351979,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4935843/v1/0f436f2d-5886-445a-938b-1d79b60bbe0c.pdf"},{"id":71682459,"identity":"d430f762-51a1-42eb-ad09-36fb288816da","added_by":"auto","created_at":"2024-12-17 16:46:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4997955,"visible":true,"origin":"","legend":"","description":"","filename":"20241213eSupplementaryFinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-4935843/v1/51c9061a6ccbfc87f937eef8.docx"}],"financialInterests":"","formattedTitle":"The Comparative Efficacy and Safety of Sweet Solutions to Reduce Preterm Infants’ Pain Level: A Systematic Review and Network Meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eCompared to healthy-term neonates, preterm newborns are more likely to experience prolonged and repetitive painful procedures (Anand, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Obeidat et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). These unpleasant stimuli were reported to have negative clinical, physiological, and psychological consequences (Efendi, Rustina, et al., 2018; Gao et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Li et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Previous studies showed the impacts of painful exposures on brain development (Duerden et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Ranger et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), cognitive delays (Campbell-Yeo et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Vinall \u0026amp; Grunau, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Walker, \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), and persistent internalizing behavioral problems across toddlerhood to age 8 years (McLean et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Furthermore, premature infants experiencing pain are more likely to develop non-communicable diseases (Greer, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Huang et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Williams \u0026amp; Lascelles, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Thus, measures to reduce pain sensations in this vulnerable population are urgently needed.\u003c/p\u003e \u003cp\u003eAs a simple non-invasive method (Harrison et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Kassab et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Stevens et al., \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), the utilization of sweet solutions to reduce acute discomfort in neonates has garnered significant attention and investigation (Harrison et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Previous systematic reviews and meta-analyses extensively examined the efficacy of glucose, sucrose, and breast milk (Bueno et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Disher et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Gao et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Harrison et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Li et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Liu et al., \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Shah et al., \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Stevens et al., \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Stevens et al., \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), and these sweet solutions can reduce pain or crying times during various procedures such as heel lances, venipuncture, intramuscular injections, and eye examinations. However, the most effective sweet solutions intervention has yet to be definitively ascertained, and there is a notable absence of a comprehensive approach for evaluating the efficacy of diverse sweet solutions interventions within the contemporary scientific domain. Comparing more than two interventions using multiple pairwise meta-analyses may lead to incoherent estimates of the relative effects of every intervention compared to every other one (Dias \u0026amp; Caldwell, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition, several significant findings in previous syntheses relied on a fixed-effect model despite statistical heterogeneity concerns, whereas other syntheses aggregated data using a random-effects model. Comparing the effects of various sweet solutions interventions across these syntheses is inappropriate, especially given differences in analytical assumptions and statistical models.\u003c/p\u003e \u003cp\u003eA network meta-analysis (NMA) is a reliable method for synthesizing data from multiple treatment comparisons across trials (Dias \u0026amp; Caldwell, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Salanti, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Salanti et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). For each outcome, it provides estimates of the effect for all possible pairwise comparisons and offers a comprehensive overview of the impact of sweet solution interventions on pain alleviation in preterm infants. This study aimed to rank sweet solution interventions for preterm infants undergoing painful procedures based on their efficacy and safety, using a consistent model through network meta-analysis (R\u0026uuml;cker \u0026amp; Schwarzer, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA frequentist framework was used in this NMA. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) with an NMA extension to report this study (Hutton et al., 2015). The protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (PROSPERO CRD42023389288).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eSearch Strategy and Study Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe searched relevant randomized controlled trials (RCTs) to compare different kinds of sweet solutions to reduce pain for various procedures in hospitals from six databases (CINAHL, MEDLINE, EMBASE, CENTRAL, Scopus, and ProQuest Dissertation and Thesis) starting from their inception to 26 December 2022. In addition, we use the automatic alert function of the database to track whether there are newly published studies until July 2024. Reference lists of published systematic reviews were also searched. Details of the search strategy sample are provided in Supplemental eTable 1.\u003c/p\u003e\n\u003cp\u003ePreterm infants who were less than 28 days old and experiencing procedural pain such as heel pricking, suctioning, orogastric/nasogastric insertion, or intravenous line cannulation were the target population in this study (Supplemental eTable 2) (Hall \u0026amp; Anand, 2014; Shen et al., 2021). Infants who were critically ill with altered consciousness or who had received analgesics were excluded from the study. Two researchers (OO and OO) independently screened titles and abstracts using Endnote 20 and assessed the full text for potential inclusion in the study. Any disagreement was resolved through a discussion moderated by the first author (OO).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis review incorporated three different sweet solutions. The following solutions containing sugar were defined as (1) glucose or dextrose as a single sugar sweetness from the monosaccharide class; (2) sucrose as a single sugar\u0026rsquo;s sweetness from the disaccharide class; (3) fructose as a single sugar\u0026rsquo;s sweetness from the monosaccharide class; and (4) expressed breast milk as a natural sweetener that contains sugar in the form of lactose and belongs to the disaccharide class (Assary \u0026amp; Curtiss, 2012; Eggleston et al., 2018; Engelking, 2015). Finally, we defined the control group as a placebo, no intervention, or other active intervention given above.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePrimary and secondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe included pain as the primary outcome which was measured by validated instruments as described in Supplemental eTable 3. We modified previous definitions to categorize the pain level time measurement (De Clifford-Faugere et al., 2020; Disher et al., 2018; Efendi, Caswini, et al., 2018), comprised of pain reactivity (during a procedure), pain regulation (immediately after a procedure), and pain recovery (more than 2 minutes after a procedure). Secondary outcomes comprising heart rate, respiratory rate, and oxygen saturation in the reactivity, regulation, and recovery phases were analyzed. In addition, we assessed the impacts of interventions on the total crying time and adverse events (AEs).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOO and OO independently extracted data from the reviewed studies. Any discrepancies were resolved through discussion. We extracted characteristics of study participants such as gestational age, birth weight, gender, and other required data. We further extracted arm-level data including the sample size, mean, median, standard deviation, interquartile range, and other types of data for all of the given time measurements. Ten different scenarios were used to calculate missing data as described in a previous study (Chi et al., 2023).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eQuality of evidence and risk of bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo independent researchers (OO and OO) evaluated the risk of bias (RoB) among studies using the Cochrane risk of bias 2.0 (JPT et al., 2022; Sterne et al., 2019). Additionally, confidence in the NMA (CINeMA) framework covering within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence was used to assess the certainty of the evidence (CoE) (Nikolakopoulou et al., 2020). This approach relies on the methodology proposed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group for pairwise meta-analyses (PMAs) (Salanti et al., 2014).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData synthesis and statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTransitivity assumptions were evaluated by checking distributions of potential confounding variables nested in the infants\u0026rsquo; characteristics as described in Supplemental eTable 4. The DerSimonian-Laird random-effects model was used to calculate the contrast-based model meta-analysis (DerSimonian \u0026amp; Laird, 2015; George \u0026amp; Aban, 2016). Cohen\u0026rsquo;s D was used to estimate and classify mean differences (MDs), standardized mean differences (SMDs), and risk ratios (RRs) between groups (Durlak, 2009). Some empirical studies have suggested that there may be minimal practical differences between Frequentist and Bayesian approaches to network meta-analysis (L\u0026aacute;zaro et al., 2020; Seide et al., 2020). Given that our confidence ratings are derived from CINeMA, which is grounded in Frequentist principles (Nikolakopoulou et al., 2020), we opted to estimate relative treatment effects and rankings using a Frequentist framework (Watt et al., 2019).\u003c/p\u003e\n\u003cp\u003eTo illustrate treatment comparisons based on direct evidence, the network plot geometry was used for each outcome of interest (Tonin et al., 2019). The sizes of nodes in the plots corresponded to sample sizes, and the width of the edges was proportional to the total studies involved in the comparisons. Statistical analyses were performed in R, version 4.2.2 using the \u003cem\u003e\u0026ldquo;netmeta\u0026rdquo;\u003c/em\u003e package (R\u0026uuml;cker et al., 2023; van Valkenhoef et al., 2012).\u003c/p\u003e\n\n\u003cp\u003eTo summarize the findings with treatment rankings, we used P score that analogue to the surface under the cumulative ranking curve (SUCRA) (Harrer et al., 2021; R\u0026uuml;cker \u0026amp; Schwarzer, 2015; Salanti et al., 2011). Then, we employed beading plot to visually summarize the ranking probabilities for all outcomes of interest using the \u003cem\u003e\u0026quot;rankinma\u0026quot;\u003c/em\u003e package (Chen et al., 2023). This innovative graphic technique provides a concise representation of complex NMA rankings with multiple outcomes in a single linear plot. Each line corresponds to a specific outcome, and the position of the dots along the line indicates the relative ranking of treatments. In our meta-analysis, treatments positioned further to the right are considered more effective (Chen et al., 2024).\u003c/p\u003e\n\u003cp\u003eHeterogeneity, incoherence, and outliers within network models were evaluated. We assessed heterogeneity using t\u003csup\u003e2\u003c/sup\u003eby estimating the variance caused by the true effect size (Higgins, 2008). Values of t\u003csup\u003e2 \u003c/sup\u003eof 0.04, 0.09, and 0.16 are respectively defined as low, moderate, and high heterogeneity (Borenstein et al., 2008). Alternatively, I\u003csup\u003e2\u003c/sup\u003e \u0026gt; 50% was also considered an attribute of higher between-study heterogeneity by assessing the amount of variance observed (Higgins et al., 2019; Higgins et al., 2003). We also examined the mean path length to estimate the degree of indirectness of an estimate (Papakonstantinou et al., 2020) with a threshold of \u0026gt; 2 which indicated a less-reliable NMA estimate (Konig et al., 2013). \u003c/p\u003e\n\u003cp\u003eWe used split direct and indirect evidence to detect the local consistency. Global inconsistency and a design-by-treatment interaction model were considered to detect inconsistencies within the entire NMA using Cochrane\u0026rsquo;s Q statistic with a significant level of \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.1 (Higgins et al., 2012). Meanwhile, Egger\u0026apos;s test and visual inspection of the comparison-adjusted funnel plots were used to evaluate publication bias and small study effect (Chaimani \u0026amp; Salanti, 2012; Egger et al., 1997). \u003c/p\u003e\n\u003cp\u003eForward search algorithm was used to detect extreme study effects through \u003cem\u003e\u0026ldquo;NMAoutlier\u0026rdquo;\u003c/em\u003e package (Petropoulou et al., 2021). Cook\u0026apos;s distance and the variance ratio were used to detect potential outliers. Furthermore, we created a forward plot with z-values to visually demonstrate whether the results were significantly impacted by each individual study, considering both direct and indirect evidence. \u003c/p\u003e\n\u003cp\u003eTo explore the source of heterogeneity, we performed a sensitivity analysis and network meta-regression. Sensitivity analysis in this study was carried by removing single trial with a high risk of bias and an extremely high dose of sweet solutions (Dehghani et al., 2019). In addition, a meta-regression was further performed to assess the impact of risk of bias and type of procedure on relative effect of treatment comparisons using R package \u003cem\u003e\u0026ldquo;rjags\u0026rdquo; and \u0026ldquo;gemtc\u0026rdquo;\u003c/em\u003e with 10,000 simulation iterations. We explored whether the overall evidence differs from results based on low-bias studies, and whether a single painful procedure, such as heel sticking, affects the overall outcomes.\u003c/p\u003e"},{"header":"Results","content":"\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eStudy characteristics\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe literature searches from six databases identified 10,043 potential references. After screening for duplicates and excluded studies, 52 full-text articles were assessed for eligibility. Six studies were excluded for reasons listed in Supplemental eTable 5. After adding from the previous review\u0026apos;s reference list, 42 RCTs were eligible for the current synthesis (Figure 1).\u003c/p\u003e\n\u003cp\u003eThe total sample included in this review consisted of 2,733 preterm infants with a mean gestational age of 32.16 weeks and a birth weight of 1643.12 g. Our NMA was produced from three oral sweeteners consisting of dextrose, sucrose, and expressed breast milk. Most of the comparisons were constructed from direct evidence with a mean path length of \u0026lt; 2 (Supplemental eFigure 1), indicating the high reliability of the NMA estimate (Konig et al., 2013). Characteristics of the included trials are described in Table 1. Half of the 38 trials revealed a low risk of overall bias. Ten studies (26.3%) demonstrated a moderate, and the last nine studies (23.7%) were categorized as having a high RoB. Details of the RoB are reported in supplementary eFigure 2.\u003c/p\u003e\n\u003col start=\"2\"\u003e\n \u003cli\u003e\u003cstrong\u003ePrimary outcome: Pain\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003ePain levels were assessed using several pain measurement instruments including the Premature Infant Pain Profile (PIPP), PIPP-R (Premature Infant Pain Profile-Revised), Douleur Aigu\u0026euml; Nouveau-n\u0026eacute; (DAN; Newborn Acute Pain) Scale, Neonatal/Infant Pain Scale (NIPS), and Neonatal Facial Coding Scale (NFCS). In the reactivity phase, glucose and sucrose mostly showed better clinical outcomes as depicted in Figure 2.\u003c/p\u003e\n\u003cp\u003eFigures 3 and 4 show network and forest plots of direct comparisons of sweet solutions as analgesia. A total of 23 studies involving 1,553 infants were investigated for pain reactions (Supplemental eTable 6). Compared to the controls alone, glucose (standardized mean difference [SMD], -0.72; 95% confidence interval [CI], -1.19 to -0.25) and sucrose (SMD, -0.56; 95% CI, -1.04 to -0.07) were associated with lower pain responses in reaction phase. In the regulation phase, glucose (SMD, -1.09; 95% CI, -1.43 to -0.75), sucrose (SMD, -0.80; 95% CI, -1.30 to -0.29), and expressed breast milk SMD, -0.80; 95% CI, -1.30 to -0.29) were likely to reduce pain compared to the controls. Thirdly, compared to the controls, glucose (SMD, -0.76; 95% CI, -1.06 to -0.47), sucrose (SMD, -0.62; 95% CI, -0.94 to -0.30), and expressed breast milk (SMD, -0.57; 95% CI, -0.91 to -0.22) were likely to reduce pain during recovery phase. A summary of the NMA is given in Table 2. These interventions were further supported by P-scores that ranged from 0.877 to 0.917 showing glucose\u0026apos;s superiority in the three phases (Supplemental eTable 7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Summary of Network Meta-analysis for Comparative Efficacy and Safety of Glucose, Sucrose, and Expressed Breast Milk (EBM)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"945\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucose vs. controls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSucrose vs. controls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEBM vs. controls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucose vs. sucrose\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucose vs. EBM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSucrose vs. EBM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 945px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Reaction\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.72\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-1.19; -0.25]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.56\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-1.04; -0.07]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-0.22\u003c/p\u003e\n \u003cp\u003e[-0.80;\u0026nbsp;0.36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e-0.16\u003c/p\u003e\n \u003cp\u003e[-0.78;\u0026nbsp;0.47]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-0.50\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-1.13;\u0026nbsp;0.13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-0.34\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-1.00;\u0026nbsp;0.32]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Regulation\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1.09\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-1.43; -0.75]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.80\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-1.30; -0.29]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.80\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-1.30; -0.29]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e-0.30\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-0.82;\u0026nbsp;0.23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-0.30\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-0.79;\u0026nbsp;0.19]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-0.00\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-0.68;\u0026nbsp;0.67]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Recovery\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.76\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-1.06; -0.47]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.62\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-0.94; -0.30]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.57\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-0.91; -0.22]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e-0.20\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-0.56;\u0026nbsp;0.17]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-0.14\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-0.47;\u0026nbsp;0.19]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.06\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[0.47;\u0026nbsp;-0.36]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCrying time\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-12.31\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-21.32; -3.31]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-19.53\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-30.76; -8.30]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-6.60\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-32.75; 19.55]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e7.22\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[20.46;\u0026nbsp;-6.03]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-5.71\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-31.25; 19.84]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-12.92\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-40.99; 15.15]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 945px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeart rate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Reaction\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-0.99\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-6.10; 4.12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e-0.16\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-1.98; 1.67]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-0.15\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-6.56; 6.25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e-0.83\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-6.08; 4.42]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-0.84\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-9.02; 7.34]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-0.01\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-6.61; 6.60]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Regulation\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-6.56\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-14.90;\u0026nbsp;1.77]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e-3.10\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[ -7.67;\u0026nbsp;1.46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-6.50\u003c/p\u003e\n \u003cp\u003e[-14.45;\u0026nbsp;1.45]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e-3.46\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-11.58;\u0026nbsp;4.66]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-0.06\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-11.58; 11.45]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e3.40\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[12.57;\u0026nbsp;-5.77]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Recovery\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-2.07\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[ -7.14;\u0026nbsp;2.99]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e-1.64\u003c/p\u003e\n \u003cp\u003e[ -6.53;\u0026nbsp;3.26]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-5.23\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-10.23; -0.23]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e-0.44\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[ -6.57;\u0026nbsp;5.69]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e3.16\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[ 9.35;\u0026nbsp;-3.04]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e3.59\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[ 9.76;\u0026nbsp;-2.57]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 945px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOxygen saturation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Reaction\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.40\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-1.50; 2.30]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.41\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-1.16; 1.99]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.05\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-2.61; 2.70]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e0.01\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-2.31; 2.34]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e0.35\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-2.90; 3.61]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.37\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-2.60; 3.34]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Regulation\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003cp\u003e[-2.54; 3.03]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e-0.75\u003c/p\u003e\n \u003cp\u003e[2.00; -3.49]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.50\u003c/p\u003e\n \u003cp\u003e[-2.60; 5.60]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e0.99\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-2.39; 4.37]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-1.26\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[3.70; -6.21]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-2.25\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[2.69; -7.18]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Recovery\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003cp\u003e[-1.00; 1.32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e-0.94\u003c/p\u003e\n \u003cp\u003e[0.48;\u0026nbsp;-2.36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.72\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[ 0.45;\u0026nbsp;2.99]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e1.11\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-0.58;\u0026nbsp;2.79]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e-1.56\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[0.04;\u0026nbsp;-3.15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-2.66\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[-0.81;\u0026nbsp;-4.52]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 945px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRespiratory rate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Reaction\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e1.98\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[8.62; -4.65]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.81\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[7.46; -5.84]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e1.17\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[9.30; -6.96]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp; Recovery\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e-1.33\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;[-4.88; 2.22]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e-0.22\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-5.91; 5.47]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-2.93\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-8.15; 2.29]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e-1.10\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[-7.06; 4.85]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e1.60\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[6.25; -3.05]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2.71\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[9.97; -4.55]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse events\u003csup\u003e$\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.55\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[1.09; 2.19]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0.83\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[0.36; 1.92]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.47\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[0.44; 4.89]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 136px;\"\u003e\n \u003cp\u003e1.86\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[0.76; 4.54]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e1.05\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[0.33; 3.35]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.56\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[0.13; 2.42]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eNote:\u0026nbsp;\u003c/strong\u003eFor pain, a negative standardised mean difference (SMD) indicates that the intervention favoured reducing pain compared to the control. Similarly, for crying time, heart rate, respiratory rate, and adverse events, a negative mean difference (MD) or risk ratio (RR) indicates that the intervention was beneficial. Conversely, for oxygen saturation, a positive MD reflects a favourable outcome for the intervention.. NA, not available. \u0026Dagger;, standardised mean difference (SMD). \u0026yen;, mean difference (MD). $, risk ratio (RR).\u003c/p\u003e\n\u003col start=\"3\"\u003e\n \u003cli\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003e3.1\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCrying time\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCrying times were reported in 13 trials involving 731 preterm infants, across four treatment groups (Supplemental eFigure 3, eTable 6). Among groups, both glucose (SMD, -12.31; 95% CI, -21.32 to -3.31) and sucrose (SMD, -19.53; 95% CI, -30.76 to -8.30) showed significantly lower total crying times (Supplemental eFigure 4). Meanwhile expressed breast milk did not show a statistically significant effect of reducing crying times compared to the controls (SMD, -6.60; 95% CI, -32.75 to 19.55). P-scores indicated that sucrose and glucose were superior to the other groups (Supplemental eTable 7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Heart rate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifteen studies reported heart rate in the three phases. Most of the comparisons showed that there was no evidence of efficacy. Compared to the controls, only expressed breast milk in the recovery state (number of studies = 3, \u003cem\u003en\u003c/em\u003e = 186) was associated with a statistically significant HR reduction (SMD, -5.23; 95% CI, -10.23 to -0.23) (Table 2; Supplemental eTable 6). P-scores also revealed the highest probability for expressed breast milk among the others at 0.8981 (Supplemental eTable 7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Respiratory rate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 shows that there was no efficacy of the interventions in reducing the respiratory rate in the reaction and recovery stages. The NMA was not performed in the regulation stage due to an inadequate number of studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Oxygen saturation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMost of the treatment comparisons did not show a statistically significant effect on oxygen saturation in any phase. Compared to the controls (13, \u003cem\u003en\u003c/em\u003e = 741), expressed breast milk and sucrose were associated with higher oxygen saturation levels (SMD, 1.72; 95% CI, 0.45 to 2.99) and (SMD, 2.66; 95% CI, 0.81 to 4.52). P-scores indicated that expressed breast milk was the most effective treatment (0.9886; Supplemental eTable 7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Adverse events (AEs)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifteen studies (\u003cem\u003en\u003c/em\u003e = 1107) reported one or more AEs through all phases, consisting of desaturation, bradycardia, regurgitation, or vomiting. Compared to the controls, only glucose showed a risk of having higher AEs (RR, 1.55; 95% CI, 1.09 to 2.19).\u003c/p\u003e\n\u003col start=\"4\"\u003e\n \u003cli\u003e\u003cstrong\u003eEvaluation\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eHeterogeneity, Inconsistency,\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOutlier, and Small-study\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eeffect\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eHeterogeneity varied across different pain-related outcomes (Supplemental eTable 8). Our NMA showed no local inconsistencies (Supplemental eTable 9). Some inconsistencies were detected in the global assessment and design-by-treatment, but most of them were resolved after removing studies in the sensitivity analysis (Supplemental eTables 10, 11). Furthermore, Cook\u0026rsquo;s distance (Supplemental eFigure 5) and ratio of variance (Supplemental eFigure 6) concurrently indicated four outliers in the model of primary outcome. However, these extreme values did not seriously affect the findings. They were only weakly linked to the differences between direct and indirect evidence without statistical significance (absolute z-values \u0026lt; 2; Supplemental eFigure 7), and the treatment rankings based on global metrics remained largely stable (Supplemental eFigure 8). Comparison-adjusted funnel plots did not show obvious asymmetric (Supplementary eFigure 9).\u003c/p\u003e\n\u003col start=\"5\"\u003e\n \u003cli\u003e\u003cstrong\u003eSensitivity Analyses and Meta-regression\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eGlucose maintained its superiority in relieving pain in the sensitivity analysis. A summary of the sensitivity analysis is presented in Supplemental eTable 12. The meta-regression analysis showed that high risk of bias was a source of heterogeneity in the consistency model of pain during reaction phase (\u003cem\u003e\u0026beta;\u003c/em\u003e = -1.87, CrI: -3.35 to -0.46), but trends and treatment rands were not affected by the risk of bias (Supplemental eFigure 10). On the other hand, painful procedure (i.e. heel sticking) seemed to be not critical source of heterogeneity on pain during reaction phase (\u003cem\u003e\u0026beta;\u003c/em\u003e = -0.716, CrI: -1.88 to 0.454; Supplemental eFigure 11).\u003c/p\u003e\n\u003col start=\"6\"\u003e\n \u003cli\u003e\u003cstrong\u003eQuality-of-Evidence Assessment\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eTable 3 presents the certainty of the evidence as assessed using the CINeMA. Confidence ratings ranged from moderate to very low for the primary outcome. Meanwhile, other secondary outcomes revealed high to very low confidence ratings.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first NMA to systematically examine the comparative effectiveness of various sweet solutions for optimal pain management in preterm infants. This review included 42 studies of three kinds of sweet solutions involving 2,733 preterm infants to reduce pain responses in the reaction, regulation, and recovery stages. All of the sweet solutions provided better effects of reducing pain than the control groups, with glucose showing the greatest reduction in pain. However, the secondary outcomes revealed differences in the efficacy of the interventions.\u003c/p\u003e\n\u003cp\u003eOur study proved the efficacy of sucrose, glucose, and expressed breast milk in reducing procedural pain in preterm infants. In line with this study, a former PMA proved the analgesic effects of sucrose (Gao et al., 2016; Li et al., 2022; Liu et al., 2017; Stevens et al., 2013; Stevens et al., 2016) and glucose (Bueno et al., 2013) in relieving procedural pain in neonates. As a natural sweet-tasting solution, expressed breast milk was also proven to be an effective analgesic (Benoit et al., 2017; Shah et al., 2007; Shah et al., 2006; Shah et al., 2012). Additionally, some studies examined the composite effects of those solutions aggregated into a single category which showed procedural pain reduction in newborns (Disher et al., 2018; Harrison et al., 2017). Hence, based on those previous reviews, the optimal treatment among them remained inconclusive. Our study contributes to providing a ranking of the treatment efficacies, and showed that glucose, sucrose, and expressed breast milk were the most effective in reducing pain intensity. These findings are consistent with the sensitivity analysis model. The mean path length for the pain reduction outcome was below the threshold, suggesting sufficient direct evidence across all comparisons, which should contribute to the robustness of our model.\u0026nbsp;Moreover, this present review elaborated large of included studies and sample sizes, with very specific criteria and rigorous methods. Thus, these findings should be considered credible.\u003c/p\u003e\n\u003cp\u003eThe mechanism of analgesia induced by oral sweet solutions in humans is still not well understood (Bembich et al., 2018; Gradin \u0026amp; Schollin, 2005; Oliveira et al., 2021). It was postulated that endogenous opioids may be involved in the underlying mechanism (Oliveira et al., 2021). Intraoral sucrose activates two key brainstem sites which are critically involved in modulating descending pain: neurons in the periaqueductal gray matter and in the nucleus raphe magnus (Carbajal, 2020). This process should be mediated by the sweet sensation from the solutions (Bembich et al., 2018). Glucose is the only monosaccharide among the sweeteners examined (Eggleston et al., 2018; Engelking, 2015), which may make it easier to absorb (Herman \u0026amp; Birnbaum, 2021). Meanwhile, although both expressed breast milk and sucrose are in the disaccharide group\u0026nbsp;(Eggleston et al., 2018), due to high concentrations of tryptophan as a precursor of melatonin\u0026nbsp;(Heine, 1999), they may induce an increase in beta-endorphin concentrations\u0026nbsp;(Fitri et al., 2020).\u003c/p\u003e\n\u003cp\u003eA former Cochrane review and a PMA depicted no effect of sucrose use on heart rate, respiration rate, or oxygen saturation during or after painful procedures (Li et al., 2022; Stevens et al., 2013; Stevens et al., 2016). Another MA also showed no effect of expressed breast milk administration on heart range changes (Shah et al., 2012). \u0026nbsp;Due to an inadequate number of studies, the effects of glucose or other sweeteners on those given outcomes remain inconclusive (Bueno et al., 2013; Disher et al., 2018). Our current review provides additional evidence of expressed breast milk\u0026apos;s superiority in reducing heart and respiratory rates in the recovery stage.\u003c/p\u003e\n\u003cp\u003eSeveral PMAs proposed glucose, sucrose, or expressed breast milk to reduce the total crying time of neonates undergoing painful procedures (Bueno et al., 2013; Harrison et al., 2017; Liu et al., 2017; Stevens et al., 2013; Stevens et al., 2016). This current review supported the efficacies of glucose and sucrose in reducing crying times. However, our NMA estimate did not prove the efficacy of expressed breast milk. Although current and former meta-analyses did not depict signs of inconsistency, the contrasting results may have been induced by the different populations. This NMA only focused on preterm infants, while a preceding PMA also included healthy term infants (Shah et al., 2012).\u003c/p\u003e\n\u003cp\u003eWe found a review that reported similar AEs between sweet solutions and topical anesthesia (Disher et al., 2018). However, this NMA had insufficient studies to produce estimates to systematically compare AEs among treatments. Our results provide additional evidence which indicates potential AEs for preterm infants consuming glucose as oral analgesia. This finding was congruent with a previous report which showed higher AEs in infants receiving glucose, compared to those who received water (Bueno et al., 2013). Nevertheless, AEs self-recovered with no requirement for professional interventions (Bueno et al., 2012; Kumari et al., 2017). AEs more likely occur in preterm infant subjects on which our study focused (Li et al., 2022; Stevens et al., 2016). Meanwhile, previous meta-analyses incorporated healthy newborns in their studies (Liu et al., 2017; Stevens et al., 2016). Moreover, using the inverse variance to estimate effect of rare events in an NMA may potentially cause biases (Evrenoglou et al., 2022).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. \u0026nbsp; Given the reflection of the heterogeneity in the synthesis, preterm newborns may have different stages of illness severity, which the study did not differentiate or account for. This stratification could potentially have introduced variability in the study\u0026apos;s outcomes. Regrettably, a notable dearth of data impeded any in-depth exploration of how the varying health statuses of preterm infants may have impacted the aggregated results. Second, there was a vast difference in how the sweet solutions were administered, such as the frequency, concentration, and tools used for administration. This practical heterogeneity added a layer of complexity when attempting to draw universal conclusions regarding optimal parameters for sweet solutions administration. Third, some evidence produced in this study relied on weak certainty of evidence. Particularly for glucose vs breast milk which suffers from very low certainty of evidence. Most treatment comparisons in heart rate recovery outcomes are also based on very low certainty. Notably, our review lacked direct evidence comparing EBM and Sucrose for pain reactivity and adverse events. The limitations of this study, such as heterogeneity in sweet solution administration, population differences, and uncertainty in evidence quality, necessitate cautious interpretation of the findings in clinical settings. Finally, the effects of repeated sweet solutions administration could not be evaluated in the current synthesis due to a paucity of data.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this study, based on the evidence with low-to-moderate certainty, sweet solutions effectively reduced pain in preterm infants undergoing painful procedures, and glucose seemed to be the most effective sweet solutions intervention because it was more likely to have a greater analgesic effect across all phases, with a moderate to low CR. Given the potential for adverse effects, glucose administration should be carefully monitored and implemented by experienced healthcare professionals. In cases where glucose is not appropriate, expressed breast milk or sucrose may be considered as alternative options. Among the various types of sweet solutions, the evidence from expressed breast milk is graded as having low certainty. Therefore, any comparisons involving expressed breast milk should be interpreted with caution. For a more comprehensive understanding and to improve clinical practice, further RCTs should investigate the efficacy and safety of sweet solutions, both as standalone interventions and in combination with other pain management methods, especially in extremely premature infants. Additionally, future studies should explore the effects of repeated applications of sweet solutions, across different doses as this is often necessary in clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAEs adverse events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCINeMA\u0026nbsp;Confidence in Network Meta-Analysis\u003c/p\u003e\n\u003cp\u003eCoE certainty of the evidence\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI confidence interval\u003c/p\u003e\n\u003cp\u003eDAN Douleur Aigu\u0026euml; Nouveau-n\u0026eacute; (Newborn Acute Pain) Scale\u003c/p\u003e\n\u003cp\u003eGRADE Grading of Recommendations Assessment, Development and Evaluation\u003c/p\u003e\n\u003cp\u003eMDs mean differences\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNFCS Neonatal Facial Coding Scale\u003c/p\u003e\n\u003cp\u003eNIPS Neonate/Infant Pain Scale\u003c/p\u003e\n\u003cp\u003eNMA network meta-analysis\u003c/p\u003e\n\u003cp\u003ePIPP Premature Infant Pain Profile\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePIPP-R Premature Infant Pain Profile-Revised\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePMAs pairwise meta-analyses\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analysis\u003c/p\u003e\n\u003cp\u003eRCTs Randomized clinical trials\u003c/p\u003e\n\u003cp\u003eRoB risk of bias\u003c/p\u003e\n\u003cp\u003eRRs risk ratios\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSMD standardized mean difference\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSUCRA surface under the cumulative ranking curve\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAnand, K. 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Early Neonatal Pain-A Review of Clinical and Experimental Implications on Painful Conditions Later in Life. \u003cem\u003eFront Pediatr\u003c/em\u003e,\u003cem\u003e 8\u003c/em\u003e, 30. https://doi.org/10.3389/fped.2020.00030 \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 3 are not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sweetener, pain management, calming effect, physiological stability, low birth weight, newborn, network meta-analysis, meta-regression","lastPublishedDoi":"10.21203/rs.3.rs-4935843/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4935843/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The efficacy of sweet solutions in alleviating pain for preterm infants has been extensively investigated, yet the most efficacious sweet solutions remain unknown.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted a search in the CINAHL, MEDLINE, EMBASE, CENTRAL, Scopus, and ProQuest databases for studies. Randomized controlledtrials (RCTs) utilizing glucose, sucrose, or expressed breast milk for managing pain in preterm infants were included in this study. A random-effects frequentist network meta-analysis was conducted to evaluate outcomes in three pain measurement time points.\u003cstrong\u003e \u003c/strong\u003eThe primary outcome was the pain level in the reactivity phase. The secondary outcomes were pain in the regulation and recovery phases, as well as heart rate, oxygen saturation, respiratory rate, crying time, and adverse events. P-scores and beading plot were utilized to rank the efficacy of the sweet solutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOf 10,043 references, 42 RCTs (2,733 newborns) were analyzed. Compared to the controls alone, glucose (standardized mean difference [SMD], -0.72; 95% confidence interval [CI], -1.19 to -0.25]) and sucrose (SMD, -0.56; 95% CI, -1.04 to -0.07]) were associated with lower pain responses in reaction phase. In the regulation and recovery phases, pain reduction was consistently linked to glucose, sucrose, and expressed breast milk. Those interventions were supported by results of P-scores that ranged from 0.877 to 0.917 showing glucose's superiority in the three phases. Glucose was associated with a higher risk of adverse events. Half of the 38 trials had a low risk of bias. Meanwhile, the certainty of the evidence was high to very low.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur findings indicate that glucose was ranked best for lowering pain in preterm infants, followed by sucrose and expressed breast milk. Future RCTs are expected to investigate the efficacy of sweet solutions, both alone and combined with other pain management methods, as well as the effects of repeated applications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic review registration: \u003c/strong\u003ePROSPERO CRD42023389288.\u003c/p\u003e","manuscriptTitle":"The Comparative Efficacy and Safety of Sweet Solutions to Reduce Preterm Infants’ Pain Level: A Systematic Review and Network Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-17 16:45:58","doi":"10.21203/rs.3.rs-4935843/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-12-16T14:12:11+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-12-16T06:22:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-12-16T04:25:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2024-12-15T03:53:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e144cc47-9354-4b12-9c1f-eeba22b3b406","owner":[],"postedDate":"December 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:04:40+00:00","versionOfRecord":{"articleIdentity":"rs-4935843","link":"https://doi.org/10.1186/s13643-025-03043-3","journal":{"identity":"systematic-reviews","isVorOnly":false,"title":"Systematic Reviews"},"publishedOn":"2026-01-10 15:58:31","publishedOnDateReadable":"January 10th, 2026"},"versionCreatedAt":"2024-12-17 16:45:58","video":"","vorDoi":"10.1186/s13643-025-03043-3","vorDoiUrl":"https://doi.org/10.1186/s13643-025-03043-3","workflowStages":[]},"version":"v1","identity":"rs-4935843","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4935843","identity":"rs-4935843","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}