The comparative efficacy and safety of sweet solutions to reduce preterm infants’ pain levels: a systematic review and network meta-analysis

Abstract Background Sweet solutions are widely used to reduce procedural pain in preterm infants, but their comparative efficacy and safety remain unclear. Methods We searched CINAHL, MEDLINE, Embase, CENTRAL, Scopus, and ProQuest for randomized controlled trials comparing glucose, sucrose, or expressed breast milk with control or with each other in preterm infants. We performed a random-effects frequentist network meta-analysis across three pain time points (reactivity, regulation, recovery). Pain level served as the primary outcome, while heart rate, oxygen saturation, respiratory rate, crying time, and adverse events were designated as secondary outcomes. Treatment efficacy was subsequently ranked using P-scores and a beading plot. Results We screened 10,043 records, included 42 RCTs (2733 infants), and analyzed 38 RCTs (2367 infants) in the network meta-analysis. 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 the 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 in the network meta-analysis had a low risk of bias. The evidence certainty for the primary outcome was moderate to very low, while the certainty for the secondary outcomes spanned a range from high to very low. Conclusions Glucose ranked most effective for reducing procedural pain in preterm infants, followed by sucrose and expressed breast milk. Future trials should evaluate optimal dosing, repeated administration, and combinations with other non-pharmacological pain-management strategies to maximize efficacy and safety. Systematic review registration PROSPERO CRD42023389288 Tweetable abstract Glucose is the most effective sweet solution in alleviating pain scores in preterm infants, followed by sucrose and expressed breast milk.