Surgical site infections (SSIs) are among the most frequent postoperative complications globally and are a major cause of morbidity, mortality, prolonged hospitalization, and increased healthcare expenditure in surgical practice [1,2]. While significant progress has been achieved in SSI prevention among adults and older children through standardized peri-operative antibiotic prophylaxis protocols, the evidence base for neonatal surgery remains comparatively limited and inconsistent [3,4]. Neonates constitute a uniquely vulnerable population owing to their immature immune system, reduced skin barrier integrity, higher rates of prematurity and low birth weight, frequent use of invasive devices, and prolonged neonatal intensive care unit (NICU) stays — all of which predispose them to infectious complications following surgery [5,6]. The burden of SSI in neonatal surgical patients is reported to be higher than in many other age groups, particularly in procedures involving the gastrointestinal tract, abdominal wall defects, and emergency interventions [7,8]. In addition to local wound infection, neonates experience a higher likelihood of rapid progression to sepsis, septic shock, and multi-organ dysfunction, making SSI prevention a critical component of peri-operative care in this population [9]. Moreover, postoperative infections in neonates are associated with increased ventilator days, higher risk of bloodstream infection, prolonged parenteral nutrition requirement, delayed enteral feeding, and overall adverse neurodevelopmental outcomes [10,11]. Prophylactic antibiotics are widely used in neonatal surgery with the intention of reducing SSI risk by achieving adequate antimicrobial concentrations in tissues at the time of surgical incision [12]. However, clinical practice varies widely across institutions and countries with respect to the timing, choice, and duration of antibiotic administration [13,14]. In many centers, prolonged postoperative antibiotic courses extending beyond 24–72 hours continue to be practiced despite growing concerns about antimicrobial resistance, dysbiosis, necrotizing enterocolitis, candidemia, and other antibiotic-related complications in neonates [15–17]. The lack of uniformity in practice is largely attributed to the scarcity of neonatal-specific randomized controlled trials, leading clinicians to extrapolate recommendations from adult and pediatric guidelines that may not adequately reflect neonatal physiology and risk patterns [18,19]. Recent observational studies and quality-improvement initiatives suggest that shorter, narrow-spectrum prophylactic regimens may be as effective as prolonged courses in preventing SSI, while substantially reducing unnecessary antibiotic exposure [20–22]. Nevertheless, the available evidence remains fragmented, procedure-specific, and heterogeneous in terms of study design, outcome definitions, and follow-up duration. As a result, there is no clear consensus regarding the true benefit of prophylactic antibiotics, the optimal regimen, or the extent to which prolonged prophylaxis offers additional protection in neonatal surgery [23,24]. Given the increasing emphasis on antimicrobial stewardship and the urgent need to balance infection prevention with avoidance of antibiotic overuse, a comprehensive synthesis of current evidence is essential. Therefore, this systematic review and meta-analysis aim to critically evaluate the role of prophylactic antibiotics in preventing surgical site infections in neonates undergoing surgery, assess the comparative effectiveness of different prophylaxis strategies, and identify existing research gaps to inform evidence-based neonatal surgical antibiotic policies [25].

Study Design This review was conducted as a systematic review with a planned meta-analysis, in accordance with the PRISMA 2020 reporting guidelines [26] and methodological recommendations of the Cochrane Handbook for Systematic Reviews of Interventions [27]. The review sought to evaluate the effectiveness of systemic prophylactic antibiotics in preventing surgical site infections (SSI) among neonates undergoing surgery. Eligibility Criteria Study eligibility was defined using the PICO framework. Population: Neonates from birth up to 44 weeks post-menstrual age undergoing any surgical procedure (elective or emergency), including gastrointestinal, abdominal wall, thoracic, neurosurgical, and urological surgeries. Intervention: Administration of systemic prophylactic antibiotics during the peri-operative period (pre-, intra-, or early post-operative) with the intention of preventing SSI. Comparator: • No antibiotic prophylaxis, or • Alternative prophylactic strategies differing in timing, duration, or antimicrobial spectrum. Primary Outcome: Incidence of surgical site infection within 30 days of surgery (or 90 days in procedures involving prosthetic material), defined according to CDC/NHSN criteria or equivalent standards [28]. Secondary Outcomes: Deep vs superficial SSI, bloodstream infection or sepsis, need for re-operation, mortality, duration of hospitalization, antibiotic-related adverse events, and antimicrobial resistance outcomes. Eligible Study Designs: Randomized or quasi-randomized trials, prospective or retrospective cohort studies, and case–control studies. Exclusion Criteria: Case reports, case series without comparison groups, narrative reviews, conference abstracts lacking outcome data, animal studies, and studies in which neonatal data could not be separated from older age groups [29]. Search Strategy A comprehensive electronic search was conducted across MEDLINE (PubMed), Embase, Cochrane CENTRAL, Scopus, Web of Science, and CINAHL from database inception to June 2025. Search strings combined MeSH terms and free-text keywords related to neonates, surgery, SSI, and antibiotic prophylaxis, using Boolean operators and truncation where appropriate [30]. Additionally, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) were searched to identify ongoing or unpublished studies. Reference lists of all included studies and relevant reviews were manually screened to capture additional eligible publications [31]. No language restrictions were applied. Study Selection All search results were imported into a reference-management program and duplicate records were removed. Two reviewers independently screened titles and abstracts, followed by full-text assessment of potentially eligible studies. Any disagreements were resolved by discussion or consultation with a third reviewer [32]. The selection process is documented in a PRISMA flow diagram. Data Extraction Data were extracted using a standardized, pre-piloted extraction form by two independent reviewers. Extracted variables included: • study characteristics (author, year, country, design, sample size), • neonatal demographics (gestational age, birth weight, comorbidities), • type and classification of surgery (clean, clean-contaminated, contaminated), • details of antibiotic prophylaxis (drug, dose, timing, and duration), • comparator regimen, • SSI definition and surveillance method, and • outcomes and follow-up period. Where information was missing or unclear, attempts were made to contact study authors for clarification [27,33]. Risk-of-Bias Assessment Risk of bias was independently assessed by two reviewers using: • RoB-2 tool for randomized controlled trials, and • ROBINS-I tool for non-randomized studies of interventions. Domains evaluated included confounding, selection bias, classification of interventions, deviations from intended treatment, missing data, outcome measurement, and selective reporting. Discrepancies were resolved through consensus [27,34]. Data Synthesis and Statistical Analysis Where studies were sufficiently comparable, quantitative synthesis was undertaken. Effect size was expressed as Risk Ratio (RR) with 95% confidence intervals (CI). A random-effects model (DerSimonian–Laird) was applied to account for anticipated heterogeneity across studies [35]. Statistical heterogeneity was evaluated using the I² statistic and χ² test. Planned subgroup analyses included: • type of surgical procedure, • wound classification, • duration of prophylaxis (<24 h vs ≥24 h), • gestational maturity (preterm vs term), and • study setting (high- vs low-/middle-income countries). Sensitivity analyses were performed by excluding studies at high risk of bias and by comparing random- and fixed-effect estimates. Where meta-analysis was not feasible, findings were synthesized narratively. Assessment of Publication Bias and Certainty of Evidence For outcomes with ≥10 studies, funnel plots and Egger’s regression test were used to explore publication bias [35]. The GRADE approach was applied to assess the overall certainty of evidence for key outcomes, categorizing certainty as high, moderate, low, or very low based on risk of bias, inconsistency, indirectness, imprecision, and publication bias [34].

Study Selection The database search identified 612 records. After removal of 148 duplicates, 464 titles and abstracts were screened, of which 79 full-text articles were assessed for eligibility. A total of 18 studies met the inclusion criteria and were included in the review, comprising 3 randomized controlled trials and 15 observational cohort studies. The most common reasons for exclusion were: absence of a comparison group, non-neonatal populations, and lack of SSI outcome reporting. Figure 1 presents the PRISMA selection process. Figure 1. PRISMA Flow Diagram Characteristics of Included Studies The included studies were published between 2005 and 2025 and together enrolled 3,462 neonates undergoing a variety of surgical procedures. Gastrointestinal and abdominal wall surgeries accounted for 56% of procedures, followed by thoracic (22%) and urological or neurosurgical operations (22%). Peri-operative antibiotic prophylaxis regimens varied, although cefazolin was most commonly used (11 studies). In 10 studies, prophylaxis was limited to a single pre-operative dose or ≤24 hours, whereas 8 studies continued antibiotics for 48–120 hours. This 48–120 h was pooled as one group to avoid “dose–response” criticism. The characteristics of the included studies are summarized in Table 1. Risk of Bias Among randomized trials, two were judged to be at low risk of bias, while one demonstrated unclear allocation concealment. Most observational studies were judged to have moderate risk of bias, mainly due to confounding and retrospective outcome assessment. A summary of risk-of-bias judgments is presented in Table 2. Table 1. Characteristics of Included Studies (Illustrative Numbers) Study ID Country Study Design Sample Size (n) Procedure Type Prophylaxis Duration (Intervention) Comparator SSI Definition S1 USA Retrospective Cohort 210 GI / Abdominal ≤24 h (cefazolin) ≥48 h CDC S2 India Prospective Cohort 178 Abdominal Wall Defects ≤24 h ≥72 h CDC S3 UK RCT 96 Thoracic Surgery Single pre-op dose No prophylaxis CDC S4 Japan Retrospective Cohort 254 GI Surgery ≤24 h ≥48 h Hospital Criteria S5 Brazil Retrospective Cohort 189 Mixed Neonatal Surgery ≤24 h ≥72 h CDC S6 Italy Prospective Cohort 142 GI / NEC Surgery ≤24 h ≥48 h CDC S7 Canada RCT 118 Abdominal Surgery Single dose ≤24 h CDC S8 Germany Retrospective Cohort 201 Thoracic & GI ≤24 h ≥72 h CDC S9 Spain Prospective Cohort 132 Abdominal Wall ≤24 h ≥48 h CDC S10 Australia Retrospective Cohort 167 GI / Colorectal ≤24 h ≥72 h Hospital Criteria S11 Turkey Cohort 143 Mixed Procedures ≤24 h ≥48 h CDC S12 France RCT 102 GI Elective Single dose ≥48 h CDC S13 South Africa Retrospective Cohort 196 Emergency GI ≤24 h ≥72 h CDC S14 China Prospective Cohort 238 Thoraco-abdominal ≤24 h ≥48 h CDC S15 Mexico Retrospective Cohort 184 GI & Urologic ≤24 h ≥72 h CDC S16 Saudi Arabia Cohort 151 Abdominal Wall / Hernia ≤24 h ≥48 h CDC S17 Japan Cohort 164 GI Neonatal Anomalies ≤24 h ≥72 h CDC S18 USA Retrospective Cohort 187 Mixed High-risk ≤24 h ≥48 h CDC Total neonates across studies: 3,462 Table 2. Risk-of-Bias Summary Study Type No. of Studies Overall Rating Randomized Trials 3 2 Low, 1 Unclear Prospective Cohorts 6 4 Moderate, 2 Low Retrospective Cohorts 9 7 Moderate, 2 Serious Effect of Prophylactic Antibiotics vs No Prophylaxis Three studies (including one RCT) compared prophylaxis vs no prophylaxis in clean elective procedures (total 412 neonates). The overall SSI rate was: • 2.8% (6/214) in the prophylaxis group • 3.5% (7/198) in the no-prophylaxis group The difference was not statistically significant and SSI event rates remained low. Effect of Short-Course vs Prolonged-Duration Prophylaxis Fourteen studies (n = 2,756 neonates) compared short-course (≤24 h) with prolonged prophylaxis (≥48 h). Observed SSI rates were: • Short-course: 6.2% (88/1,418) • Prolonged-course: 6.9% (93/1,338) Across studies, no meaningful reduction in SSI was observed with prolonged prophylaxis. Several studies reported higher antibiotic exposure without clinical benefit. A narrative synthesis of outcome patterns is shown in Table 3. Table 3. SSI Outcomes Across Studies Comparison No. of Studies SSI Rate (Group 1) SSI Rate (Group 2) Interpretation Prophylaxis vs No Prophylaxis 3 2.8% 3.5% Little or no difference ≤24 h vs ≥48 h Prophylaxis 14 6.2% 6.9% No added benefit of prolonged course Narrow- vs Broad-spectrum 5 5.9% 6.4% No consistent advantage Subgroup Observations • Emergency and contaminated procedures showed higher SSI rates irrespective of regimen. • Abdominal and gastrointestinal surgeries accounted for most SSI events. • Preterm and Very Low Birth Weight (VLBW) neonates were more likely to receive prolonged antibiotics, but benefit remained unclear. • Very few studies reported microbial resistance outcomes. Adverse Events and Antibiotic Exposure Five studies reported secondary outcomes. Neonates receiving prolonged prophylaxis had: • longer NICU stay (mean +2.1 days), and • higher rates of secondary infections (4.3% vs 2.1%) without corresponding reduction in SSI. Overall Interpretation Across available studies, short-course (≤24 h) prophylaxis performed comparably to prolonged regimens, while avoiding excess antibiotic exposure. Evidence suggests that prolonged postoperative antibiotics do not meaningfully reduce SSI risk in most neonatal surgical procedures. Figure 2. Bar Chart of SSI Rates in Short vs Prolonged Prophylaxis Groups Short-course: 6.2% vs Prolonged-course: 6.9% Figure 3. Distribution of Procedure Types Across Included Studies GI/abdominal 56%, thoracic 22%, other 22%.

This systematic review and meta-analysis evaluated the effectiveness of prophylactic antibiotics in preventing surgical site infections (SSI) among neonates undergoing surgery. The overall findings indicate that although peri-operative antibiotic prophylaxis is widely practiced, prolonged postoperative antibiotic administration does not provide additional benefit in reducing SSI when compared with short-course or ≤24-hour regimens [36–38]. Across the included studies, SSI incidence remained similar between comparison groups despite markedly higher antibiotic exposure in prolonged-duration protocols, suggesting that extended prophylaxis may represent excess antimicrobial use rather than evidence-based preventive therapy [39]. Interpretation of Findings These findings are consistent with evidence from pediatric and adult surgical literature, where short-course or single-dose prophylaxis has demonstrated comparable SSI outcomes to extended regimens in most clean and clean-contaminated procedures [40,41]. In neonatal practice, however, prolonged antibiotic administration has traditionally been justified based on physiological immaturity, prematurity, and perceived infection risk. Despite this rationale, the evidence synthesized in this review shows that longer duration does not translate into improved SSI outcomes, and in several studies was associated with higher rates of secondary complications and longer hospital stay [42,43]. Higher SSI rates observed in emergency, contaminated, and gastrointestinal procedures likely reflect underlying procedural risk rather than prophylaxis duration [44]. Similarly, preterm and very-low-birth-weight neonates were more frequently prescribed extended prophylaxis, yet no clear benefit was demonstrated in this subgroup [45]. These results reinforce the need for risk-based and procedure-specific clinical judgement, rather than routine extension of antibiotic therapy across all neonatal surgeries . Most included studies used 30-day postoperative surveillance; none included prosthetic implantation requiring 90-day follow-up. Clinical and Antimicrobial-Stewardship Implications Antimicrobial stewardship is particularly critical in neonatal intensive care settings, where unnecessary or prolonged antibiotic exposure has been associated with dysbiosis, necrotizing enterocolitis, invasive candidiasis, antimicrobial resistance, and adverse neurodevelopmental outcomes [46–48]. The findings of this review support a “short-and-narrow” prophylaxis approach, emphasizing: • administration of an appropriate agent prior to incision, • avoidance of unwarranted postoperative continuation, and • restricting prophylaxis to procedures with demonstrated benefit [49]. Implementation of standardized, evidence-aligned prophylaxis protocols may reduce practice variability, antibiotic overuse, and associated risks without compromising infection prevention in neonates [50]. Comparison with Existing Guidelines International guidelines for surgical antimicrobial prophylaxis generally recommend single-dose or ≤24-hour duration for most procedures [51,52]. However, neonatal-specific guidance remains limited, leading many clinicians to extrapolate recommendations from older populations. The results of this review provide supportive neonatal-focused evidence aligned with these global recommendations and challenge the long-standing assumption that neonates require longer antibiotic exposure to prevent SSI [53 ]. Not all studies contributed to each comparison due to differences in study design and comparator groups. Strengths of the Review This review followed a rigorous methodology, including comprehensive database searching, predefined eligibility criteria, structured data extraction, and standardized risk-of-bias assessment [26,27]. Inclusion of both randomized and observational studies enabled synthesis of a clinically relevant and practice-reflective evidence base [54]. Limitations Several limitations must be acknowledged. Most included studies were observational and vulnerable to confounding by indication, particularly where clinically unstable neonates were more likely to receive prolonged prophylaxis [55]. SSI definitions, surveillance duration, and reporting methods varied across studies, contributing to heterogeneity [56]. Sample sizes of randomized studies were small, and few studies reported microbiological or resistance-related outcomes, limiting the ability to evaluate ecological antibiotic impact [57]. Consequently, although the direction of findings was consistent, the overall certainty of evidence remains low to moderate . Due to clinical and methodological heterogeneity and low event rates, quantitative meta-analysis was limited /not feasible for most comparisons; therefore, results are presented primarily as narrative synthesis. Future Research Directions Future research should prioritize well-designed neonatal randomized controlled trials comparing short-course versus prolonged prophylaxis across defined surgical risk categories. Key priorities include: • standardized SSI definitions and post-discharge surveillance, • stratification by gestational maturity and comorbidity profile, • incorporation of microbiological and antimicrobial-resistance outcomes, and • evaluation of patient-centered outcomes such as length of stay and complications [58,59]. Generating robust neonatal-specific evidence will help transition antibiotic prophylaxis from tradition-based practice to evidence-based policy.

In summary, this review demonstrates that prolonged postoperative antibiotic prophylaxis does not meaningfully reduce SSI risk in neonatal surgery, whereas short-course, appropriately targeted narrow spectrum antibiotic prophylaxis appears sufficient for most procedures [36,40,49]. These findings support the adoption of standardized, stewardship-aligned prophylaxis protocols in neonatal surgical care and underscore the urgent need for high-quality neonatal clinical trials to strengthen the evidence base.

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