Docosahexaenoic Acid in Preventing Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial

Docosahexaenoic Acid in Preventing Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial | 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 Docosahexaenoic Acid in Preventing Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial Fatemeh Sabzevari, Aynaz Parvaz, Masoud Rezaei, Bahareh Bahman Bijari, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8909780/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background and objectives: To evaluate the effect of docosahexaenoic acid (DHA) supplementation on the incidence of NEC in preterm infants. Methods: In a randomized clinical trial, 62 preterm infants (< 34 weeks gestation) were assigned to receive either an oral supplement of docosahexaenoic acid (an omega-3 fatty acid) (n = 29) or standard care (n = 33). The supplement was administered daily at 60 mg/kg of. The primary outcome was the incidence of NEC diagnosed using modified Bell's criteria. Secondary outcomes included gastrointestinal symptoms, laboratory abnormalities, need for surgical intervention, mortality, and length of hospital stay. Results: While the incidence of any NEC (Stage ≥ IA) was not significantly reduced (48.3% vs. 66.7%; p = 0.14), the intervention group had a statistically significant lower incidence of severe NEC (Stage ≥ IIB) compared to the control group (27.6% vs. 57.6%; p = 0.03). This protective effect against severe NEC remained significant in a multivariable logistic regression analysis after adjusting for baseline confounders (OR 0.31, 95% CI [0.10, 0.98]; p = 0.047). Infants receiving DHA also had significantly lower rates of abdominal discoloration (3.4% vs. 45.5%; p < 0.001) and metabolic acidosis (31.0% vs. 57.6%; p = 0.03). Conclusions: In this trial, enteral DHA supplementation did not reduce the overall incidence of any stage NEC but was associated with a significant reduction in severe NEC in preterm infants. Despite baseline differences between groups, this finding suggests a clinically important protective effect. Trial Registration Iranian Registry of Clinical Trials IRCT20250625066253N1, Registered 10 January 2026. Necrotizing enterocolitis Preterm infants Long-chain polyunsaturated fatty acids Omega-3 Randomized clinical trial Figures Figure 1 Introduction Necrotizing enterocolitis (NEC) remains a devastating inflammatory bowel disease predominantly affecting 2–5% of premature infants, with mortality rates ranging from 10% to 50% [ 1 ]. Its multifactorial pathogenesis, deeply intertwined with intestinal immaturity and dysregulated inflammatory responses, presents significant challenges for effective prevention and treatment [ 2 ]. Long-chain polyunsaturated fatty acids (LCPUFAs), particularly the omega-3 fatty acid including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and the omega-6 fatty acid arachidonic acid (ARA), are critically important for fetal and neonatal development [ 3 ]. These fatty acids play essential roles in the maturation of the brain, retina, and gut, and are integral to the development and modulation of the immune system [ 4 , 5 ]. Preterm infants are particularly vulnerable to LCPUFA deficiencies [ 1 ]. Current nutritional practices, encompassing both parenteral and enteral routes, often fall short of restoring an optimal LCPUFA balance, potentially leaving these fragile infants at a disadvantage. For instance, standard lipid emulsions may not provide adequate DHA and ARA, and even when DHA is supplemented, an imbalance can arise if ARA is not concurrently supplied [ 6 ]. The immunomodulatory properties of LCPUFAs offer a promising avenue for NEC prevention. Omega-3 fatty acids, especially DHA, are known for their anti-inflammatory effects, partly through the modulation of pro-inflammatory cytokines, as DHA supplementation was linked to reduced IL-1β and lower NEC incidence [ 7 ]. Similarly, Tumer et al. (2022) observed trends towards lower inflammatory markers with omega-3 supplementation [ 8 ]. However, ARA is also vital, with its metabolites playing complex roles in both instigating and resolving inflammation [ 9 ]. Observational work by Martin et al. (2011) highlighted that decreased postnatal levels of both DHA and ARA are associated with an increased risk of various neonatal morbidities, suggesting that a deficiency in either can be detrimental [ 1 ]. Despite this understanding, the optimal strategy for LCPUFA supplementation to prevent NEC in preterm infants remains a subject of debate. While some studies have shown a reduction in NEC with DHA supplementation alone [ 10 ], systematic reviews and meta-analyses have raised concerns, suggesting that DHA-only supplementation might even increase NEC risk [ 11 ]. Given the profound impact of NEC, the critical developmental roles of DHA and ARA, and the current uncertainties surrounding the most effective supplementation strategy, further investigation is warranted. Therefore, this randomized clinical trial aims to investigate the efficacy of enteral supplementation of omega-3 (DHA) acids in preventing NEC in preterm infants. Methods and materials Study Design This randomized clinical trial was conducted to evaluate the effect of omega-3 supplementation on the incidence of NEC in preterm infants. The study was carried out at the Neonatal Intensive Care Unit (NICU) of Afzalipour Educational and Medical Center in Kerman, Iran, from September 2025 to January 2026. Participants The following criteria were used for enrollment of preterm infants: Inclusion Criteria Born at a gestational age of less than 34 weeks. Admitted to the Neonatal Intensive Care Unit (NICU). Able to tolerate oral feeding without significant gastrointestinal complications. Exclusion Criteria Chromosomal abnormalities. Critical illness requiring extensive resuscitation (e.g., low Apgar scores, cardiovascular shock, unstable hemodynamics). Sepsis. Life-threatening infections. Intraventricular hemorrhage (IVH) grade III or higher. Major congenital heart defects. Feeding intolerance. Suspected gastrointestinal atresia. Malrotation. Any gastrointestinal condition requiring surgical intervention. Randomization Participants were randomly assigned to either the intervention group (omega-3 supplementation) or the control group (standard care) using block randomization with a block size of four. The randomization sequence was generated using a computerized random number generator and was concealed using sequentially numbered, sealed, opaque envelopes prepared by an independent researcher not involved in the enrollment or assignment of participants. Interventions The intervention group received an oral supplement of omega-3 fatty acid in addition to standard care, while the control group received only the standard care. The omega-3 supplement (Advancis Omega Mousse syrup; Pharmodietica, Portugal) contains 129 mg DHA per 5 ml and was administered once daily at a dose of 60 mg DHA per kilogram of body weight. Feeding Protocol All infants received feedings according to a standardized protocol. Enteral feeding was initiated with minimal enteral nutrition at 10 mL per kilogram per day. Infants weighing less than 1500 grams were fed every two hours, while those weighing more than 1500 grams were fed every three hours. For infants tolerating minimal feedings, the feeding volume was increased by 20 mL per kilogram per day. The type of feeding—maternal breast milk, formula, or donor milk—was documented for each infant. Clinical Monitoring and Data Collection Vital signs were monitored and recorded every four hours. Daily clinical assessments included a systemic examination, evaluation of feeding tolerance, and observation for gastrointestinal symptoms (e.g., abdominal distension, discoloration, emesis). Weight measurements were obtained every other day. Laboratory evaluations, including complete blood count (CBC), arterial blood gas (ABG), electrolytes (sodium, potassium, calcium), blood urea nitrogen (BUN), creatinine, C-reactive protein (CRP), and blood cultures, were performed twice weekly or as clinically indicated. Radiographic imaging and abdominal ultrasonography were conducted based on clinical signs suggestive of NEC. Cranial ultrasound examinations were performed twice weekly, and more frequently if there was suspicion of intraventricular hemorrhage. All infants underwent echocardiography during the initial days of hospitalization, with repeat assessments as recommended by a pediatric cardiologist. Outcomes The primary outcome was the incidence of NEC, diagnosed using modified Bell's criteria based on clinical, laboratory, and radiographic findings [ 12 ]. Secondary outcomes included feeding intolerance, gastrointestinal signs (abdominal distension, discoloration, tenderness), laboratory abnormalities (e.g., thrombocytopenia, neutropenia, metabolic acidosis), need for surgical intervention due to NEC, mortality, and length of hospital stay. Statistical Analysis Data were analyzed using IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY). Continuous variables were presented as means and standard deviations or medians and interquartile ranges, depending on data distribution. Categorical variables were presented as frequencies and percentages. Between-group comparisons for continuous variables were performed using independent sample t-tests or Mann–Whitney U tests as appropriate. Chi-square tests or Fisher's exact tests were used for categorical variables. Multivariate logistic regression was used to assess the impact of intervention of primary outcome. A p-value of less than 0.05 was considered statistically significant. Safety Monitoring Adverse events and potential side effects of the omega-3 supplementation were closely monitored and recorded. The research team was prepared to discontinue the intervention in any infant exhibiting significant adverse reactions potentially related to the supplement. Compliance Compliance with the supplementation regimen was ensured by trained NICU nurses who administered the supplement. Documentation of administration times and doses was maintained for all participants. Results A total of 62 preterm infants with a gestational age of less than 34 weeks were enrolled in the study and randomized into two groups: 29 infants in the intervention group receiving omega-3 supplementation in addition to standard care, and 33 infants in the control group receiving standard care alone. The baseline characteristics of the infants and their mothers are summarized in Table 1. Table1. demographic characteristics of infants and their mothers. Variable Unit/Subgroup Intervention (N=29) Control (N=33) P-value Gestational Age Weeks 33.11 ± 1.01 32.36 ± 1.48 0.02 Gender Female:Male 13:16 19:14 0.31 Birth Weight Grams 1897 ± 485 1827 ± 442 0.55 Discharge Weight Grams 1955 ± 475 1860 ± 408 0.47 APGAR Score 1 min 7.28 ± 1.22 7.67 ± 1.11 0.19 APGAR Score 5 min 8.86 ± 0.79 8.73 ± 0.84 0.51 Maternal Addiction No:Yes 27:2 29:4 0.48 Maternal Underlying Disease No:Yes 11:18 14:19 0.71 Note: Values are presented as frequency of absence:presence for categorical, and mean ± SD for continuous findings. The statistically significant P values are highlighted in bold. Baseline Characteristics A statistically significant difference was observed in the mean gestational age between the groups. Infants in the intervention group were, on average, more mature than those in the control group (33.11 ± 1.01 weeks vs. 32.36 ± 1.48 weeks, respectively; p = 0.02). Despite the difference in gestational age, there were no significant differences in mean birth weight (1897 ± 485 g vs. 1827 ± 442 g; p=0.55) or discharge weight (1955 ± 475 g vs. 1860 ± 408 g; p=0.47). Apgar scores at 1 and 5 minutes were also comparable between the intervention and control groups (p=0.19 and p=0.51, respectively). The gender distribution was similar, with 13 females and 16 males in the intervention group and 19 females and 14 males in the control group (p=0.31). Furthermore, no significant differences were found in the rates of maternal addiction (p=0.48) or the presence of underlying maternal diseases (p=0.71). Neonatal Interventions and Complications As shown in Table 2 the use of prenatal betamethasone did not differ significantly between the intervention and control groups (34.5% vs. 21.2%; p = 0.24). The incidence of premature rupture of membranes (PROM) was similar in both groups (82.8% vs. 69.7%; p = 0.23). Intrauterine growth restriction (IUGR) was observed in 48.3% of infants in the intervention group and 54.5% in the control group (p = 0.62). A significantly lower proportion of infants in the intervention group required resuscitation at birth compared to the control group (3.4% vs. 21.2%; p = 0.03). The need for exogenous surfactant therapy was comparable between the groups (44.8% vs. 48.5%; p = 0.77). Table 2 Comparison of neonatal status regarding therapeutic interventions for preterm birth complications Variable Unit/Subgroup Intervention (N = 29) Control (N = 33) P value Surfactant administration No:Yes 13:16 16:17 0.77 Betamethasone use No:Yes 10:19 26:7 0.24 PROM No:Yes 24:5 23:10 0.23 IUGR No:Yes 14:15 18:15 0.62 Need for resuscitation at birth No:Yes 1:28 7:26 0.03 Note: PROM stands for Premature Rupture of Membranes; IUGR stands for Intrauterine Growth Restriction; The statistically significant P value (0.03) is highlighted in bold. NEC incidence The incidence and staging of NEC for both groups are detailed in Table 3. Overall, there was a trend towards a lower incidence of any stage NEC (Stage ≥IA) in the intervention group compared to the control group (14/29, 48.3% vs. 22/33, 66.7%), although this difference did not reach statistical significance (p=0.19, based on Chi-square test of all stages; p=0.14 when comparing Any NEC vs. No NEC). However, when examining disease severity, a significant difference emerged. The incidence of severe NEC (defined as Stage ≥IIB) was more than halved in the infants receiving omega-3 supplementation. Specifically, 27.6% (8 of 29) of infants in the intervention group developed severe NEC, compared to 57.6% (19 of 33) in the control group, a statistically significant reduction (p=0.03). Given the significant baseline differences in gestational age and need for resuscitation at birth—known risk factors for NEC—we performed a multivariable logistic regression to determine the independent predictors of severe NEC (Table 4). After adjusting for these potential confounders, assignment to the intervention group remained a significant independent predictor of a better outcome. Infants who received DHA supplementation had 69% lower odds of developing severe NEC compared to those in the control group (OR = 0.31, 95% CI [0.10, 0.98], p=0.047). In this adjusted model, neither gestational age (p=0.408) nor the need for resuscitation (p=0.890) were statistically significant predictors, strengthening the evidence for a direct therapeutic effect of the intervention. Table 3. Distribution of NEC Stages According to Modified Bell's Criteria in the Intervention and Control Groups. NEC Stage (Modified Bell's Criteria) Intervention Group (n=29) Control Group (n=33) p value n (%) n (%) No NEC 15 (51.7) 11 (33.3) 0.19 Stage IA (Suspected NEC) 3 (10.3) 2 (6.1) Stage IIA (Definite NEC, mild) 3 (10.3) 1 (3.0) Stage IIB (Definite NEC, moderate) 7 (24.1) 12 (36.4) Stage IIIA (Advanced NEC, bowel intact) 1 (3.4) 5 (15.2) Stage IIIB (Advanced NEC, perforated) 0 (0.0) 2 (6.1) Summary Categories Any NEC (Stage ≥IA) 14 (48.3) 22 (66.7) 0.14 * Severe NEC (Stage ≥IIB) 8 (27.6) 19 (57.6) 0.03 * Note: NEC, Necrotizing Enterocolitis. Data are presented as n (%). Percentages are calculated based on the total number of subjects in each respective group. Modified Bell's staging criteria are used for classification. Statistical comparison between groups for overall NEC incidence or severity performed using Chi-squared or Fisher's Exact test. * denotes that the calculated chi square was compared with No NEC (i.e., any NEC vs. No NEC, and severe NEC vs. No NEC). Table 4. Logistic Regression Analysis of Factors Associated with Severe NEC Characteristic Odds Ratio (OR) 95% Confidence Interval (CI) P-value Gestational Age (per week) 0.84 0.55 – 1.28 0.408 Need for Resuscitation 0.89 0.18 – 4.45 0.89 Intervention Group (vs. Control) 0.31 0.10 – 0.98 0.047 Note: Model fit statistics: Number of observations = 62; LR χ²(3) = 6.52, P = 0.089; Pseudo R² = 0.08. OR = Odds Ratio; CI = Confidence Interval. An OR 1 indicates increased odds of developing severe NEC. Clinical Signs and Symptoms The incidence of abdominal discoloration was significantly lower in the intervention group compared to the control group (3.4% vs. 45.5%; p < 0.001). Abdominal distension was observed in 41.4% of infants in the intervention group and 51.5% in the control group (p = 0.42). There were no significant differences between the groups regarding abdominal tenderness (27.6% vs. 45.5%; p = 0.14). No infants in either group exhibited edema, high gastric residual volumes, or hematochezia. These data have been summarized in Table 5 Table 5 Comparison of Clinical Findings in Physical Examination Between Study Groups Variable Unit/Subgroup Intervention (N = 29) Control (N = 33) P value Abdominal distension Absent:Present 17:12 16:17 0.42 Edema Absent:Present 29:0 33:0 1 High gastric residual volume No:Yes 29:0 33:0 1 Hematochezia No:Yes 29:0 33:0 1 Abdominal discoloration No:Yes 28:1 18:15 < 0.001 Abdominal tenderness Absent:Present 21:8 18:15 0.14 Note: The statistically significant P value (< 0.001) is highlighted in bold; Hematochezia refers to the passage of fresh blood in stool; Values are presented as frequency of absence:presence for each finding. Laboratory and Imaging Findings Metabolic acidosis was significantly less frequent in the intervention group compared to the control group (31.0% vs. 57.6%; p = 0.03). The incidence of neutropenia was significantly higher in the intervention group (20.7% vs. 0%; p = 0.006). There were no significant differences between the groups in terms of thrombocytopenia (10.3% vs. 6.1%; p = 0.53), thrombocytosis (34.5% vs. 30.3%; p = 0.72), leukocytosis (3.4% vs. 6.1%; p = 0.63), or hyponatremia (51.7% vs. 54.5%; p = 0.82). Cranial ultrasound findings were similar between the groups (p = 0.21). In the intervention group, 75.9% of infants had normal findings, whereas in the control group, 69.7% were normal. The remaining infants in both groups exhibited varying degrees of cerebral edema or intraventricular hemorrhage grade II. Abdominal radiographs did not reveal significant differences between the groups in terms of abnormal findings, with 24.1% of the intervention group and 36.4% of the control group showing radiographic abnormalities (p = 0.29). laboratory and imaging findings have been shown in Table 6. Table 6 Comparison of Laboratory and Imaging Findings Between Study Groups Variable Unit/Subgroup Intervention (N = 29) Control (N = 33) P value Thrombocytopenia Absent:Present 26:3 31:2 0.53 Thrombocytosis Absent:Present 19:10 23:10 0.72 Neutropenia Absent:Present 23:6 33:0 0.006 Leukocytosis Absent:Present 28:1 31:2 0.63 Hyponatremia Absent:Present 14:15 15:18 0.82 Metabolic acidosis Absent:Present 20:9 14:19 0.03 CRP mg/L 1.48 ± 0.09 1.27 ± 0.07 0.09 Brain ultrasound findings Normal 22 23 0.21 Mild edema 2 7 Moderate edema 0 1 Severe edema 3 2 IVH grade II 2 0 Radiographic findings Absent:Present 22:7 21:12 0.29 Note: CRP stands for C-Reactive Protein; IVH stands for Intraventricular Hemorrhage; The statistically significant P values (0.006 and 0.03) are highlighted in bold; CRP values are presented as mean ± standard error. Respiratory Support Requirements The need for respiratory support, including headbox oxygen therapy, continuous positive airway pressure (CPAP), intubation, and high-flow nasal cannula (HFNC), did not differ significantly between the groups throughout the first four days of life (Table 7). The frequency of CPAP need during first 4 days of life is depicted in Figure 1. Table 7 Comparison of Respiratory Status Between Study Groups. Variable Unit/Subgroup Intervention (N = 29) Control (N = 33) P value Use of HB Day 1 No:Yes 1:28 6:27 0.10 Day 2 1:28 31:2 Need for CPAP Day 1 No:Yes 3:26 15:18 0.55 Day 2 17:12 12:21 Day 3 28:1 30:3 Day 4 28:1 33:0 Need for Intubation Day 1 No:Yes 18:11 13:20 0.07 Day 2 28:1 28:5 Need for HFNC No:Yes 0.99 Day 1 9:20 11:22 Day 2 27:2 30:3 Note: HB refers to Head Box (oxygen therapy); CPAP stands for Continuous Positive Airway Pressure; HFNC stands for High-Flow Nasal Cannula; Values are presented as frequency of No:Yes for each intervention. Secondary Clinical Outcomes No infants in either group required surgical intervention due to NEC (p = 1.00). Mortality was lower in the intervention group compared to the control group (3.4% vs. 12.1%), although this difference did not reach statistical significance (p = 0.12). None of the deaths were attributed to NEC; all were due to other medical complications (Table 8). The mean length of hospital stay was shorter in the intervention group compared to the control group (12.66 ± 7.54 days vs. 16.76 ± 12.14 days), but this difference was not statistically significant (p = 0.12). Adverse Events No adverse events directly attributable to omega-3 supplementation were reported during the study period. The increased incidence of neutropenia in the intervention group is notable and warrants further investigation to determine its clinical significance and any potential association with the supplementation. Table 8 Comparison of Clinical Outcomes Between Study Groups During Hospitalization Variable Unit/Subgroup Intervention (N = 29) Control (N = 33) P value Need for surgery due to NEC No:Yes 29:0 33:0 - Mortality No:Yes 28:1 28:5 0.12 Cause of death Due to NEC 0 0 - Other causes 1 4 Length of hospital stay Days 12.66 ± 7.54 16.76 ± 12.14 0.12 Discussion This randomized clinical trial aimed to evaluate the effect of enteral supplementation with omega-3 (DHA) fatty acids on the incidence of NEC and associated outcomes in preterm infants. Our key findings indicate a statistically significant reduction in the incidence of severe NEC, alongside a non-significant trend towards a lower incidence of any NEC. Furthermore, infants in the intervention group demonstrated significantly lower rates of abdominal discoloration and metabolic acidosis, suggesting potential benefits in reducing clinical and biochemical markers associated with more severe gut injury. However, an unexpected finding was a significantly higher incidence of neutropenia in the intervention group. Regarding the primary outcome, our study find a statistically significant reduction in the incidence of severe NEC with omega-3 supplementation. This result aligns with the findings of Bernabe-García et al., who reported a statistically significant prevention of confirmed NEC using enteral DHA supplementation alone in a specific population of preterm infants weighing between 1000 and 1500g [ 10 ]. A comprehensive systematic review and meta-analysis by Alshaikh et al. highlighted that while DHA supplementation alone might increase the risk of NEC, the concurrent supplementation of ARA with DHA was associated with a significant reduction in the risk of NEC when compared to DHA alone [ 11 ]. Conversely, another study by Abou El Fadl et al. found a significant reduction in overall NEC diagnosis and staging with enteral DHA supplementation alone in preterm infants (GA ≤ 32 weeks, BW ≤ 1500g) [ 7 ]. The discrepancy between their significant finding with DHA alone and our finding, despite the protective trend in our study, might be related to differences in the specific populations studied. The observed trend towards lower severe NEC and reduced associated clinical signs in our study aligns with the hypothesized anti-inflammatory and gut-protective effects of LCPUFA supplementation. Abdominal discoloration is a sign of impaired gut perfusion and potentially severe inflammation [ 13 ], and its significant reduction in the intervention group is a clinically relevant finding. Similarly, metabolic acidosis is a recognized feature of advanced NEC [ 14 ], and its lower incidence supports the notion that the intervention may have mitigated the severity of intestinal injury. These findings are consistent with the biological understanding that LCPUFAs, including both omega-3 and omega-6 derivatives and their metabolites, play complex roles in modulating inflammatory responses and promoting tissue repair in the immature gut [ 15 , 16 ]. The observation of significantly higher neutropenia in the intervention group was unexpected. Neutrophil count can fluctuate in preterm infants and the neutrophil-to-lymphocyte ratio is considered an indicator of inflammation and stress-induced immune response [ 17 ]. While omega-3 fatty acids have been shown to modulate neutrophil function [ 18 ], the available evidence provide no clear explanation to suggest that combined DHA supplementation causes neutropenia. Tumer et al. reported lower, non-significant neutrophil-to-lymphocyte ratios with omega-3 supplementation [ 8 ]. Given the lack of supporting evidence in the literature linking this specific intervention to neutropenia, this finding should be interpreted with caution and may potentially be an incidental observation or a consequence of other, unmeasured confounding factors unique to this group. Mortality and length of hospital stay were lower in the intervention group, although these differences did not reach statistical significance. A shorter length of stay was a significant finding in the enteral DHA study by Abou El Fadl et al., and trends towards lower mortality have been observed in other studies involving omega-3 supplementation in preterm infants [ 7 ]. The consistent direction of these trends across studies, even if not individually significant, could collectively suggest a benefit, possibly related to a reduction in illness severity, including severe NEC. A limitation of our study is the statistically significant differences in mean gestational age and need for resuscitation at baseline, with the intervention group having slightly higher gestation, and lower need for resuscitation. Although our multivariable analysis adjusted for these factors, this statistical adjustment may not fully negate the profound confounding effect of these baseline imbalances. Future studies should ensure stratification to minimize such baseline imbalances. Another limitation is the open-label design of the study, as it lacked both a placebo control and blinding of clinicians and researchers. The single-center nature of the study also limits the generalizability of our findings. Furthermore, while our sample size was calculated based on an expected NEC incidence, the actual incidence rate and variability observed might have influenced the power to detect a statistically significant difference for the primary outcome. Despite these limitations, our study has several strengths. It employed a randomized controlled design, contributing valuable data to the debate on LCPUFA supplementation in preterm infants. It specifically evaluated the effect of DHA supplementation. The intervention was well-tolerated, with no adverse events directly attributed to the supplement itself. Comprehensive clinical and laboratory monitoring allowed for a detailed assessment of the intervention's impact on various outcomes and associated markers. Conclusion this randomized controlled trial demonstrated a statistically significant reduction in the incidence of severe NEC. Also, the significant reductions observed in abdominal discoloration and metabolic acidosis further support a potential clinical benefit. The intervention was well-tolerated. Given the critical need for effective NEC prevention strategies and the accumulating evidence suggesting that LCPUFA supplementation may play a protective role, these findings warrant further investigation. Larger, multi-center randomized controlled trials are necessary to confirm the efficacy of omega-3 supplementation and to fully elucidate its mechanisms of action in this vulnerable population, while carefully controlling for potential confounding factors. Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Ethics Committee of Kerman University of Medical Sciences (approval number: IR.KMU.AH.REC.1401.245). Additionally, the study was registered with the Iranian Registry of Clinical Trials (IRCT ID: IRCT20250625066253N1). Written informed consent was obtained from the parents or legal guardians of all participating infants after they were provided with detailed information about the study objectives, procedures, potential benefits, and risks. Participation was voluntary, and parents were assured that they could withdraw their infants from the study at any time without affecting their medical care. Confidentiality of patient data was maintained throughout the study, and all data were anonymized prior to analysis. Clinical trial number Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The Authors declare no conflict of interest. Funding This study has not been funded. Acknowledgements Not applicable. Authors contribution FS conceptualized and designed the study. AP was responsible for data collection. MR performed the statistical analysis and prepared the initial draft of the manuscript. B.B.B., ZJ, MN, ME, and AH collaborated in the study execution, provided supervision over intervention, and contributed to the revision of the manuscript. All authors read, critically reviewed for important intellectual content, made editions to the manuscript, and approved the final version for submission. References Martin CR, Dasilva DA, Cluette-Brown JE. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr. 2011;159:743–9. Tanner SM, Berryhill TF, Ellenburg JL, Jilling T, Cleveland DS, Lorenz RG, et al. Pathogenesis of Necrotizing Enterocolitis. Am J Pathol. 2015;185:4–16. Herrera E, Ortega-Senovilla H. Dietary implications of polyunsaturated fatty acids during pregnancy and in neonates. Life. 2023;13:1656. Singh P, Ochoa Allemant P, Brown J, Perides G, Freedman SD, Martin CR. 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Signal Transduct Target Ther. 2021;6:1–30. Bernabe-García M, Calder P, Villegas-Silva R, Rodríguez-Cruz M, Chávez-Sánchez L, Cruz-Reynoso L, et al. Efficacy of docosahexaenoic acid for the prevention of necrotizing enterocolitis in preterm infants: A randomized clinical trial. Nutrients. 2021;13:648. Alshaikh BN, Reyes Loredo A, Yusuf K, Maarouf A, Fenton TR, Momin S. Enteral long-chain polyunsaturated fatty acids and necrotizing enterocolitis: A systematic review and meta-analysis. Am J Clin Nutr. 2023;117:918–29. Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: Current difficulties and future opportunities. Pediatr Res. 2020;88 Suppl 1:10–5. DiNicolantonio JJ, O’Keefe J. The importance of maintaining a low omega-6/omega-3 ratio for reducing the risk of autoimmune diseases, asthma, and allergies. Mo Med. 2021;118:453–9. Clark DA, Munshi UK. Feeding associated neonatal necrotizing enterocolitis (primary NEC) is an inflammatory bowel disease. Pathophysiology. 2014;21:29–34. Fussbroich D, Colas RA, Eickmeier O, Trischler J, Jerkic SP, Zimmermann K, et al. A combination of LCPUFA ameliorates airway inflammation in asthmatic mice by promoting pro-resolving effects and reducing adverse effects of EPA. Mucosal Immunol. 2020;13:481–92. Ma C, Vasu R, Zhang H. The Role of Long-Chain Fatty Acids in Inflammatory Bowel Disease. Mediators Inflamm. 2019;2019:8495913. Sokou R, Mantzios P, Palioura AE, Tsantes AG, Lianou A, Piovani D, et al. Diagnostic and Prognostic Value of Hematological Parameters in Necrotizing Enterocolitis: A Systematic Review. J Clin Med. 2025;14:2530. Lee TH, Hoover RL, Williams JD, Sperling RI, Ravalese J, Spur BW, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med. 1985;312:1217–24. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8909780","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":619897233,"identity":"1b39dd41-7a81-442b-91d1-1b89d4f537d0","order_by":0,"name":"Fatemeh Sabzevari","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Fatemeh","middleName":"","lastName":"Sabzevari","suffix":""},{"id":619897235,"identity":"074e6305-c517-4835-a67b-ef47ae091ee7","order_by":1,"name":"Aynaz Parvaz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYJADxgdAgoePFC3MBiAtbKRoYZMAk4SU8c/IPfjx5w67fIPjx59Vfs2xk2FjYH746AYeLRI38pIlJM8kW244k5B2W3ZbMtBhbMbGOfisuZFjIGHYxmwg2ZBw7LbkNmagFh42aXxa5G/kGP9IbKs3kOx/2FYsua2esBaDGzlmEgfbDhvwSySzMX7cdpiwFsMzb8wsG88cB2p5xizNuO04DxszAb/IHc8xvvlzR7UBG3/6w48/t1Xb87M3P3yM1/sCCcBob4CwmXnAJD7lIMB/AKGF8Qch1aNgFIyCUTAiAQBmkkUhcTPiDAAAAABJRU5ErkJggg==","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Aynaz","middleName":"","lastName":"Parvaz","suffix":""},{"id":619897239,"identity":"b02c027e-5544-4334-82da-53baf3e36cea","order_by":2,"name":"Masoud Rezaei","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Masoud","middleName":"","lastName":"Rezaei","suffix":""},{"id":619897241,"identity":"2005489b-73b5-462c-9cb8-e70409611c0e","order_by":3,"name":"Bahareh Bahman Bijari","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Bahareh","middleName":"Bahman","lastName":"Bijari","suffix":""},{"id":619897242,"identity":"caece64d-41f4-463f-801f-d19edde3de10","order_by":4,"name":"Zahra Jamali","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Zahra","middleName":"","lastName":"Jamali","suffix":""},{"id":619897244,"identity":"f97e8c54-5c74-444e-a640-83f341768dd9","order_by":5,"name":"Marjan Nikvarz","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Marjan","middleName":"","lastName":"Nikvarz","suffix":""},{"id":619897247,"identity":"9bfe29ed-fbb5-4bdd-b2b9-34ad6011001b","order_by":6,"name":"Mahdieh Eslamian","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mahdieh","middleName":"","lastName":"Eslamian","suffix":""},{"id":619897253,"identity":"37502ac0-642b-4c05-b143-764692487b13","order_by":7,"name":"Anis Hajializadeh","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Anis","middleName":"","lastName":"Hajializadeh","suffix":""}],"badges":[],"createdAt":"2026-02-18 13:23:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8909780/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8909780/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106871188,"identity":"69fee20d-ca03-43d4-8263-535ab4ebe468","added_by":"auto","created_at":"2026-04-14 09:44:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":80580,"visible":true,"origin":"","legend":"\u003cp\u003eDaily Frequency of CPAP Need in Intervention and Control Groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNote.\u003c/em\u003e The line graph illustrates the frequency (absolute count of participants) requiring Continuous Positive Airway Pressure (CPAP) on each of the first four days of observation. Data are presented separately for the intervention group and the control group.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8909780/v1/46c7f0ade8a9f2d907097558.png"},{"id":106961348,"identity":"e1ebb98e-b307-4af0-b88c-3e94378b7bb2","added_by":"auto","created_at":"2026-04-15 09:25:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":723412,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8909780/v1/85a55873-b6cf-4153-a258-f8b4a314e148.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Docosahexaenoic Acid in Preventing Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNecrotizing enterocolitis (NEC) remains a devastating inflammatory bowel disease predominantly affecting 2\u0026ndash;5% of premature infants, with mortality rates ranging from 10% to 50% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Its multifactorial pathogenesis, deeply intertwined with intestinal immaturity and dysregulated inflammatory responses, presents significant challenges for effective prevention and treatment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLong-chain polyunsaturated fatty acids (LCPUFAs), particularly the omega-3 fatty acid including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and the omega-6 fatty acid arachidonic acid (ARA), are critically important for fetal and neonatal development [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These fatty acids play essential roles in the maturation of the brain, retina, and gut, and are integral to the development and modulation of the immune system [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Preterm infants are particularly vulnerable to LCPUFA deficiencies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent nutritional practices, encompassing both parenteral and enteral routes, often fall short of restoring an optimal LCPUFA balance, potentially leaving these fragile infants at a disadvantage. For instance, standard lipid emulsions may not provide adequate DHA and ARA, and even when DHA is supplemented, an imbalance can arise if ARA is not concurrently supplied [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe immunomodulatory properties of LCPUFAs offer a promising avenue for NEC prevention. Omega-3 fatty acids, especially DHA, are known for their anti-inflammatory effects, partly through the modulation of pro-inflammatory cytokines, as DHA supplementation was linked to reduced IL-1β and lower NEC incidence [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Similarly, Tumer et al. (2022) observed trends towards lower inflammatory markers with omega-3 supplementation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, ARA is also vital, with its metabolites playing complex roles in both instigating and resolving inflammation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Observational work by Martin et al. (2011) highlighted that decreased postnatal levels of both DHA and ARA are associated with an increased risk of various neonatal morbidities, suggesting that a deficiency in either can be detrimental [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite this understanding, the optimal strategy for LCPUFA supplementation to prevent NEC in preterm infants remains a subject of debate. While some studies have shown a reduction in NEC with DHA supplementation alone [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], systematic reviews and meta-analyses have raised concerns, suggesting that DHA-only supplementation might even increase NEC risk [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the profound impact of NEC, the critical developmental roles of DHA and ARA, and the current uncertainties surrounding the most effective supplementation strategy, further investigation is warranted. Therefore, this randomized clinical trial aims to investigate the efficacy of enteral supplementation of omega-3 (DHA) acids in preventing NEC in preterm infants.\u003c/p\u003e"},{"header":"Methods and materials","content":"\u003cp\u003eStudy Design\u003c/p\u003e \u003cp\u003eThis randomized clinical trial was conducted to evaluate the effect of omega-3 supplementation on the incidence of NEC in preterm infants. The study was carried out at the Neonatal Intensive Care Unit (NICU) of Afzalipour Educational and Medical Center in Kerman, Iran, from September 2025 to January 2026.\u003c/p\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003cp\u003eThe following criteria were used for enrollment of preterm infants:\u003c/p\u003e \u003cp\u003eInclusion Criteria\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eBorn at a gestational age of less than 34 weeks.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAdmitted to the Neonatal Intensive Care Unit (NICU).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAble to tolerate oral feeding without significant gastrointestinal complications.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eExclusion Criteria\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eChromosomal abnormalities.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eCritical illness requiring extensive resuscitation (e.g., low Apgar scores, cardiovascular shock, unstable hemodynamics).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSepsis.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLife-threatening infections.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIntraventricular hemorrhage (IVH) grade III or higher.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMajor congenital heart defects.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFeeding intolerance.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSuspected gastrointestinal atresia.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMalrotation.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAny gastrointestinal condition requiring surgical intervention.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eRandomization\u003c/p\u003e \u003cp\u003eParticipants were randomly assigned to either the intervention group (omega-3 supplementation) or the control group (standard care) using block randomization with a block size of four. The randomization sequence was generated using a computerized random number generator and was concealed using sequentially numbered, sealed, opaque envelopes prepared by an independent researcher not involved in the enrollment or assignment of participants.\u003c/p\u003e \u003cp\u003eInterventions\u003c/p\u003e \u003cp\u003eThe intervention group received an oral supplement of omega-3 fatty acid in addition to standard care, while the control group received only the standard care. The omega-3 supplement (Advancis Omega Mousse syrup; Pharmodietica, Portugal) contains 129 mg DHA per 5 ml and was administered once daily at a dose of 60 mg DHA per kilogram of body weight.\u003c/p\u003e \u003cp\u003eFeeding Protocol\u003c/p\u003e \u003cp\u003eAll infants received feedings according to a standardized protocol. Enteral feeding was initiated with minimal enteral nutrition at 10 mL per kilogram per day. Infants weighing less than 1500 grams were fed every two hours, while those weighing more than 1500 grams were fed every three hours. For infants tolerating minimal feedings, the feeding volume was increased by 20 mL per kilogram per day. The type of feeding\u0026mdash;maternal breast milk, formula, or donor milk\u0026mdash;was documented for each infant.\u003c/p\u003e \u003cp\u003eClinical Monitoring and Data Collection\u003c/p\u003e \u003cp\u003eVital signs were monitored and recorded every four hours. Daily clinical assessments included a systemic examination, evaluation of feeding tolerance, and observation for gastrointestinal symptoms (e.g., abdominal distension, discoloration, emesis). Weight measurements were obtained every other day. Laboratory evaluations, including complete blood count (CBC), arterial blood gas (ABG), electrolytes (sodium, potassium, calcium), blood urea nitrogen (BUN), creatinine, C-reactive protein (CRP), and blood cultures, were performed twice weekly or as clinically indicated. Radiographic imaging and abdominal ultrasonography were conducted based on clinical signs suggestive of NEC. Cranial ultrasound examinations were performed twice weekly, and more frequently if there was suspicion of intraventricular hemorrhage. All infants underwent echocardiography during the initial days of hospitalization, with repeat assessments as recommended by a pediatric cardiologist.\u003c/p\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003cp\u003eThe primary outcome was the incidence of NEC, diagnosed using modified Bell's criteria based on clinical, laboratory, and radiographic findings [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Secondary outcomes included feeding intolerance, gastrointestinal signs (abdominal distension, discoloration, tenderness), laboratory abnormalities (e.g., thrombocytopenia, neutropenia, metabolic acidosis), need for surgical intervention due to NEC, mortality, and length of hospital stay.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY). Continuous variables were presented as means and standard deviations or medians and interquartile ranges, depending on data distribution. Categorical variables were presented as frequencies and percentages. Between-group comparisons for continuous variables were performed using independent sample t-tests or Mann\u0026ndash;Whitney U tests as appropriate. Chi-square tests or Fisher's exact tests were used for categorical variables. Multivariate logistic regression was used to assess the impact of intervention of primary outcome. A p-value of less than 0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eSafety Monitoring\u003c/p\u003e \u003cp\u003eAdverse events and potential side effects of the omega-3 supplementation were closely monitored and recorded. The research team was prepared to discontinue the intervention in any infant exhibiting significant adverse reactions potentially related to the supplement.\u003c/p\u003e \u003cp\u003eCompliance\u003c/p\u003e \u003cp\u003eCompliance with the supplementation regimen was ensured by trained NICU nurses who administered the supplement. Documentation of administration times and doses was maintained for all participants.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 62 preterm infants with a gestational age of less than 34 weeks were enrolled in the study and randomized into two groups: 29 infants in the intervention group receiving omega-3 supplementation in addition to standard care, and 33 infants in the control group receiving standard care alone. The baseline characteristics of the infants and their mothers are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003eTable1. demographic characteristics of infants and their mothers.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUnit/Subgroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention (N=29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl (N=33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGestational Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWeeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33.11 \u0026plusmn; 1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32.36 \u0026plusmn; 1.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFemale:Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13:16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19:14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBirth Weight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eGrams\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1897 \u0026plusmn; 485\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1827 \u0026plusmn; 442\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDischarge Weight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eGrams\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1955 \u0026plusmn; 475\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1860 \u0026plusmn; 408\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAPGAR Score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.28 \u0026plusmn; 1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.67 \u0026plusmn; 1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAPGAR Score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.86 \u0026plusmn; 0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.73 \u0026plusmn; 0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMaternal Addiction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29:4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMaternal Underlying Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11:18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14:19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Values are presented as frequency of absence:presence for categorical, and mean \u0026plusmn; SD for continuous findings. The statistically significant P values are highlighted in bold.\u003c/p\u003e\n\u003cp\u003eBaseline Characteristics\u003c/p\u003e\n\u003cp\u003eA statistically significant difference was observed in the mean gestational age between the groups. Infants in the intervention group were, on average, more mature than those in the control group (33.11 \u0026plusmn; 1.01 weeks vs. 32.36 \u0026plusmn; 1.48 weeks, respectively; p = 0.02).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite the difference in gestational age, there were no significant differences in mean birth weight (1897 \u0026plusmn; 485 g vs. 1827 \u0026plusmn; 442 g; p=0.55) or discharge weight (1955 \u0026plusmn; 475 g vs. 1860 \u0026plusmn; 408 g; p=0.47). Apgar scores at 1 and 5 minutes were also comparable between the intervention and control groups (p=0.19 and p=0.51, respectively). The gender distribution was similar, with 13 females and 16 males in the intervention group and 19 females and 14 males in the control group (p=0.31). Furthermore, no significant differences were found in the rates of maternal addiction (p=0.48) or the presence of underlying maternal diseases (p=0.71).\u003c/p\u003e\n\u003cp\u003eNeonatal Interventions and Complications\u003c/p\u003e\n\u003cp\u003eAs shown in Table 2 the use of prenatal betamethasone did not differ significantly between the intervention and control groups (34.5% vs. 21.2%; p = 0.24). The incidence of premature rupture of membranes (PROM) was similar in both groups (82.8% vs. 69.7%; p = 0.23). Intrauterine growth restriction (IUGR) was observed in 48.3% of infants in the intervention group and 54.5% in the control group (p = 0.62). A significantly lower proportion of infants in the intervention group required resuscitation at birth compared to the control group (3.4% vs. 21.2%; p = 0.03). The need for exogenous surfactant therapy was comparable between the groups (44.8% vs. 48.5%; p = 0.77).\u003c/p\u003e\n\u003cp\u003eTable 2 Comparison of neonatal status regarding therapeutic interventions for preterm birth complications\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUnit/Subgroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention (N = 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl (N = 33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSurfactant administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13:16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16:17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBetamethasone use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10:19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26:7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePROM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23:10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIUGR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14:15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18:15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeed for resuscitation at birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1:28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7:26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: PROM stands for Premature Rupture of Membranes; IUGR stands for Intrauterine Growth Restriction; The statistically significant P value (0.03) is highlighted in bold.\u003c/p\u003e\n\u003cp\u003eNEC incidence\u003c/p\u003e\n\u003cp\u003eThe incidence and staging of NEC for both groups are detailed in\u0026nbsp;Table 3. Overall, there was a trend towards a lower incidence of any stage NEC (Stage \u0026ge;IA) in the intervention group compared to the control group (14/29, 48.3% vs. 22/33, 66.7%), although this difference did not reach statistical significance (p=0.19, based on Chi-square test of all stages; p=0.14 when comparing Any NEC vs. No NEC).\u003c/p\u003e\n\u003cp\u003eHowever, when examining disease severity, a significant difference emerged. The incidence of severe NEC (defined as Stage \u0026ge;IIB) was more than halved in the infants receiving omega-3 supplementation. Specifically, 27.6% (8 of 29) of infants in the intervention group developed severe NEC, compared to 57.6% (19 of 33) in the control group, a statistically significant reduction (p=0.03).\u003c/p\u003e\n\u003cp\u003eGiven the significant baseline differences in gestational age and need for resuscitation at birth\u0026mdash;known risk factors for NEC\u0026mdash;we performed a multivariable logistic regression to determine the independent predictors of severe NEC (Table 4). After adjusting for these potential confounders, assignment to the intervention group remained a significant independent predictor of a better outcome. Infants who received DHA supplementation had\u0026nbsp;69% lower odds\u0026nbsp;of developing severe NEC compared to those in the control group (OR = 0.31, 95% CI [0.10, 0.98],\u0026nbsp;p=0.047). In this adjusted model, neither gestational age (p=0.408) nor the need for resuscitation (p=0.890) were statistically significant predictors, strengthening the evidence for a direct therapeutic effect of the intervention.\u003c/p\u003e\n\u003cp\u003eTable 3. Distribution of NEC Stages According to Modified Bell\u0026apos;s Criteria in the Intervention and Control Groups.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"620\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNEC Stage (Modified Bell\u0026apos;s Criteria)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention Group (n=29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl Group (n=33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNo NEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (51.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStage IA (Suspected NEC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStage IIA (Definite NEC, mild)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStage IIB (Definite NEC, moderate)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStage IIIA (Advanced NEC, bowel intact)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStage IIIB (Advanced NEC, perforated)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSummary Categories\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAny NEC (Stage \u0026ge;IA)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (48.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.14\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSevere NEC (Stage \u0026ge;IIB)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19 (57.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003csup\u003e*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote:\u003c/em\u003e NEC, Necrotizing Enterocolitis. Data are presented as n (%). Percentages are calculated based on the total number of subjects in each respective group. Modified Bell\u0026apos;s staging criteria are used for classification. Statistical comparison between groups for overall NEC incidence or severity performed using Chi-squared or Fisher\u0026apos;s Exact test. * denotes that the calculated chi square was compared with No NEC (i.e., any NEC vs. No NEC, and severe NEC vs. No NEC).\u003c/p\u003e\n\u003cp\u003eTable 4. Logistic Regression Analysis of Factors Associated with Severe NEC\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOdds Ratio (OR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e95% Confidence Interval (CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGestational Age (per week)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.55 \u0026ndash; 1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.408\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeed for Resuscitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.18 \u0026ndash; 4.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention Group (vs. Control)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.10 \u0026ndash; 0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNote:\u003c/em\u003e\u003c/strong\u003e \u003cem\u003eModel fit statistics: Number of observations = 62; LR \u0026chi;\u0026sup2;(3) = 6.52, P = 0.089; Pseudo R\u0026sup2; = 0.08.\u003c/em\u003e \u003cem\u003eOR = Odds Ratio; CI = Confidence Interval.\u003c/em\u003e \u003cem\u003eAn OR \u0026lt; 1 indicates decreased odds, while an OR \u0026gt; 1 indicates increased odds of developing severe NEC.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eClinical Signs and Symptoms\u003c/p\u003e\n\u003cp\u003eThe incidence of abdominal discoloration was significantly lower in the intervention group compared to the control group (3.4% vs. 45.5%; p \u0026lt; 0.001). Abdominal distension was observed in 41.4% of infants in the intervention group and 51.5% in the control group (p = 0.42). There were no significant differences between the groups regarding abdominal tenderness (27.6% vs. 45.5%; p = 0.14). No infants in either group exhibited edema, high gastric residual volumes, or hematochezia. These data have been summarized in Table 5\u003c/p\u003e\n\u003cp\u003eTable 5 Comparison of Clinical Findings in Physical Examination Between Study Groups\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUnit/Subgroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention (N = 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl (N = 33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAbdominal distension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17:12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16:17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEdema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHigh gastric residual volume\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHematochezia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAbdominal discoloration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18:15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAbdominal tenderness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21:8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18:15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: The statistically significant P value (\u0026lt; 0.001) is highlighted in bold; Hematochezia refers to the passage of fresh blood in stool; Values are presented as frequency of absence:presence for each finding.\u003c/p\u003e\n\u003cp\u003eLaboratory and Imaging Findings\u003c/p\u003e\n\u003cp\u003eMetabolic acidosis was significantly less frequent in the intervention group compared to the control group (31.0% vs. 57.6%; p = 0.03). The incidence of neutropenia was significantly higher in the intervention group (20.7% vs. 0%; p = 0.006). There were no significant differences between the groups in terms of thrombocytopenia (10.3% vs. 6.1%; p = 0.53), thrombocytosis (34.5% vs. 30.3%; p = 0.72), leukocytosis (3.4% vs. 6.1%; p = 0.63), or hyponatremia (51.7% vs. 54.5%; p = 0.82).\u003c/p\u003e\n\u003cp\u003eCranial ultrasound findings were similar between the groups (p = 0.21). In the intervention group, 75.9% of infants had normal findings, whereas in the control group, 69.7% were normal. The remaining infants in both groups exhibited varying degrees of cerebral edema or intraventricular hemorrhage grade II.\u003c/p\u003e\n\u003cp\u003eAbdominal radiographs did not reveal significant differences between the groups in terms of abnormal findings, with 24.1% of the intervention group and 36.4% of the control group showing radiographic abnormalities (p = 0.29). laboratory and imaging findings have been shown in Table 6.\u003c/p\u003e\n\u003cp\u003eTable 6 Comparison of Laboratory and Imaging Findings Between Study Groups\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUnit/Subgroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention (N = 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl (N = 33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eThrombocytosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19:10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23:10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23:6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLeukocytosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14:15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15:18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMetabolic acidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20:9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14:19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003emg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.48 \u0026plusmn; 0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.27 \u0026plusmn; 0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\"\u003e\n \u003cp\u003eBrain ultrasound findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMild edema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eModerate edema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSevere edema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIVH grade II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRadiographic findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAbsent:Present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22:7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21:12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: CRP stands for C-Reactive Protein; IVH stands for Intraventricular Hemorrhage; The statistically significant P values (0.006 and 0.03) are highlighted in bold; CRP values are presented as mean \u0026plusmn; standard error.\u003c/p\u003e\n\u003cp\u003eRespiratory Support Requirements\u003c/p\u003e\n\u003cp\u003eThe need for respiratory support, including headbox oxygen therapy, continuous positive airway pressure (CPAP), intubation, and high-flow nasal cannula (HFNC), did not differ significantly between the groups throughout the first four days of life (Table 7). The frequency of CPAP need during first 4 days of life is depicted in Figure 1.\u003c/p\u003e\n\u003cp\u003eTable 7 Comparison of Respiratory Status Between Study Groups.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUnit/Subgroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntervention (N = 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eControl (N = 33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUse of HB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1:28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6:27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1:28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31:2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeed for CPAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3:26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15:18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17:12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12:21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30:3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33:0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeed for Intubation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18:11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13:20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28:5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeed for HFNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd rowspan=\"3\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9:20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11:22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30:3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: HB refers to Head Box (oxygen therapy); CPAP stands for Continuous Positive Airway Pressure; HFNC stands for High-Flow Nasal Cannula; Values are presented as frequency of No:Yes for each intervention.\u003c/p\u003e\n\u003cp\u003eSecondary Clinical Outcomes\u003c/p\u003e\n\u003cp\u003eNo infants in either group required surgical intervention due to NEC (p = 1.00). Mortality was lower in the intervention group compared to the control group (3.4% vs. 12.1%), although this difference did not reach statistical significance (p = 0.12). None of the deaths were attributed to NEC; all were due to other medical complications (Table 8).\u003c/p\u003e\n\u003cp\u003eThe mean length of hospital stay was shorter in the intervention group compared to the control group (12.66 \u0026plusmn; 7.54 days vs. 16.76 \u0026plusmn; 12.14 days), but this difference was not statistically significant (p = 0.12).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdverse Events\u003c/p\u003e\n\u003cp\u003eNo adverse events directly attributable to omega-3 supplementation were reported during the study period. The increased incidence of neutropenia in the intervention group is notable and warrants further investigation to determine its clinical significance and any potential association with the supplementation.\u003c/p\u003e\n\u003cp\u003eTable 8 Comparison of Clinical Outcomes Between Study Groups During Hospitalization\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 29px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 26px;\"\u003e\n \u003cp\u003eUnit/Subgroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 15px;\"\u003e\n \u003cp\u003eIntervention (N = 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 18px;\"\u003e\n \u003cp\u003eControl (N = 33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 9px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 29px;\"\u003e\n \u003cp\u003eNeed for surgery due to NEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 26px;\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 15px;\"\u003e\n \u003cp\u003e29:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 18px;\"\u003e\n \u003cp\u003e33:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 9px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 29px;\"\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 26px;\"\u003e\n \u003cp\u003eNo:Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 15px;\"\u003e\n \u003cp\u003e28:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 18px;\"\u003e\n \u003cp\u003e28:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" rowspan=\"2\" style=\"width: 29px;\"\u003e\n \u003cp\u003eCause of death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 26px;\"\u003e\n \u003cp\u003eDue to NEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 26px;\"\u003e\n \u003cp\u003eOther causes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 18px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 29px;\"\u003e\n \u003cp\u003eLength of hospital stay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 26px;\"\u003e\n \u003cp\u003eDays\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12.66 \u0026plusmn; 7.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 18px;\"\u003e\n \u003cp\u003e16.76 \u0026plusmn; 12.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis randomized clinical trial aimed to evaluate the effect of enteral supplementation with omega-3 (DHA) fatty acids on the incidence of NEC and associated outcomes in preterm infants. Our key findings indicate a statistically significant reduction in the incidence of severe NEC, alongside a non-significant trend towards a lower incidence of any NEC. Furthermore, infants in the intervention group demonstrated significantly lower rates of abdominal discoloration and metabolic acidosis, suggesting potential benefits in reducing clinical and biochemical markers associated with more severe gut injury. However, an unexpected finding was a significantly higher incidence of neutropenia in the intervention group.\u003c/p\u003e \u003cp\u003eRegarding the primary outcome, our study find a statistically significant reduction in the incidence of severe NEC with omega-3 supplementation. This result aligns with the findings of Bernabe-Garc\u0026iacute;a et al., who reported a statistically significant prevention of confirmed NEC using enteral DHA supplementation alone in a specific population of preterm infants weighing between 1000 and 1500g [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA comprehensive systematic review and meta-analysis by Alshaikh et al. highlighted that while DHA supplementation alone might increase the risk of NEC, the concurrent supplementation of ARA with DHA was associated with a significant reduction in the risk of NEC when compared to DHA alone [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Conversely, another study by Abou El Fadl et al. found a significant reduction in overall NEC diagnosis and staging with enteral DHA supplementation alone in preterm infants (GA\u0026thinsp;\u0026le;\u0026thinsp;32 weeks, BW \u0026le;\u0026thinsp;1500g) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The discrepancy between their significant finding with DHA alone and our finding, despite the protective trend in our study, might be related to differences in the specific populations studied.\u003c/p\u003e \u003cp\u003eThe observed trend towards lower severe NEC and reduced associated clinical signs in our study aligns with the hypothesized anti-inflammatory and gut-protective effects of LCPUFA supplementation. Abdominal discoloration is a sign of impaired gut perfusion and potentially severe inflammation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and its significant reduction in the intervention group is a clinically relevant finding. Similarly, metabolic acidosis is a recognized feature of advanced NEC [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and its lower incidence supports the notion that the intervention may have mitigated the severity of intestinal injury. These findings are consistent with the biological understanding that LCPUFAs, including both omega-3 and omega-6 derivatives and their metabolites, play complex roles in modulating inflammatory responses and promoting tissue repair in the immature gut [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe observation of significantly higher neutropenia in the intervention group was unexpected. Neutrophil count can fluctuate in preterm infants and the neutrophil-to-lymphocyte ratio is considered an indicator of inflammation and stress-induced immune response [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. While omega-3 fatty acids have been shown to modulate neutrophil function [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], the available evidence provide no clear explanation to suggest that combined DHA supplementation causes neutropenia. Tumer et al. reported lower, non-significant neutrophil-to-lymphocyte ratios with omega-3 supplementation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Given the lack of supporting evidence in the literature linking this specific intervention to neutropenia, this finding should be interpreted with caution and may potentially be an incidental observation or a consequence of other, unmeasured confounding factors unique to this group.\u003c/p\u003e \u003cp\u003eMortality and length of hospital stay were lower in the intervention group, although these differences did not reach statistical significance. A shorter length of stay was a significant finding in the enteral DHA study by Abou El Fadl et al., and trends towards lower mortality have been observed in other studies involving omega-3 supplementation in preterm infants [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The consistent direction of these trends across studies, even if not individually significant, could collectively suggest a benefit, possibly related to a reduction in illness severity, including severe NEC.\u003c/p\u003e \u003cp\u003eA limitation of our study is the statistically significant differences in mean gestational age and need for resuscitation at baseline, with the intervention group having slightly higher gestation, and lower need for resuscitation. Although our multivariable analysis adjusted for these factors, this statistical adjustment may not fully negate the profound confounding effect of these baseline imbalances. Future studies should ensure stratification to minimize such baseline imbalances. Another limitation is the open-label design of the study, as it lacked both a placebo control and blinding of clinicians and researchers. The single-center nature of the study also limits the generalizability of our findings. Furthermore, while our sample size was calculated based on an expected NEC incidence, the actual incidence rate and variability observed might have influenced the power to detect a statistically significant difference for the primary outcome.\u003c/p\u003e \u003cp\u003eDespite these limitations, our study has several strengths. It employed a randomized controlled design, contributing valuable data to the debate on LCPUFA supplementation in preterm infants. It specifically evaluated the effect of DHA supplementation. The intervention was well-tolerated, with no adverse events directly attributed to the supplement itself. Comprehensive clinical and laboratory monitoring allowed for a detailed assessment of the intervention's impact on various outcomes and associated markers.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ethis randomized controlled trial demonstrated a statistically significant reduction in the incidence of severe NEC. Also, the significant reductions observed in abdominal discoloration and metabolic acidosis further support a potential clinical benefit. The intervention was well-tolerated. Given the critical need for effective NEC prevention strategies and the accumulating evidence suggesting that LCPUFA supplementation may play a protective role, these findings warrant further investigation. Larger, multi-center randomized controlled trials are necessary to confirm the efficacy of omega-3 supplementation and to fully elucidate its mechanisms of action in this vulnerable population, while carefully controlling for potential confounding factors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Ethics Committee of Kerman University of Medical Sciences (approval number: IR.KMU.AH.REC.1401.245). Additionally, the study was registered with the Iranian Registry of Clinical Trials (IRCT ID: IRCT20250625066253N1). Written informed consent was obtained from the parents or legal guardians of all participating infants after they were provided with detailed information about the study objectives, procedures, potential benefits, and risks. Participation was voluntary, and parents were assured that they could withdraw their infants from the study at any time without affecting their medical care. Confidentiality of patient data was maintained throughout the study, and all data were anonymized prior to analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has not been funded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFS conceptualized and designed the study. AP was responsible for data collection. MR performed the statistical analysis and prepared the initial draft of the manuscript. B.B.B., ZJ, MN, ME, and AH collaborated in the study execution, provided supervision over intervention, and contributed to the revision of the manuscript. All authors read, critically reviewed for important intellectual content, made editions to the manuscript, and approved the final version for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMartin CR, Dasilva DA, Cluette-Brown JE. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr. 2011;159:743\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eTanner SM, Berryhill TF, Ellenburg JL, Jilling T, Cleveland DS, Lorenz RG, et al. Pathogenesis of Necrotizing Enterocolitis. Am J Pathol. 2015;185:4\u0026ndash;16.\u003c/li\u003e\n\u003cli\u003eHerrera E, Ortega-Senovilla H. Dietary implications of polyunsaturated fatty acids during pregnancy and in neonates. Life. 2023;13:1656.\u003c/li\u003e\n\u003cli\u003eSingh P, Ochoa Allemant P, Brown J, Perides G, Freedman SD, Martin CR. Effect of polyunsaturated fatty acids on postnatal ileum development using the fat-1 transgenic mouse model. Pediatr Res. 2019;85:556\u0026ndash;65.\u003c/li\u003e\n\u003cli\u003eUauy R, Mena P, Rojas C. Essential fatty acids in early life: Structural and functional role. Proc Nutr Soc. 2000;59:3\u0026ndash;15.\u003c/li\u003e\n\u003cli\u003eSantoro K, Martin CR. Lipids and long chain polyunsaturated fatty acids in preterm infants. Clin Perinatol. 2022;49:381\u0026ndash;91.\u003c/li\u003e\n\u003cli\u003eAbou El Fadl DK, Ahmed MA, Aly YA, Darweesh EAG, Sabri NA. Impact of Docosahexaenoic acid supplementation on proinflammatory cytokines release and the development of Necrotizing enterocolitis in preterm Neonates: A randomized controlled study. Saudi Pharm J SPJ. 2021;29:1314\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eTumer G, Mercanlıgil SM, Seren CA, Dağ A. Effect of omega-3 fatty acid added to parenteral nutrition on inflammatory in preterm infants. Prog Nutr. 2022;24:e2022091.\u003c/li\u003e\n\u003cli\u003eWang B, Wu L, Chen J, Dong L, Chen C, Wen Z, et al. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther. 2021;6:1\u0026ndash;30.\u003c/li\u003e\n\u003cli\u003eBernabe-Garc\u0026iacute;a M, Calder P, Villegas-Silva R, Rodr\u0026iacute;guez-Cruz M, Ch\u0026aacute;vez-S\u0026aacute;nchez L, Cruz-Reynoso L, et al. Efficacy of docosahexaenoic acid for the prevention of necrotizing enterocolitis in preterm infants: A randomized clinical trial. Nutrients. 2021;13:648.\u003c/li\u003e\n\u003cli\u003eAlshaikh BN, Reyes Loredo A, Yusuf K, Maarouf A, Fenton TR, Momin S. Enteral long-chain polyunsaturated fatty acids and necrotizing enterocolitis: A systematic review and meta-analysis. Am J Clin Nutr. 2023;117:918\u0026ndash;29.\u003c/li\u003e\n\u003cli\u003ePatel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: Current difficulties and future opportunities. Pediatr Res. 2020;88 Suppl 1:10\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eDiNicolantonio JJ, O\u0026rsquo;Keefe J. The importance of maintaining a low omega-6/omega-3 ratio for reducing the risk of autoimmune diseases, asthma, and allergies. Mo Med. 2021;118:453\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eClark DA, Munshi UK. Feeding associated neonatal necrotizing enterocolitis (primary NEC) is an inflammatory bowel disease. Pathophysiology. 2014;21:29\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eFussbroich D, Colas RA, Eickmeier O, Trischler J, Jerkic SP, Zimmermann K, et al. A combination of LCPUFA ameliorates airway inflammation in asthmatic mice by promoting pro-resolving effects and reducing adverse effects of EPA. Mucosal Immunol. 2020;13:481\u0026ndash;92.\u003c/li\u003e\n\u003cli\u003eMa C, Vasu R, Zhang H. The Role of Long-Chain Fatty Acids in Inflammatory Bowel Disease. Mediators Inflamm. 2019;2019:8495913.\u003c/li\u003e\n\u003cli\u003eSokou R, Mantzios P, Palioura AE, Tsantes AG, Lianou A, Piovani D, et al. Diagnostic and Prognostic Value of Hematological Parameters in Necrotizing Enterocolitis: A Systematic Review. J Clin Med. 2025;14:2530.\u003c/li\u003e\n\u003cli\u003eLee TH, Hoover RL, Williams JD, Sperling RI, Ravalese J, Spur BW, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med. 1985;312:1217\u0026ndash;24.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Necrotizing enterocolitis, Preterm infants, Long-chain polyunsaturated fatty acids, Omega-3, Randomized clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-8909780/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8909780/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground and objectives: To evaluate the effect of docosahexaenoic acid (DHA) supplementation on the incidence of NEC in preterm infants.\u003c/p\u003e \u003cp\u003eMethods: In a randomized clinical trial, 62 preterm infants (\u0026lt;\u0026thinsp;34 weeks gestation) were assigned to receive either an oral supplement of docosahexaenoic acid (an omega-3 fatty acid) (n\u0026thinsp;=\u0026thinsp;29) or standard care (n\u0026thinsp;=\u0026thinsp;33). The supplement was administered daily at 60 mg/kg of. The primary outcome was the incidence of NEC diagnosed using modified Bell's criteria. Secondary outcomes included gastrointestinal symptoms, laboratory abnormalities, need for surgical intervention, mortality, and length of hospital stay.\u003c/p\u003e \u003cp\u003eResults: While the incidence of any NEC (Stage\u0026thinsp;\u0026ge;\u0026thinsp;IA) was not significantly reduced (48.3% vs. 66.7%; p\u0026thinsp;=\u0026thinsp;0.14), the intervention group had a statistically significant lower incidence of severe NEC (Stage\u0026thinsp;\u0026ge;\u0026thinsp;IIB) compared to the control group (27.6% vs. 57.6%; p\u0026thinsp;=\u0026thinsp;0.03). This protective effect against severe NEC remained significant in a multivariable logistic regression analysis after adjusting for baseline confounders (OR 0.31, 95% CI [0.10, 0.98]; p\u0026thinsp;=\u0026thinsp;0.047). Infants receiving DHA also had significantly lower rates of abdominal discoloration (3.4% vs. 45.5%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and metabolic acidosis (31.0% vs. 57.6%; p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003eConclusions: In this trial, enteral DHA supplementation did not reduce the overall incidence of any stage NEC but was associated with a significant reduction in severe NEC in preterm infants. Despite baseline differences between groups, this finding suggests a clinically important protective effect.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrial Registration\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIranian Registry of Clinical Trials IRCT20250625066253N1, Registered 10 January 2026.\u003c/p\u003e","manuscriptTitle":"Docosahexaenoic Acid in Preventing Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-14 09:44:36","doi":"10.21203/rs.3.rs-8909780/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-17T04:24:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56012293930190225923600650028588599500","date":"2026-04-17T04:11:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T21:27:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"266448561145396142091815299824685244817","date":"2026-04-07T17:47:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-07T07:30:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-05T20:47:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-23T05:28:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-22T20:17:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-02-22T20:13:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6bb3ba23-103e-4aa8-b2ad-55ac4d0da809","owner":[],"postedDate":"April 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-14T09:44:36+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-14 09:44:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8909780","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8909780","identity":"rs-8909780","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}