Patent ductus arterious and increased conjugated bilirubin in the second week after birth are independent risk factors for necrotizing enterocolitis in preterm infants: an observational study.

BACKGROUND: Neonatal necrotizing enterocolitis (NEC) is a common critical illness of the gastrointestinal system in neonatal intensive care units with complex causes. We want to explore effects of serum-conjugated bilirubin on the occurrence of NEC in preterm infants. METHODS: A retrospective study of clinical case data of premature infants from 2017 to 2020 in the Department of pediatrics of the First Affiliated Hospital of Nanjing Medical University was conducted. Among these, 41 were diagnosed with NEC. After screening, 2 cases were excluded because of incomplete data. Propensity-matching score (PSM) was performed according to the ratio of 1:2(2 preterm infants in the NEC group were not matched), and finally, 37 cases were in the NEC group (average time to diagnosis was 18.9 days), and 74 cases in the non-NEC group. We compared the difference between the NEC and non-NEC groups in early serum-conjugated bilirubin and total bilirubin levels (time points: the first day of birth, 1 week after birth, 2 weeks after birth). RESULTS: (1) The changing trend of conjugated bilirubin was different between the two groups(F = 4.085, P = 0.019). The NEC group's serum-conjugated bilirubin levels gradually increased ([Formula: see text] ± s:12.64±2.68; 17.11±4.48; 19.25±11.63), while the non-NEC group did not show a continuous upward trend ([Formula: see text] ± s:13.39±2.87; 15.63±3.75; 15.47±4.12). (2) Multiple analyses showed that patent ductus arteriosus(PDA) (odds ratio[OR] = 5.958, 95%confidence interval[CI] = 2.102 ~ 16.882) and increased conjugated bilirubin in the 2nd week (OR = 1.105, 95%CI = 1.013 ~ 1.206) after birth were independent risk factors for NEC. CONCLUSIONS: The body had already experienced an elevation of conjugated bilirubin before the occurrence of NEC. The change of early conjugated bilirubin may be an important factor in the occurrence of NEC.

Evaluation of antibiotic stewardship among near-term and term infants admitted to a neonatal unit.

To evaluate the safety and effectiveness of evidence-based antibiotic stewardship in a neonatal unit in China. The study period consisted of two phases, one retrospective (the baseline period, January to December 2018, and the transition period, January 2019 to August 2020) and one prospective intervention period (September 2020 to August 2021). During the prospective period, evidence-based antibiotic stewardship was applied to neonates with suspected infections, pneumonia, and culture-negative sepsis. The antibiotic stewardship included the observation form of neonatal infections, antibiotic therapy of no more than 48 h for suspected infections, and 5 days for pneumonia and culture-negative sepsis. The change in antibiotic use measured by days of therapy per 1000 patient-days between the baseline and intervention period was analyzed. Safety outcomes included reinitiation of antibiotics within 14 days, length of stay, occurrence of late-onset sepsis and necrotizing enterocolitis (Bell stage ≥ II), multidrug-resistant organism infections, and mortality. A total of 7705 neonates were enrolled during the baseline (n = 4804) and the intervention periods (n = 2901). The total antibiotic usage during the baseline period was 771 days of therapy per 1000 patient-days, while that was 525 days of therapy per 1000 patient-days during the intervention period, indicating a 32% decrease in antibiotic consumption. No significant difference in safety outcomes was observed between the baseline and intervention period (P > 0.05), whereas the length of stay was longer during the intervention period (P < 0.001). CONCLUSION: The evidence-based antibiotic stewardship can safely and effectively reduce antibiotic use and shorten the duration of therapy in the neonatal unit. WHAT IS KNOWN: • Overuse of antibiotics has been associated with adverse events in neonates, including necrotizing enterocolitis, multidrug-resistant organism infections, and death. • More clinical effectiveness evidence is needed to support antibiotic stewardship of neonates in China. WHAT IS NEW: • Using prospective audit, targeted stewardship interventions, this study shows that a 32% reduction in overall antibiotic consumption was achieved safely. • Implementation of evidence-based neonatal antibiotic stewardship, including the observation form of neonatal infections, antibiotic therapy of no more than 48 h for suspected infections, and 5 days for pneumonia and culture-negative sepsis, is safe and effective among newborns in a developing country.

Butyrate induces development-dependent necrotizing enterocolitis-like intestinal epithelial injury via necroptosis.

BACKGROUND: The accumulation of short-chain fatty acids (SCFAs) from bacterial fermentation may adversely affect the under-developed gut as observed in premature newborns at risk for necrotizing enterocolitis (NEC). This study explores the mechanism by which specific SCFA fermentation products may injure the premature newborn intestine mucosa leading to NEC-like intestinal cell injury. METHODS: Intraluminal injections of sodium butyrate were administered to 14- and 28-day-old mice, whose small intestine and stool were harvested for analysis. Human intestinal epithelial stem cells (hIESCs) and differentiated enterocytes from preterm and term infants were treated with sodium butyrate at varying concentrations. Necrosulfonamide (NSA) and necrostatin-1 (Nec-1) were used to determine the protective effects of necroptosis inhibitors on butyrate-induced cell injury. RESULTS: The more severe intestinal epithelial injury was observed in younger mice upon exposure to butyrate (p = 0.02). Enterocytes from preterm newborns demonstrated a significant increase in sensitivity to butyrate-induced cell injury compared to term newborn enterocytes (p = 0.068, hIESCs; p = 0.038, differentiated cells). NSA and Nec-1 significantly inhibited the cell death induced by butyrate. CONCLUSIONS: Butyrate induces developmental stage-dependent intestinal injury that resembles NEC. A primary mechanism of cell injury in NEC is necroptosis. Necroptosis inhibition may represent a potential preventive or therapeutic strategy for NEC. IMPACT: Butyrate induces developmental stage-dependent intestinal injury that resembles NEC. A primary mechanism of cell injury caused by butyrate in NEC is necroptosis. Necroptosis inhibitors proved effective at significantly ameliorating the enteral toxicity of butyrate and thereby suggest a novel mechanism and approach to the prevention and treatment of NEC in premature newborns.

Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: a multicenter cohort study.

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003). CONCLUSION: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. WHAT IS KNOWN: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. WHAT IS NEW: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.

Increased antibiotic exposure in early life is associated with adverse outcomes in very low birth weight infants.

BACKGROUND: The use of antibiotics in the early lives of premature infants may alter the microbiota and influence their clinical outcomes. However, whether the administration of probiotics can influence these outcomes remains unknown. In our study, probiotics were routinely administered unless contraindicated. We explored whether increased antibiotic exposure with the routine use of probiotics was associated with necrotizing enterocolitis (NEC) or bronchopulmonary dysplasia (BPD). METHODS: A retrospective cohort study was conducted, enrolling very low birth weight (VLBW) infants admitted between January 1, 2016, and March 31, 2020, to a medical center. Days of antibiotic exposure in the first 14 days of life were recorded. The primary outcomes were NEC and BPD. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using multivariable regression analyses to assess risk factors. RESULTS: Of 185 VLBW infants admitted to the medical center, 132 met the inclusion criteria. Each additional day of antibiotic treatment was associated with increased odds of NEC (aOR, 1.278; 95% CI, 1.025-1.593) and BPD (aOR, 1.630; 95% CI, 1.233-2.156). The association remained in the NEC analysis after adjustment for probiotic use. CONCLUSION: Increased antibiotic exposure in the early lives of VLBW infants was associated with increased risks of NEC and BPD. The probiotics did not influence the outcomes. Our findings suggest that clinicians should be alerted to the adverse outcomes of antibiotic use in infants with VLBWs.

Association Between Antibiotic Overexposure and Adverse Outcomes in Very-Low-Birth-Weight Infants Without Culture-Proven Sepsis or Necrotizing Enterocolitis: A Multicenter Prospective Study.

OBJECTIVES: To explore the associations between higher antibiotic use rates (AURs) and adverse outcomes in very-low-birth-weight (VLBW) infants without culture-proven sepsis or necrotizing enterocolitis (NEC) in a multicenter of China. METHODS: A prospective cohort study was performed on VLBW infants admitted to 24 neonatal intensive care units from January 1, 2018, to December 31, 2018. AUR was calculated as calendar days of antibiotic therapy divided by total hospital days. The composite primary outcome was defined as mortality or severe morbidity, including any of the following: severe neurologic injury, bronchopulmonary dysplasia (BPD), and stage 3 or higher retinopathy of prematurity. RESULTS: A total of 1,034 VLBW infants who received antibiotics without culture-proven sepsis or NEC were included in this study. The overall AUR of eligible VLBW infants was 55%, and the AUR of each eligible VLBW infant ranged from 3 to 100%, with a median of 56% (IQR 33%, 86%). After generalized propensity score and logistic regression analysis of 4 groups of VLBW infants with different AUR range, infants in the higher quartile AUR, (Q3, 0.57~0.86) and (Q4, 0.87~1.00), had higher odds of composite primary outcome (adjusted OR: 1.81; 95% CI: 1.23-2.67; adjusted OR 2.37; 95% CI: 1.59-3.54, respectively) and BPD (adjusted OR: 3.09; 95% CI: 1.52-6.57; adjusted OR 3.17; 95% CI: 1.56-6.57, respectively) than those in the lowest AUR (Q1). CONCLUSIONS: Antibiotic overexposure in VLBW infants without culture-proven sepsis or NEC was associated with increased risk of composite primary outcome and BPD. Rational empirical antibiotic use in VLBW infants is urgently needed in China.

Topiramate Is Safe for Refractory Neonatal Seizures: A Multicenter Retrospective Cohort Study of Necrotizing Enterocolitis Risk.

BACKGROUND: A previously published, single-institution, case series suggested an association between topiramate administration in neonates and subsequent development of necrotizing enterocolitis (NEC). This contradicted our more extensive experiences using topiramate in this population. We therefore studied safety and tolerability of topiramate for treating refractory neonatal seizures, hypothesizing that the risk of developing NEC following topiramate exposure was low and that most infants tolerate topiramate. METHODS: This multicenter retrospective cohort study included seventy-five neonates who received topiramate to treat seizures from January 2011 to October 2019 at three geographically diverse level IV neonatal intensive care units affiliated with pediatric tertiary hospitals. Data included demographics, birth history, seizure etiology, treatment response, side effects, and occurrence and details of NEC. RESULTS: Three of seventy-five infants (4%) developed NEC following topiramate exposure. These infants did not differ in gestational age, birth weight, seizure etiology, postmenstrual age, weight when topiramate was initiated, or dosing of topiramate. Topiramate was well tolerated. Only three infants (4%) discontinued due to side effects. The most common side effect (20%) was weight loss (typically <5%). Topiramate was felt to be efficacious (61%). Most infants (72%) continued topiramate when discharged. CONCLUSIONS: Our multicenter, 75-infant study demonstrated that development of NEC after treatment with topiramate was rare (4%) and refutes prior literature suggesting an association. Topiramate was felt to be efficacious and was well tolerated. Although limited by retrospective design, study data are broadly applicable and support thoughtful use of topiramate as a safe, reasonable option for treating refractory neonatal seizures.

Early initiation of broad-spectrum antibiotics in premature infants.

BACKGROUND: Neonatal sepsis remains one of the main reasons for mortality among premature infants, and the early initiation of empirical broad-spectrum antibiotics could increase the risk of complications, including late-onset sepsis. This study aimed to investigate the complications related to the use of empirical broad-spectrum antibiotics in the first week of life. METHODS: A retrospective study of 365 neonates with gestational age ≤32 weeks and birth weight <1500 g who survived and had no confirmed sepsis in the first week of life from July 2015 to June 2018 was performed in a large tertiary Neonatal Intensive Care Unit. The primary outcome of this study was the incidence of a composite outcome consisting of late-onset sepsis, necrotizing enterocolitis, and mortality. The secondary outcomes were the incidences of late-onset sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, and infant mortality. RESULTS: Of the 365 premature infants, 75 (20.5%) received broad-spectrum antibiotics. Multivariate regression analysis revealed that administration of broad-spectrum antibiotics in infants was independently associated with adverse outcomes. The composite outcome (late-onset sepsis, necrotizing enterocolitis, and death) had an odds ratio of 3.03 with 95% confidence interval of 1.41-6.49. CONCLUSIONS: Administration of empirical broad-spectrum antibiotics in the first week of life is associated with severe adverse outcomes. Thus, the restricted use of broad-spectrum antibiotics in the first week of life is recommended.

Inhibition of Interleukin-6 signaling: A novel therapeutic approach to necrotizing enterocolitis.

OBJECTIVES: This study investigated the effects of tocilizumab on the prevention and treatment of experimental necrotizing enterocolitis (NEC) in newborn rats. METHODS: Forty-two newborn Sprague-Dawley rats were randomly separated into three groups: NEC + placebo, NEC + tocilizumab, and the control group. NEC + placebo and NEC + tocilizumab groups were given 1 mg/kg lipopolysaccharide intraperitoneally once only on the first day, were fed with a special rodent formula every 3 h, inhaled 100% CO2 for 10 min, were exposed to cold stress at + 4 °C for 5 min, and 97% O2 for 5 min twice a day for 3 days. NEC + tocilizumab group was treated with 8 mg/kg/day tocilizumab (Actemra®) intraperitoneally, while NEC + placebo group was given intraperitoneal 0.9% saline at a dose of 2 mL/kg/day from the first day to the end of the study. All newborn rats were sacrificed on day 4. Specimens were taken for histopathologic, immunohistochemical and biochemical evaluation from the ileum and proximal colon. RESULTS: NEC + tocilizumab group had higher weight gain and survival rate compared to NEC + placebo group and clinical sickness score was reduced in NEC + tocilizumab group (p < 0.05). Lower tissue damage and apoptosis were found in the NEC + tocilizumab group compared to the NEC + placebo group (p < 0.01). Tissue Interleukin-6, Interleukin-1ß, TNF-α, myeloperoxidase and caspase-3 levels were significantly decreased in the NEC + tocilizumab group (p < 0.01). CONCLUSIONS: Tocilizumab could be a potential option in the prevention and treatment of NEC.

Angiopoietin-2 silence alleviates lipopolysaccharide-induced inflammation, barrier dysfunction and endoplasmic reticulum stress of intestinal epithelial cells by blocking Notch signaling pathway.

Necrotizing enterocolitis, a devastating gastrointestinal disease with high mortality, poses great threats to global health. Therefore, we conducted this study to explore the role of ANGPT2, as well as the potential mechanism, in necrotizing enterocolitis. IEC-6 cells were stimulated with lipopolysaccharide (LPS) to induce necrotizing enterocolitis model in vitro. The expression of ANGPT2 was measured by RT-qPCR. The cell viability was detected using CCK-8. Besides, the expressions of endoplasmic reticulum (ER) stress-related proteins, Notch signaling pathway-related proteins and tight junction proteins were checked by western blot. The apoptosis and inflammatory response were detected by TUNEL and ELISA, respectively. Moreover, with the adoption of TEER, the cell monolayer permeability was detected. The results showed that ANGPT2 expression was greatly increased after LPS induction. In addition, ANGPT2 knockdown significantly decreased the apoptosis, inflammatory response, barrier dysfunction and endoplasmic reticulum stress of LPS-induced IEC-6 cells. What is more, ANGPT2 knockdown could block Notch signaling pathway. Additionally, with the treatment of Jagged-1, the protective effect of ANGPT2 knockdown on LPS-induced intestinal injury was partly abolished. To sum up, silencing ANGPT2 could improve LPS-induced inflammation, barrier dysfunction and ER stress of intestinal epithelial cells via blocking Notch signaling pathway.

The Effects of Ranitidine Treatment on the Risk of Necrotizing Enterocolitis in Preterm Infants: A Case-Control Study.

INTRODUCTION: Gastric acidity plays an important role in the protection of infants against various pathogens from the environment. The histamine-2 receptor blockers (H2-blockers) are off-labeled drugs that are frequently prescribed in preterm neonates to prevent stress ulcers. The impact of the H2-blockers on the development of the necrotizing enterocolitis (NEC) in preterm infants is still controversial, particularly in the developing world. MATERIALS AND METHODS: One hundred twenty-two preterm infants were enrolled in the study. The multivariate logistic regression model was used to identify potential postnatal risk factors associated with NEC. RESULTS: Preterm infants (n = 51) with total NEC, medical NEC, and surgical NEC had the highest rate of receiving ranitidine compared with controls (n = 71) (39.2%, 19.6%, and 47.6%, p < 0.05). Logistic regression analysis revealed that ranitidine use and nosocomial infections were significantly associated with NEC development (odds ratios 1.55 and 3.3). CONCLUSIONS: We confirm that ranitidine administration was associated with an increased risk of NEC in preterm infants. H2-blockers use should be only administered in very strictly selected cases after careful consideration of the risk-benefit ratio.

Intestinal Goblet Cell Loss during Chorioamnionitis in Fetal Lambs: Mechanistic Insights and Postnatal Implications.

Chorioamnionitis, an important cause of preterm birth, is linked to necrotizing enterocolitis (NEC). NEC is characterized by a disrupted mucus barrier, goblet cell loss, and endoplasmic reticulum (ER) stress of the intestinal epithelium. These findings prompted us to investigate the mechanisms underlying goblet cell alterations over time in an ovine chorioamnionitis model. Fetal lambs were intra-amniotically (IA) exposed to lipopolysaccharides (LPS) for 5, 12, or 24 h, or 2, 4, 8, or 15 d before premature delivery at 125 d gestational age (GA). Gut inflammation, the number, distribution, and differentiation of goblet cells, ER stress, and apoptosis were measured. We found a biphasic reduction in goblet cell numbers 24 h-2 d after, and 15 d after IA LPS exposure. The second decrease of goblet cell numbers was preceded by intestinal inflammation, apoptosis, and crypt ER stress, and increased SAM-pointed domain-containing ETS transcription factor (SPDEF)-positive cell counts. Our combined findings indicated that ER stress drives apoptosis of maturating goblet cells during chorioamnionitis, ultimately reducing goblet cell numbers. As similar changes have been described in patients suffering from NEC, these findings are considered to be clinically important for understanding the predecessors of NEC, and targeting ER stress in this context is interesting for future therapeutics.

The Risk of Necrotizing Enterocolitis following the Administration of Hyperosmolar Enteral Medications to Extremely Preterm Infants.

INTRODUCTION: Necrotizing enterocolitis (NEC) is a disease predominantly affecting preterm infants. The administration of hyperosmolar solutions could lead to the development of NEC. The objective of this study was to measure the osmolality of enteral medications used in clinical practice and to assess the risk of NEC following exposure to hyperosmolar medications. METHODS: A retrospective cohort study in extremely preterm infants (gestational age <28 weeks) born between 2010 and 2016 at a tertiary neonatal intensive care unit in Sweden. 465 infants were identified via the Swedish Neonatal Quality register. Data relating to enteral administrations received during a two-week period were collected from the medical records. The osmolalities of medications were measured using an osmometer. Logistic regression was used to calculate the odds ratio of developing NEC. RESULTS: A total of 253 patients met the inclusion criteria. The osmolalities of 5 commonly used medications significantly exceeded the recommended limit of 450 mOsm/kg set by the American Academy of Paediatrics (AAP). Most patients (94%) received at least one hyperosmolar medication. No significant risk of developing NEC could be found. CONCLUSION: The medications used in clinical practice can significantly exceed the limit set by the AAP. This study does not indicate an increased risk of developing NEC in extremely preterm infants following exposure to hyperosmolar medications. Further studies in larger cohorts are needed to determine the specific cut-off level of osmolality in relation to the pathogenesis of NEC.

Indomethacin for symptomatic patent ductus arteriosus in preterm infants.

BACKGROUND: Symptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored. OBJECTIVES: To determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding. MAIN RESULTS: We included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision. AUTHORS' CONCLUSIONS: High-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.

Necrotizing Enterocolitis in Neonates With Hyperinsulinemic Hypoglycemia Treated With Diazoxide.

The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration-approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006-April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.

Pathogenesis of necrotising enterocolitis: The impact of the altered gut microbiota and antibiotic exposure in preterm infants.

Necrotising enterocolitis (NEC) is a devastating condition with high morbidity and mortality seen predominately in preterm infants. Multiple factors are associated with the pathogenesis of NEC. The widespread use of antibiotics in the neonatal intensive care unit might play a role in the pathogenesis of NEC in preterm infants. This review provides a summary on the intestinal microbiota in preterm infants with a focus on how antibiotic exposure may reduce the biodiversity of the intestinal microbiota and may predispose preterm infants to NEC. CONCLUSION: Prolonged antibiotic therapy has been suggested as a risk factor for the development of NEC in preterm infants.

Necrotising enterocolitis in newborns receiving diazoxide.

BACKGROUND: Frequent and severe gastrointestinal disturbances have been reported with the use of diazoxide in adults and older children. However, no studies have investigated the incidence of necrotising enterocolitis (NEC) in diazoxide-exposed newborns. OBJECTIVE: To evaluate a possible association between diazoxide treatment for neonatal hypoglycaemia and the occurrence of NEC. DESIGN: Multicentre retrospective cohort study. SETTING: Three tertiary neonatal intensive care units in Toronto, Canada. PATIENTS: All patients treated with diazoxide for persistent hypoglycaemia between July 2012 and June 2017 were included. Overall incidence of NEC during those years on the participating units was obtained for comparison from the Canadian Neonatal Network database. MAIN OUTCOME: Incidence of NEC after diazoxide exposure. RESULTS: Fifty-five neonates were exposed to diazoxide during the study period. Eighteen patients (33%) showed signs of feeding intolerance, and 7 developed NEC (13%). A diagnosis of NEC was more prevalent in the diazoxide-exposed, as compared with non-exposed infants of similar gestational age (OR 5.07, 95% CI 2.27 to 11.27; p<0.001), and greatest among infants born at 33-36 weeks' gestation (OR 13.76, 95% CI 3.77 to 50.23; p<0.001). All but one of the neonates diagnosed with NEC developed the disease within 7 days from initiation of diazoxide treatment. CONCLUSION: The present data suggest a possible association between diazoxide exposure and the development of NEC in neonates. Further evaluation of the diazoxide-associated risk of NEC in neonates treated for persistent hypoglycaemia is warranted.