乳铁蛋白与早产儿坏死性小肠结肠炎

坏死性小肠结肠炎是早产儿常见主要并发症之一,具有较高的病死率和发病率,可以导致多种远期并发症,如短肠综合征、全身感染、眼部疾病、营养不良和神经系统发育障碍等.乳铁蛋白是母乳中的一种成分,具有抗细菌、抗病毒、抗真菌、增强免疫力等多种作用.新近许多研究评估了乳铁蛋白防治坏死性小肠结肠炎的效果和安全性.应用乳铁蛋白预防和治疗坏死性小肠结肠炎对于提高早产儿的预后具有很重要作用.     

Maternal preeclampsia is associated with increased risk of necrotizing enterocolitis in preterm infants

Background

Necrotizing enterocolitis (NEC) is an important cause of mortality and morbidity in preterm infants.

Aims

To evaluate the effect of maternal preeclampsia on the development and severity of NEC in premature infants.

Study design

Prospective observational study in a tertiary neonatal intensive care unit.

Subjects

The preterm infants of ≤ 37 gestational age who were consecutively hospitalized were enrolled. The study group contained preterm infants born to a preeclamptic mother and the comparison group contained preterm infants born to a normotensive mother.

Outcome measures

The primary outcome was to determine the association between preeclampsia and NEC.

Results

A total of 88 infants had NEC diagnosis. The incidence of NEC in infants born to preeclamptic mothers (22.9%) was significantly higher compared with those born to normotensive mothers (14.6%). According to NEC stages, NEC was more advanced in preeclamptic mother infants. NEC developed significantly earlier in infants with NEC in the study group. The duration of NEC was also significantly longer in infants born to preeclamptic mothers. In multiple logistic regression model, preeclampsia was found to be predictive of NEC with an odds ratio of 1.74 (95% confidence interval 0.64–0.92).

Conclusions

Maternal preeclampsia may be an important risk factor for the development of NEC in premature infants as NEC incidence and severity of NEC were found to be significantly higher in premature infants born to preeclamptic mothers. The onset of NEC was significantly earlier and duration of NEC was longer in these infants.     

Plasma citrulline levels in preterm neonates with necrotizing enterocolitis

Background and aim

Citrulline is a non-protein amino acid synthesized in the small intestine. In children with short-bowel syndrome, citrulline has served as a reliable marker of the residual bowel length and parenteral nutrition (PN) independence. In the present study we aim to assess the value of citrulline measurement in preterm neonates developing necrotizing enterocolitis (NEC).

Methods

Plasma citrulline levels were measured prospectively in 17 preterm neonates with NEC stage II during the entire course of the disease. Serial citrulline determinations in 24 healthy preterm neonates on 2, 7, 14, 21 and 28 days of life (DOL), served as reference values.

Results

In healthy preterm neonates plasma citrulline levels showed a progressive increase in relation to age. In neonates presenting with NEC, mean citrulline levels were significantly lower as compared to controls' citrulline levels of the most approximate day of life (DOL 7: 16.85 ± 4.2 vs 20.5 ± 4.5 μmol/L, p < 0.05; DOL 14: 18 ± 4.2 vs 23.5 ± 4.3 μmol/L, p < 0.01; DOL 21: 17 ± 2.5 vs 30 ± 5.7 μmol/L, p < 0.01). The optimal citrulline cut-off distinguishing NEC patient from controls was 17.75 μmol/L (sensitivity 76%, specificity 87%). Plasma citrulline at presentation correlated inversely with the duration of parenteral nutrition (r = − 0.49, p < 0.05). Consecutive citrulline determinations revealed that plasma citrulline increased during reintroduction and gradual increase of enteral nutrition.

Conclusions

Our findings provide preliminary evidence that citrulline levels that are reduced in preterm neonates with NEC in comparison to age-matched controls and serial citrulline determinations could help to monitor improvement of functional enterocyte mass during the course and resolution of NEC.     

早产儿坏死性小肠结肠炎影响因素分析及发病预测模型的构建

目的 探讨早产儿坏死性小肠结肠炎（necrotizing enterocolitis,NEC）发生的影响因素,制定一个可以预测NEC发生并指导预防的评分表。 方法 回顾性收集2011年1月至2020年12月吉林大学白求恩第一医院新生儿科收治的早产儿的临床资料,分为NEC组（Bell Ⅱ期及以上）（n=298）和非NEC组（n=300）,对NEC影响因素进行单因素及多因素统计分析,明确NEC的独立影响因素,并根据影响因素构建预测NEC的列线图,用受试者工作特征曲线及一致性指数（C指数）测量列线图的预测性能。 结果 多因素logistic回归分析显示：Ⅱ度及以上颅内出血、经外周静脉穿刺中心静脉置管、使用母乳强化剂、输红细胞悬液、红细胞比容>49.65%、平均红细胞体积>114.35 fL、平均血小板体积>10.95 fL是NEC的独立危险因素（P<0.05）;使用肺表面活性物质、使用益生菌、血小板分布宽度>11.8 fL是NEC的保护因素（P<0.05）。列线图预测NEC风险的准确性良好,bootstrap校正的C指数为0.844。预测有无NEC的列线图总分最佳截断值为171.02分,灵敏度、特异度分别为74.7%、80.5%。 结论 NEC发病风险预估列线图在指导NEC的早期预判及有针对性的预防及早期干预方面有一定的临床价值。     

肠道微生态与早产儿坏死性小肠结肠炎的研究进展

坏死性小肠结肠炎（NEC）是早产儿常见的严重胃肠道疾病,其发病率及病死率与早产儿胎龄及出生体重呈负相关,可引起多种胃肠道并发症,并可对患儿神经系统发育造成不良影响。近年来研究发现肠道微生态失调在NEC发病中起重要作用,探究肠道微生态改变与NEC的相关性有助于NEC早期诊断及严重程度的预测。益生菌在降低早产儿NEC发病率和病死率中的作用已受到业界广泛关注,但其在临床应用中的有效性和安全性仍存在较大争议。本文主要就新生儿肠道微生态发育及其与早产儿NEC之间的关系,以及益生菌对NEC的预防作用作一综述。     

肠道微生态和新生儿坏死性小肠结肠炎

肠道微生态是由体内有益菌及有害菌共同构成的生态环境,是人体最大、最复杂的微生态系统.研究表明,适当的肠道微生物定植过程有助于肠道结构和功能发育以及免疫系统成熟,它决定了之后肠道发生疾病的风险.肠道微生态或益生菌与新生儿坏死性小肠结肠炎（neonatal necrotizing enterocolitis,NEC）的关系已越来越受到关注.该文就新生儿肠道微生态的构成及作用、肠道微生态在NEC发生中的作用及机制、益生菌对NEC的防治作用等研究进展作一综述.     

肠屏障功能障碍与新生儿坏死性小肠结肠炎

坏死性小肠结肠炎( necrotizing enterocolitis,NEC)是严重危及新生儿生命的消化系统疾病,是导致新生儿,尤其是早产儿死亡的重要病因之一。新生儿,尤其是早产儿维持肠屏障功能的作用元件发育不成熟,极易受损,不能有效形成上皮细胞间的紧密连接,无法早期形成正常肠道蠕动以及分泌型IgA的减少,因此各种致病因素极易诱发肠屏障功能障碍,导致菌群移位和败血症,造成严重的肠道损害甚至并发症。缺氧缺血、炎症反应、病原体感染均可造成肠机械屏障损害,微生态屏障建立延迟、免疫屏障发育的不成熟以及病理情况下的肠微循环障碍均参与NEC的发生。此外,miRNA在肠上皮细胞的分化、结构和屏障功能调控中也发挥重要作用。 NEC的组织病理改变是肠屏障功能障碍的结果,而肠屏障功能的损害则加重NEC的病理改变。因此,认识肠屏障功能障碍在 NEC发病过程中的作用,对于防治NEC意义重大。     

新生儿感染与新生儿坏死性小肠结肠炎

新生儿坏死性小肠结肠炎(necrotizing enterocolitis,NEC)是新生儿时期比较常见的消化系统危重症,严重者甚至可能危及新生儿生命.NEC的发生机制具有复杂性和不确定性,新生儿期的感染是其中重要的环节.早产儿肠道屏障结构和功能未成熟,肠道固有免疫存在缺陷以及异常的肠道细菌定植均会导致早产儿NEC的高发生率.目前明确有效的特异性治疗措施是有限的,对已经发现的风险因素采取有效的预防措施对于减少NEC发生是有益的.     

小剂量多巴胺辅助治疗对坏死性小肠结肠炎早产儿炎症因子及预后的影响

目的 探讨小剂量多巴胺辅助治疗对坏死性小肠结肠炎（NEC）早产儿炎症因子及预后的影响。方法 将2017年6月至2019年6月住院治疗的NEC早产儿100例,依据随机数字表法分为多巴胺治疗组（多巴胺组）和常规治疗组（常规组）,每组50例。常规组给予常规对症治疗,多巴胺组在常规治疗基础上给予小剂量多巴胺辅助治疗。ELISA法检测两组C反应蛋白（CRP）、肿瘤坏死因子-α（TNF-α）、白介素-8（IL-8）水平;观察并记录两组患儿临床症状缓解时间、禁食时间、治疗疗效、预后及不良反应。结果 多巴胺组和常规组治疗后CRP、TNF-α、IL-8水平均明显低于治疗前,多巴胺组治疗后CRP、TNF-α、IL-8水平均明显低于常规组（P < 0.05）;多巴胺组大便改善时间、腹胀及腹泻缓解时间、禁食时间均明显短于常规组（P < 0.05）;多巴胺组治疗有效率明显高于常规组,手术率明显低于常规组（P < 0.05）;两组病死率、不良反应发生率比较差异无统计学意义（P > 0.05）。结论 小剂量多巴胺辅助治疗可有效改善NEC早产儿炎症因子水平及临床症状,有利于提高患儿治疗疗效,且安全性好,值得临床推广。     

Brainstem auditory response findings in preterm infants after necrotizing enterocolitis

Aim: To examine brainstem auditory function and detect any abnormality at term in preterm infants after neonatal necrotizing enterocolitis (NEC). Methods: Brainstem auditory evoked response (BAER) was recorded at 21/sec and 60 dB nHL in 37 preterm infants who had NEC. The data obtained at term equivalent age were analyzed and compared with those in normal term infants. Results: The threshold of BAER in infants after NEC, though slightly elevated, did not differ significantly from that in the controls. The latencies of waves I and III were slightly longer than in the controls, without any statistical significance. However, wave V latency was prolonged and differed significantly from the controls (p < 0.01). I-V interpeak interval was also prolonged (p < 0.05). The data point distribution of wave V latency and I-V interval was higher in the infants after NEC than in the controls. The amplitudes of BAER wave components in the infants after NEC did not differ significantly from those in the controls. Conclusion: Preterm infants after NEC have no major abnormality in peripheral auditory function. However, neural conduction in the brainstem auditory pathway is abnormal, suggesting that NEC adversely affects brainstem auditory conduction.     

肠道微生物稳态对坏死性小肠结肠炎新生大鼠模型造血系统的影响北大核心CSCD

目的探讨肠道菌群对坏死性小肠结肠炎(necrotizing enterocolitis,NEC)新生大鼠模型造血系统的影响。方法Sprague-Dawley新生大鼠随机分为对照组和模型组(NEC组),每组6只。采用配方奶结合缺氧和冷刺激构建NEC新生大鼠模型。苏木精-伊红染色观察肠组织及造血相关器官病理变化;检测各组血常规;免疫组化法检测造血相关器官中特定细胞的改变;流式细胞术检测骨髓中特定细胞的变化;采用16S rDNA测序技术检测分析各组肠道菌群的组成及丰度。结果与对照组比较,NEC组肠组织充血坏死,肠绒毛破损、萎缩脱落,NEC病理评分显著增加;NEC组外周血白细胞及淋巴细胞计数显著低于对照组(P<0.05);NEC组脾脏、胸腺、骨髓的有核细胞及肝脏的嗜碱性细胞核的小细胞聚集体数量均明显少于对照组;NEC组肝脏中CD71^(+)红系祖细胞显著减少,脾脏、骨髓中的CD45^(+)白细胞及胸腺中的CD3^(+)T淋巴细胞显著降低,骨髓中CD45^(+)CD3^(-)CD43^(+)SSChi的中性粒细胞比例明显下降(P<0.05);NEC组肠道菌群组成与对照组比较差异明显,NEC组利乳杆菌属的相对丰度降低,而埃希菌-志贺菌属的相对丰度显著升高(P<0.05),取代利乳杆菌属成为优势菌属。结论NEC新生大鼠模型存在多谱系造血异常,可能与肠道微生物稳态失衡及致病菌属埃希菌-志贺菌属的异常扩增有关。     

维生素D缺乏与早产儿坏死性小肠结肠炎的相关性

目的 评估维生素D水平对早产儿坏死性小肠结肠炎（NEC）的影响。方法 选取2016年1~12月于生后2 h内入新生儿科住院治疗的胎龄 < 36周的早产儿429例为研究对象,依据患儿是否发生NEC,将429例患儿分为NEC组（n=22）和非NEC组（n=407）。采集早产儿及其母亲入院时外周静脉血进行25-羟基维生素D（25-OHD）水平检测,比较两组早产儿和母亲血清25-OHD水平,Pearson相关分析早产儿和母亲血清25-OHD水平相关性,比较两组早产儿维生素D缺乏情况,单因素logistic回归分析早产儿NEC影响因素。结果 NEC组母亲和早产儿血清25-OHD水平均显著低于非NEC组（P < 0.001）。两组母亲和早产儿之间血清25-OHD水平均呈正向关（P < 0.001）。非NEC组与NEC组早产儿维生素D水平在正常、不足、缺乏、严重缺乏等状况的分布上比较差异有统计学意义（P < 0.001）。单因素logistic回归分析结果显示：胎龄、出生体重、母亲和早产儿25-OHD水平、机械通气持续时间、用氧持续时间和住院时间可能是NEC发生的影响因素（P < 0.05）。结论 母亲和早产儿低血清25-OHD水平与早产儿NEC的发生可能具有相关性,提示母孕期补充维生素D对于预防早产儿NEC的发生有重要意义。     

预防性使用益生菌对降低极低出生体重早产儿坏死性小肠结肠炎发病率和病死率的Meta分析

目的 运用循证医学方法,评价益生菌在降低极低出生体重(VLBW)早产儿坏死性小肠结肠炎(NEC)的发病率和病死率方面的安全性和有效性。方法 系统检索PubMed、EMBASE、Cochrane 临床对照试验资料库(CENTRAL)、the ISI Web of Knowledge Databases、中国生物医学文献数据库(CBM)、中文期刊全文数据库(CNKI)和维普中文科技期刊数据库(VIP)、万方数据库,检索时间均为建库至2014年3月,查找所有研究预防性使用益生菌对降低VLBW早产儿NEC的发病率和病死率的随机对照试验。按纳入排除标准进行RCT的筛选、资料提取和质量评价,应用RevMan 5.1软件进行Meta分析。结果 共纳入21项研究(4 607例VLBW早产儿),Meta分析发现预防性使用益生菌能显著降低VLBW早产儿NEC的发病率[RR=0.47;95%CI(0.35~0.62);PRR=0.63;95%CI(0.51~0.78),PRR=0.87;95%CI(0.72~1.06);P=0.17]及NEC相关病死率[RR=0.68;95%CI(0.31~1.48),P=0.33]差异无统计学意义。结论 预防性使用益生菌能降低VLBW早产儿NEC的发病率和病死率,但其对早产儿的长期影响仍需大量的临床研究来评估。     

早产儿坏死性小肠结肠炎危险因素的Meta分析北大核心CSCD

目的 系统评价早产儿发生坏死性小肠结肠炎(necrotizing enterocolitis,NEC)的危险因素。方法 计算机检索PubMed、Embase、Cochrane Library、中国知网和万方数据库,检索时限均为建库起至2021年12月。收集关于早产儿发生NEC的危险因素的病例对照研究和队列研究,采用RevMan 5.3软件进行Meta分析。结果 共纳入38项研究,其中病例对照研究28项,队列研究10项。Meta分析结果显示:母妊娠糖尿病(OR=2.96,P<0.001)、孕期肝内胆汁淤积症(OR=2.53,P<0.001)、子痫前期(OR=1.73,P=0.020),以及新生儿窒息史(OR=2.13,P<0.001)、低胎龄(OR=1.23,P=0.010)、败血症(OR=5.32,P<0.001)、动脉导管未闭(OR=1.57,P=0.001)、先天性心脏病(OR=3.78,P<0.001)、机械通气(OR=2.23,P=0.020)、抗生素应用史(OR=1.07,P<0.001)、使用血管加压药(OR=2.34,P=0.040)、禁食(OR=1.08,P<0.001)是早产儿发生NEC的危险因素;而剖宫产出生(OR=0.73,P=0.004)、使用肺表面活性剂(OR=0.43,P=0.008)、母乳喂养(OR=0.24,P=0.020)是早产儿发生NEC的保护因素。结论 母妊娠糖尿病、孕期肝内胆汁淤积症、子痫前期、低胎龄、禁食、败血症、动脉导管未闭、先天性心脏病、窒息史、机械通气史、抗生素应用史、血管加压药应用史可增加早产儿发生NEC的风险;而剖宫产出生、使用肺表面活性剂、母乳喂养可降低早产儿发生NEC的风险。[中国当代儿科杂志,2022,24 (8):908-916]     

Early blood thyroxine concentration and necrotizing enterocolitis in premature infants

OBJECTIVES: To determine the association between the first thyroxine blood concentration and necrotizing enterocolitis (NEC) among preterm infants. STUDY DESIGN: The study group included a cohort of 34 preterm infants with NEC developed at least 48 h after thyroid function screening was obtained. The control group was consisted of 102 preterm infants (3 infants for each infant with NEC, born at the same gestational age) without NEC. Clinical data and first filter paper of total blood thyroxine concentration taken in the first 2 weeks of life were recorded retrospectively and compared between the study and control groups. RESULTS: Mean filter paper total thyroxine concentration was slightly lower in the study group compared to the control group (86.2 nmol/L and 97.8 nmol/L, respectively) but did not reach statistical significance (p=0.14). Nine infants (26.5%) in the study group were small for gestational age (SGA) in comparison to 11 infants (10.8%) in the control group (p=0.07). CONCLUSIONS: It seems that the first thyroxin serum concentration is not a significant predisposing risk factor for NEC in preterm infants.     

Early feeding after necrotizing enterocolitis in preterm infants

OBJECTIVE: To report our experience with an early initiation of enteral feedings after necrotizing enterocolitis (NEC). STUDY DESIGN: Over a 4-year period, all inborn infants with NEC Bell stage II or greater received enteral feedings, increased by 20 mL/kg/d, once no portal vein gas had been detected on ultrasound for 3 consecutive days (group 1). Infants were compared with a historic comparison group (group 2). RESULTS: Necrotizing enterocolitis rates were 5% (26/523) in the early feeding group and 4% (18/436) in the comparison group. One early feeding infant and two comparison group infants died of NEC, whereas two and one, respectively, had recurrent NEC. Enteral feedings were restarted at a median of 4 days (range, 3-14) versus 10 days (range, 8-22) after onset of NEC. Early feeding was associated with shorter time to reach full enteral feedings (10 days [range, 7-31] vs 19 days [range, 9-76], P<.001), a reduced duration of central venous access (13.5 days [range, 8-24] vs 26.0 days [range, 8-39], P<.01), less catheter-related septicemia (18% vs 29%, P<.01), and a shorter duration of hospital stay (63 days [range, 28-133] vs 69 days [range, 36-150], P<.05). CONCLUSION: Early enteral feeding after NEC was associated with significant benefits and no apparent adverse effects. This study was underpowered, however, to exclude a higher NEC recurrence risk potentially associated with this change in practice.     

新生儿坏死性小肠结肠炎患儿的远期预后

目的 了解新生儿坏死性小肠结肠炎（NEC）患儿的远期预后。方法 将2014年12月至2016年9月存活出院的83例NEC早产儿分为手术组（n=57）和非手术组（n=26）。手术组Ⅰ期、Ⅱ期、Ⅲ期NEC患儿分别有0、33、24例,非手术组分别有7、19、0例。对患儿出院后体格发育、神经系统发育等情况进行随访分析。结果 83例患儿随访结束时平均纠正年龄为21±6个月。31例（37%）体重落后,其中手术组体重落后率高于非手术组（P < 0.05）;22例（27%）身长落后;14例（17%）头围落后。运动发育落后/发育障碍患儿共18例（22%）,其中手术组发生率高于非手术组（28% vs 8%,P < 0.05）。共有5例（6%）患儿诊断为脑瘫,其中手术组4例,非手术组1例。结论 NEC会影响患儿的远期体格发育及神经系统发育等,尤其对病情严重需接受手术治疗的患儿影响更大,应对NEC患儿进行长期随访。     

IL-23受体和IL-17单核苷酸多态性与汉族早产儿坏死性小肠结肠炎的关系

目的 探讨白细胞介素-23受体（IL-23R）基因rs10889677位点、IL-17A基因rs2275913位点和IL-17F基因rs763780位点单核苷酸多态性（SNP）与汉族早产儿坏死性小肠结肠炎（NEC）的关系。方法 前瞻性选取2017年1月至2019年1月新生儿重症监护病房收治的100例汉族NEC早产儿为研究对象,其中Ⅱ期63例,Ⅲ期37例;另选取与NEC患儿胎龄、性别匹配的100例早产儿作为对照。采用PCR法和Sanger测序法鉴定rs10889677、rs2275913、rs763780位点的SNP。采用非条件logistic回归分析基因多态性与NEC易感性和病情严重程度的关系。结果 rs10889677位点、rs2275913位点基因型和等位基因频率对NEC发病无影响（P > 0.05）;rs763780位点基因型对NEC发病无影响（P > 0.05）,但C等位基因携带者相对于T等位基因携带者的NEC发病风险为1.652倍（95% CI：1.052~2.695,P < 0.05）。TC+CC基因携带者相对于TT基因携带者的NEC发病风险为1.856倍（95% CI：1.045~3.201,P < 0.05）。TC+CC基因携带者相对于TT基因携带者的NEC Ⅲ期的发生风险为2.965倍（95% CI：1.052~6.330,P < 0.05）;C等位基因携带者相对于T等位基因携带者的NEC Ⅲ期的发生风险为2.363倍（95% CI：1.034~4.093,P < 0.05）。结论 IL-23R基因rs10889677位点和IL-17A基因rs2275913位点SNP与汉族早产儿的NEC易感性无关,IL-17F基因rs763780位点TC+CC基因型和C等位基因与NEC易感性和NEC病情严重程度有关。     

Sonographic demonstration of portal venous gas in necrotizing enterocolitis

Portal vein gas embolism was demonstrated by ultrasound in a preterm infant with necrotizing enterocolitis. This sign could not be detected radiographically. It is speculated that portal venous gas occurs more frequently than hitherto inferred from radiological studies. This observation points to the value of ultrasonography in providing early objective evidence in support of the diagnosis of NEC. The favourable outcome for the patient proves that portal venous gas embolism is not necessarily associated with a fulminant course of enterocolitis.Abbreviations NEC Necrotizing enterocolitis - PVG Portal venous gas     

Microbiological factors associated with neonatal necrotizing enterocolitis: protective effect of early antibiotic treatment

AIM: The incidence of necrotizing enterocolitis (NEC) strongly increased in an neonatal intensive care unit (NICU) in 1997 and 1998 compared with previous years, which coincided with increased incidence of nosocomial sepsis. Specific risk factors related to this NICU and a possible relationship between NEC and nosocomial sepsis were studied retrospectively, including all patients with NEC since 1990 and matched controls. METHODS: Clinical and bacteriological data from the period before the development of NEC and a similar period for the controls were collected retrospectively and corrected for birthweight and gestational age. Statistical analysis was performed by a stepwise regression model. RESULTS: Data of 104 neonates with NEC and matched controls were analysed. The median day of onset of NEC was 12 d (range 1-63 d). Significant risk factors for NEC were: insertion of a peripheral artery catheter [odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.3-3.9] and a central venous catheter (OR 5.6, 95% CI 3.1-10.1), colonization with Klebsiella sp. (OR 3.4, 95% CI 1.5-7.5) and Escherichia coli (OR 2.1, 95% CI 1.0-4.5), and the occurrence of sepsis, in particular due to coagulase-negative staphylococci (OR 2.6, 95% CI 1.4-5.1). The risk for NEC was decreased after the early use (< 48 h after birth) of amoxicillin-clavulanate and gentamicin (OR 0.3, 95% CI 0.2-0.6). CONCLUSION: Insertion of central venous and peripheral arterial catheters is positively associated with NEC, as is colonization with the Gram-negative bacilli Klebsiella and E. coli and the occurrence of sepsis, particularly due to coagulase-negative staphylococci. Early treatment with amoxicillin-clavulanate and gentamicin is negatively associated with NEC and may be protective against NEC.