The role of nutrition in analysis of risk factors and short-term outcomes for late-onset necrotizing enterocolitis among very preterm infants: a nationwide, multicenter study in China
Authors: Hong Kun-Yao , Zhu Yao , Wu Fan , Mao Jian , Liu Ling , Zhang Rong , Chang Yan-Mei , Shen Wei , Tang Li-Xia , Ye Xiu-Zhen , Qiu Yin-Ping , Ma Li , Cheng Rui , Wu Hui , Chen Dong-Mei , Chen Ling , Xu Ping , Mei Hua , Wang San-Nan , Xu Fa-Lin , Ju Rong , Zheng Zhi , Tong Xiao-Mei , Lin Xin-Zhu ,   the Chinese Multicenter EUGR Collaborative Group, Hong Kun Yao , Zhu Yao , Shen Wei , Tang Li-Xia , Zheng Zhi , Lin Xin-Zhu , Wu Fan , Tian Qian-Xin , Cui Qi-Liang , Mao Jian , Yuan Yuan , Ren Ling , Liu Ling , Shi Bi-Zhen , Wang Yu-Mei , Chang Yan-Mei , Zhang Jing-Hui , Tong Xiao-Mei , Zhang Rong , Zhu Yan , Ye Xiu-Zhen , Zou Jing-Jing , Qiu Yin-Ping , Li Yu-Huai , Zhao Bao-Yin , Liu Shu-Hua , Ma Li , Xu Ying , Cheng Rui , Zhou Wen-Li , Wu Hui , Liu Zhi-Yong , Chen Dong-Mei , Gao Jin-Zhi , Liu Jing , Chen Ling , Li Cong , Yang Chun-Yan , Xu Ping , Zhang Ya-Yu , Hu Si-Le , Mei Hua , Yang Zu-Ming , Feng Zong-Tai , Wang San-Nan , Meng Er-Yan , Shang Li-Hong , Xu Fa-Lin , Ou Shaoping , Ju Rong , Li Gui-Nan , Yi Juan , Li Long , Liu Yong-Qiao , Zhang Zhe , Wu Mei-Gui , Bei Fei , Liu Ye , Deng Chun , Yang Hui-Jie , Su Ping , Chen Shi-Feng , Luo Ling-Ying , Wang Lin-Lin , Liu Xiao-Hong , Yan Li-Hua , Wang Li-Jun , Wang Xiao-Kang , Yu Shu-Qun , Zhu Qiao-Mian 
Published: March 2024

Abstract
Background
Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times.

Method
Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups.

Results
Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation.

Conclusion
Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs.

Trial registration
ChiCTR1900023418 (26/05/2019).