Analysis of risk factors for parenteral nutrition-associated cholestasis in preterm infants: A multicenter observational study
Authors: Wang Ya-sen , Wei Shen , Yang Qing , Lin Rong , Tang Li-xia , Bai Rui-miao , Yang Dong , Zhang Juan , Zhang Yi-jia , Yu Wen-ting , Song Shi-rong , Kong Juan , Song Si-yu , Mao Jian , Tong Xiao-mei , Li Zhan-kui , Wu Fan , Lin Xin-zhu 
Published: March 2023

Abstract
Background: In recent years, a lot of research has been conducted on the risk factors and prevention measures associated with parenteral nutrition-associated cholestasis (PNAC). It is proposed that the development of PNAC was significantly associated with preterm birth, low birth weight, infection, long duration of fasting, necrotizing enterocolitis (NEC), extrauterine growth retardation (EUGR) and nutritional factors, including the use of amino acids and fat emulsion; however, the etiology and pathogenesis of PNAC are not fully understood. Most of the studies examining PNAC-associated risk factors were single-center studies with relatively small sample sizes.
Objective: To analyze the risk factors associated with PNAC in preterm infants in China.
Methods: This is a retrospective multicenter observational study. Clinical data on the effect of multiple oil-fat emulsions (soybean oil-medium chain triglycerides-olive oil-fish oil, SMOF) in preterm infants were collected from a prospective multicenter randomized controlled study. The study was conducted at five tertiary care hospitals with a neonatal intensive care unit (NICU) of IIIB or higher in China between January 2021 and December 2021. A secondary analysis was performed in which preterm infants were divided into the PNAC group and the non-PNAC group based on the PNAC status. Risk factors for the development of PNAC in preterm infants were analyzed using the χ2 test (or Fisher's exact probability method), Student’s t-test or rank sum test, and logistic regression analysis.
Results: A total of 465 very preterm infant (VPI) or very low birth weight infant (VLBWI) cases were included in the study in which 81 (17.4%) were assigned to the PNAC group and 384 (82.6%) were assigned to the non-PNAC group. Compared with the non-PNAC group, the PNAC group had a lower mean gestational age, lower mean birth weight, longer duration of invasive and non-invasive mechanical ventilation, a longer duration oxygen support, and longer hospital stay (P < 0.001 for all). The PNAC group had higher respiratory distress syndrome (RDS), hemodynamically significant patent ductus arteriosus (hsPDA), NEC with stage II or higher or surgically treated NEC, late-onset sepsis (LOS), metabolic bone disease (MBD), and extrauterine growth retardation (EUGR) compared to the non-PNAC group (P < 0.05 for all). In contrast with the non-PNAC group, the PNAC group received a higher maximum dose of amino acids and fat emulsion, more medium/long-chain fatty emulsion, less SMOF, had a longer duration of parenteral nutrition, lower rates of breastfeeding, higher incidence of feeding intolerance (FI), more accumulated days to achieve total enteral nutrition, less accumulated days of total calories up to standard 110 kcal/kg/day, and slower velocity of weight growth (P < 0.05 for all). Logistic regression analysis indicated that the maximum dose of amino acids (OR, 5.352; 95% CI, 2.355 to 12.161), EUGR (OR, 2.396; 95% CI, 1.255 to 4.572), FI (OR, 2.581; 95% CI, 1.395 to 4.775), surgically treated NEC (OR, 11.300; 95% CI, 2.127~60.035), and longer total hospital stay (OR, 1.030; 95% CI, 1.014 to 1.046) were independent risk factors for the development of PNAC. SMOF (OR, 0.358; 95% CI, 0.193 to 0.663) and breastfeeding (OR, 0.297; 95% CI, 0.157 to 0.559) were protective factors for PNAC.
Conclusions: Increasing breastfeeding rates in VPI or VLBWI can reduce the incidence of PNAC by promoting feeding tolerance using fat emulsion (SOMF), avoiding excessive parenteral amino acid intake, preventing the development of severe NEC requiring surgery, and reducing the incidence of EUGR.