This retrospective cohort study was performed at the Department of Neonatology, Changhua Christian Children Hospital, Taiwan, between January 2009 and November 2017. A total of 399 premature neonates who were eligible, of gestational age ≤ 32 weeks, birth weight ≤ 1,250g, and received parenteral nutrition for at least seven days, were enrolled. The study was approved by the Institutional Review Board at Changhua Christian Hospital. Infants with conditions associated with cholestasis independent of PN (i.e., infection with cytomegalovirus, HIV, hepatitis B or C), hemolytic diseases, primary liver diseases, inborn errors of metabolism, multiorgan failure or hypoxic-ischemic encephalopathy were excluded. The first cohort of 204 preterm infants from January 2009 to April 2013 received soybean oil-based lipid emulsion (Lipovenoes 20%, control group). The second cohort of 195 preterm infants from May 2013 to November 2017 received SMOFlipid 20% (study group) composed of 30% soybean oil, 30% MCTs, 25% olive oil, and 15% fish oil as the PN lipid emulsion. Both cohorts were cared for by the same multidisciplinary team, including medical, pharmacy, dietetic, nursing, and nutritional care.
Regardless of whether the PN contained SMOFlipid or Lipovenoes, the dosage of both groups started at 1g/kg/day on day 1, and this was increased daily by increments of 1g/kg/day up to a maximum of 3g/kg/day. The lipid emulsion was administered as part of a PN regimen along with other nutrients (glucose, amino acids, vitamins, trace elements, and electrolytes) in two separate syringes. The dosages of other nutrients were standardized in accordance with current recommendations . The infants received nasogastric tube feeding supplement with formula or breast milk as early as possible. All preterm infants received probiotics after they started feeding. PN was withdrawn when infants received enteral energy > 80kcal/kg/day.
Demographic data, medical history, concomitant diseases, clinical assessments, and medications of the infants were recorded daily beginning on day 0. Blood samples for assessment of parameters for safety and efficacy evaluation were obtained weekly. Adverse events and their possible relation to study treatment were documented. The primary outcome, PN-associated cholestasis, was defined as serum direct bilirubin levels more than 1.5mg/dl, and greater than 20% of serum total bilirubin levels. Peak levels of liver enzymes (aspartate aminotransferase [GOT], alanine aminotransferase [GPT], γ-glutamyl transferase [γGT], alkaline phosphatase [ALP]), c-reactive protein (CRP), albumin, cholesterol, and triglyceride, were also analyzed during hospitalization. Secondary clinical and developmental outcomes included severe retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), sepsis and mortality. ROP was screened by an ophthalmologist beginning at four weeks of age. Treatment with intravitreal bevacizumab was performed at ROP ≥ stage 3. IVH was diagnosed by cerebral ultrasound on day 0, 3, 7, 21 and monthly. Severe IVH was identified as stage ≥ 3. NEC was diagnosed clinically (Bell’s stage ≥ IIa) or after surgical exploration. BPD was defined as requiring an oxygen supplement after 36 weeks postmenstrual age. Sepsis was proven by blood culture.
Data from all of the assessments were tabulated using descriptive statistics. Standard summary statistics and 95% confidence intervals were calculated appropriately. To compare the mean values from parametric variables, data were analyzed using the Student t test. Secondary outcomes were compared between the groups with the χ2 or Fisher’s exact tests when appropriate for categorical data. A P Value of < 0.05 was considered statistically significant. Statistical evaluation of results was carried out for the entire patient population and according to the stratification. The results of the study and control groups are presented below.