Is there data to suggest early lipid administration is beneficial in the nicu? If so what patient populations and what is the optimal timing?

Comment by InpharmD Researcher

Available evidence suggests that early intravenous lipid administration in preterm infants, particularly those with very low birth weight who require parenteral nutrition, may improve selected short-term growth outcomes and appears generally well tolerated, although increased hypertriglyceridemia has been reported with early high-dose administration. However, evidence supporting early initiation is limited, with some studies combining earlier initiation with higher lipid doses or other nutritional interventions, making the independent effect of timing difficult to determine. Studies have evaluated lipid initiation within the first 24–48 hours of life, but an optimal initiation time has not been established, and no significant mortality benefit compared with later initiation has been demonstrated in the reviewed meta-analyses. Additional clinical trials in specific NICU populations, controlling for lipid dose, formulation, and other nutritional interventions, are needed to establish the optimal timing and clinical benefits of early lipid initiation.

PubMed and Google Scholar were searched using keywords “early lipid administration,” “parenteral lipid emulsions,” “preterm infants,” “very low birth weight,” and “neonatal intensive care unit.” References of relevant articles were screened for additional studies evaluating lipid initiation timing, growth, and neonatal outcomes.

Background

The 2023 American Society for Parenteral and Enteral Nutrition (ASPEN) guideline recommends prompt initiation of parenteral nutrition (PN) after birth once appropriate vascular access is obtained in preterm infants. However, the guideline notes that evidence regarding the timing of PN initiation, including intravenous lipid emulsion (ILE), is of very low quality. Similarly, the 2020 National Institute for Health and Care Excellence (NICE) guideline recommends initiating PN as soon as possible and within 8 hours of establishing the indication. For preterm and term infants starting PN within the first 4 days after birth, NICE recommends an initial lipid dose of 1 to 2 g/kg/day, gradually increased to 3 to 4 g/kg/day. For infants starting PN more than 4 days after birth, NICE recommends 3 to 4 g/kg/day. In contrast, the 2018 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guideline recommends that lipid emulsions in preterm infants may be started immediately after birth and no later than day 2 of life. When enteral feeding is withdrawn, lipids may be initiated when PN begins. The 2020 Australasian neonatal PN consensus similarly recommends commencing parenteral lipids on day 1 of PN administration, particularly in extremely preterm infants. It recommends an initial dose of 1 g/kg/day, increased by 1 g/kg/day to a target of 3 g/kg/day. Overall, these guidelines support early lipid administration in preterm infants, with ESPGHAN and the Australasian consensus providing explicit recommendations for early initiation. However, these recommendations are based largely on nutritional rationale and limited evidence rather than demonstrated improvements in major clinical outcomes. [1], [2], [3], [4]

A 2021 meta-analysis evaluated the safety and efficacy of early initiation and attainment of a high dose of parenteral lipid emulsions on growth and clinical outcomes in preterm infants. The review incorporated data from 8 randomized controlled trials (RCTs) encompassing a total of 520 very low birth weight preterm infants, with 262 receiving early (typically between 2 to 24 hours after birth) high-dose (≥1.5 g/kg/day, increasing to 2–3 g/kg/day over the following days) intravenous lipid emulsions (IVLE) and 258 serving as controls who either received lower doses or later initiation (beyond 12 to 48 hours after birth) of lipids. Primary outcomes focused on growth parameters including weight gain rate, proportional postnatal weight loss, time to regain birth weight, body weight and head circumference near term-equivalent age (TEA), and incidence of extrauterine growth restriction (EUGR). Secondary outcomes included mortality, length of NICU stay, and major morbidities such as bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), sepsis, intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and metabolic parameters including hypertriglyceridemia, glucose dysregulation, and serum bilirubin levels. The results demonstrated that early high-dose IVLE administration was associated with significantly reduced postnatal weight loss (mean difference [MD] –2.73%; 95% confidence interval [CI] –3.69, –1.78; p<0.00001) and increased head circumference near TEA (MD 0.67 cm; 95% CI 0.25, 1.09; p= 0.002). Additionally, a significant increase in body weight near TEA (MD 70.27 g; 95% CI 4.73, 135.81; p= 0.04) and a marked reduction in the incidence of EUGR (relative risk [RR] 0.27; 95% CI 0.15, 0.48; p<0.00001) were observed in infants receiving early high lipid supplementation. No statistically significant differences were detected in weight gain rate, time to regain birth weight, mortality, length of NICU stay, or incidences of BPD, NEC, sepsis, and severe IVH. Notably, the incidence of ROP was significantly lower in the early high lipid group (RR 0.37; 95% CI 0.18, 0.73; p 0.004). While episodes of hypertriglyceridemia occurred more frequently with early high-dose IVLE (RR 2.72; 95% CI 1.15, 6.43; p= 0.02), no corresponding adverse clinical outcomes were reported. Glucose imbalances and serum bilirubin levels showed no significant differences. The findings suggest that early high-dose parenteral lipid administration, defined as ≥1.5 g/kg/day within the first 24 hours after birth is both safe and beneficial for promoting growth in preterm infants without increasing the risk of major morbidities. [5]

A 2012 meta-analysis synthesized findings from 14 RCTs to determine the optimal timing for lipid introduction in VLBW infants, and to assess the impact of different lipid compositions on growth and morbidity outcomes. The early-versus-late lipid initiation analysis included data from 456 preterm infants, with lipid administration initiated between 12 hours and 2 days after birth versus days 5 to 8, and evaluated growth rates, mortality, incidences of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and sepsis. The analysis found that initiating lipids within the first two days of life was safe and well-tolerated but did not significantly enhance growth during hospital admission or demonstrate efficacy in reducing mortality, BPD, NEC, or sepsis incidence. However, non-soybean-based lipid emulsions showed a weakly favorable association with reduced sepsis rates. While no definitive growth benefits were observed, the study underscored the importance of timely lipid introduction for energy provision, supporting protein synthesis and essential fatty acids crucial for central nervous system development. The authors advocated for large-scale trials to explore potential long-term benefits of early lipid administration and alternative lipid formulations. [6]

Background References: [1] Robinson DT, Calkins KL, Chen Y, et al. Guidelines for parenteral nutrition in preterm infants: The American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr. 2023;47(7):830-858. doi:10.1002/jpen.2550
[2] Lapillonne A, Fidler Mis N, Goulet O, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Lipids. Clin Nutr. 2018;37(6 Pt B):2324-2336. doi:10.1016/j.clnu.2018.06.946
[3] Bolisetty S, Osborn D, Schindler T, et al. Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017. BMC Pediatr. 2020;20(1):59. Published 2020 Feb 8. doi:10.1186/s12887-020-1958-9
[4] National Institute for Health and Care Excellence. Neonatal parenteral nutrition. NICE guideline NG154. Published February 26, 2020. Accessed October 12, 2026. https://www.nice.org.uk/guidance/NG154/chapter/recommendations
[5] Kim K, Kim NJ, Kim SY. Safety and Efficacy of Early High Parenteral Lipid Supplementation in Preterm Infants: A Systematic Review and Meta-Analysis. Nutrients. 2021;13(5):1535. Published 2021 May 2. doi:10.3390/nu13051535
[6] Vlaardingerbroek H, Veldhorst MA, Spronk S, van den Akker CH, van Goudoever JB. Parenteral lipid administration to very-low-birth-weight infants--early introduction of lipids and use of new lipid emulsions: a systematic review and meta-analysis. Am J Clin Nutr. 2012;96(2):255-268. doi:10.3945/ajcn.112.040717
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there data to suggest early lipid administration is beneficial in the nicu? If so what patient populations and what is the optimal timing?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-2 for your response.

Intravenous Lipid for Preterm Infants: The Right Amount, at the Right Time, of the Right Kind
Design

Randomized, nonblinded study

N= 83
Objective To evaluate the effects of earlier and higher dosing of intravenous soy-based lipid emulsion on growth outcomes in very preterm infants
Study Groups

Intervention group (n= 45)

Control group (n= 38)
Inclusion Criteria Very preterm infants with a mean gestational age of approximately 27 weeks
Exclusion Criteria Not specified
Methods The intervention group (early/higher-dose) received 2 g/kg of intravenous soy-based lipid emulsion on day 1, then 3 g/kg/day. The control group received 0.5-1.0 g/kg on day 1, advancing to 3 g/kg/day by daily increments of 0.5-1.0 g/kg.
Duration Not specified
Outcome Measures

Primary: Head circumference growth at 36 weeks corrected gestational age (CGA)

Secondary: Head circumference z-scores, cumulative lipid intake in first 7 days, weight gain velocity, maximal percentage postnatal weight loss
Baseline Characteristics   Intervention (n= 45) Control (n= 38)
Mean gestational age, weeks 27.1 27.3
Results   Intervention (n= 45) Control (n= 38) p-value
Head circumference growth at 36 weeks CGA +2.6%  less growth 0.05
Head circumference z-scores at 36 weeks CGA +31%  lower scores 0.04
Cumulative lipid intake in first 7 days, g/kg 13.5 ± 4.2 10.9 ± 3.5 0.03
Weight gain velocity 15.2 ± 2.0  15.3 ± 3.5  0.89
The intervention group also had an 18% lower maximal percentage postnatal weight loss.
Adverse Events More episodes of hypertriglyceridemia occurred in the early/high lipid group, though the difference compared to the control group was not statistically significant.
Study Author Conclusions Insufficient energy and insufficient lipids are not good for normal development, but there might not be solid justification—yet—for simply providing more in the way of early intravenous lipid infusion, especially with a less-than-optimal intravenous lipid product.
Critique The study's small sample size and nonblinded design limit the generalizability of the findings. The lack of long-term neurodevelopmental outcomes and sophisticated assessments of brain development, such as MRI, further limits the conclusions. The study also did not account for potential biases in feeding care and differences in enteral feeding amounts.

 

Table 1 References:
[7] Hay WW. Intravenous lipid for preterm infants: the right amount, at the right time, of the right kind. The Journal of Pediatrics. 2021;228:8-10. doi:10.1016/j.jpeds.2020.08.083
The Effect of Early Versus Late Lipid Infusion in Parenteral Nutrition on the Biochemical and Cortical Auditory Evoked Potential Parameters in Preterm Neonates
Design

Comparative study

N= 49
Objective To compare the effect of delayed versus early introduction of intravenous lipid in preterm neonates on biochemical parameters and on brain development by the cortical auditory evoked potential (CAEP) latency and amplitude
Study Groups

Early lipid infusion (n= 26)

Late lipid infusion (n= 23)
Inclusion Criteria Neonates aged <32 weeks and weight <1500 g; received total parenteral nutrition infusion for the 1st week of age and not more than 2 weeks before enteral feeding initiation
Exclusion Criteria Comorbidities during NICU admission such as increased mechanical ventilation >5 days, secondary neonatal sepsis, necrotizing enterocolitis, patent ductus arteriosus, intraventricular hemorrhage, and hypoxic-ischemic encephalopathy; history of hearing loss, ear disease, trauma, ototoxic drug intake, or ear operation.
Methods Participants were divided into two groups: early lipid infusion and late lipid infusion. The early lipid infusion group received lipid infusion earlier than 48 hours of life, while the late lipid infusion group received it later. Biochemical parameters were documented during the first 2 weeks of life. CAEP was performed at the age of 6 months. Lipid infusion in the early lipid infusion group was started on day 2 at 1.5gm/kg/day with 0.5gm/kg/day increments to reach 3gm/kg/day. Late lipid infusion was started from day 3 at 0.5 gm/kg/day up to 3gm/kg/day.
Duration February 2017 to February 2018
Outcome Measures

Primary: Biochemical parameters, CAEP latency and amplitude

Secondary: Weight gain, parenteral (post-natal age of lipid start, duration to full lipid infusion) and enteral nutrition (start of oral feed, achievement of full oral intake) characteristics, length of NICU stay, incidence of cholestasis and hyperglycemia
Baseline Characteristics   Early lipid infusion (n= 26) Late lipid infusion (n= 23) p-value
Gestational age, weeks 30.67 ± 1.24 30.89 ± 1.26 0.537
Female 11 (42.3%) 13 (56.5%) 0.321
Body weight, kg 1.22 ± 0.11 1.25 ± 0.13 0.352
Apgar at 5 min 7.46 ± 0.71 7.35 ± 1.11 0.667
Results   Early lipid infusion (n= 26) Late lipid infusion (n= 23) p-value
Weight gain/day during hospital stay, g 20.85 ± 4.95 15.35 ± 2.50 0
Weight gain/month after discharge, g 771.92 ± 58.8 707 ± 59.16 0
Postnatal age of lipid start, days 2.37 ± 0.42 3.75 ± 0.75 0
Duration to full lipid infusion, days 5.5 ± 0.57 7.67 ± 0.87 0
Start of oral feed, days 4.46 ± 1.3 5.61 ± 1.31 0
Achievement of full oral intake, days 15.19 ± 2.86 19.13 ± 2.6 0
Length of NICU stay, days 18.96 ± 5.37 22.61 ± 5.24 0.02
Cholestasis incidence 0 (0.0%) 8 (34.8%) 0.001
Hyperglycemia incidence 8 (30.8%) 14 (60.9%) 0.035

The early lipid infusion group had significantly shorter CAEP latency and amplitude of P1, better weight gain, and significantly better glucose control than the late lipid infusion group.

There was no significant difference in the other chemical parameters (urea, creatinine, sodium, potassium, HCO3, albumin, indirect bilirubin) between the two groups, except for the higher incidence of cholestasis in the group of late lipid infusion.
Adverse Events See results section.
Study Author Conclusions Early effective nutrition positively affects feeding tolerance, weight gain, and maturation of higher brain centers.
Critique The study provides valuable insights into the benefits of early lipid infusion in preterm neonates, showing improvements in weight gain and brain development. However, the small sample size and single-center design may limit the generalizability of the findings. Additionally, the exclusion of neonates with comorbidities may not reflect real-world scenarios where such conditions are common.

 

Table 2 References:
[8] Abdou RM, Weheiba HMI. The effect of early versus late lipid infusion in parenteral nutrition on the biochemical and cortical auditory evoked potential parameters in preterm neonates. Egypt Pediatric Association Gaz. 2019;67(1):8. doi:10.1186/s43054-019-0006-6