BACKGROUND/RATIONALE
Optimal nutritional support for extremely preterm infants (EP) remains controversial, with no widely accepted feeding guidelines [1]. While neonatal nutrition may impact survival and long-term neurodevelopmental outcomes, data on current enteral feeding practices are needed to inform the design of clinical trials to study common variations in practice.
METHODS
We conducted an anonymous online survey between August to October 2023 using Research Electronic Data Capture. The survey investigated enteral feeding practices for EP across U.S. NICUs, including feeding protocols, donor milk use, fortification practices, and target volumes. The questionnaire was developed through iterative testing with neonatologists, pharmacists, and dietitians at seven diverse NICUs. Healthcare providers were recruited through professional networks including the Pediatric Pharmacy Association, PEDI-RD listserv, AAP Section on Neonatal-Perinatal Medicine, and Pediatrix Neonatology Forum [2]. Response rates were calculated based on national NICU center numbers to capture units rather than individual practices. Differences between affiliation and level of care were assessed using Pearson’s chi-squared test or Fisher’s exact test.
RESULTS
We analyzed responses from 253 NICUs, including 63% level III and 37% level IV centers (Table 1). Over half (57%) of the surveyed centers were affiliated with an academic institution. Using the information provided by Pineda et al. to estimate NICU representation in our survey [3], most academic centers (177/181, 81%) and over half of level IV centers (94/152, 62%) across the U.S. participated in the survey. However, representation from non-academic centers (108/669, 16%) and level III NICUs (159/702, 23%) was lower [2].
Table:
Nutritional Practices for Extremely Preterm Infants in Neonatal Intensive Care Units in the U.S.
| Academic (%)1 N = 1442 |
Non-academic (%)1 N = 1082 |
p-value3 | Level III NICU (%)1 N = 159 |
Level IV NICU (%)1 N = 94 |
p-value3 | Overall (%)1 N = 253 |
|
|---|---|---|---|---|---|---|---|
| Feeding protocol use | 128 (89%) | 91 (85%) | 0.40 | 135 (85%) | 85 (91%) | 0.14 | 220 (87%) |
| Classification of the feeding protocol | 0.40 | 0.80 | |||||
| By gestational age | 7 (6%) | 6 (7%) | 9 (7%) | 5 (7%) | 14 (7%) | ||
| By weight | 79 (72%) | 65 (79%) | 93 (76%) | 51 (73%) | 144 (75%) | ||
| Both | 23 (21%) | 11 (13%) | 20 (16%) | 14 (20%) | 34 (18%) | ||
| Number of categories | 0.30 | <0.01 | |||||
| 2 | 19 (19%) | 22 (29%) | 33 (29%) | 8 (13%) | 41 (23%) | ||
| 3 | 70 (70%) | 49 (65%) | 74 (66%) | 45 (71%) | 119 (68%) | ||
| ≥4 | 11 (11%) | 4 (5%) | 5 (5%) | 10 (16%) | 15 (9%) | ||
| Donor human milk use | 144 (100%) | 107 (99%) | 0.40 | 158 (99%) | 92 (98%) | >0.99 | 250 (99%) |
| Discontinuing donor human milk | 0.06 | 0.40 | |||||
| By the days after birth | 12 (9%) | 3 (3%) | 11 (7%) | 4 (4%) | 15 (6%) | ||
| By postmenstrual gestational age | 128 (91%) | 102 (97%) | 144 (93%) | 87 (96%) | 231 (94%) | ||
| Weeks Mean (SD) | 34.0 (1.3) | 34.4 (1.4) | 0.03 | 34.2 (1.3) | 34.3 (1.4) | 0.51 | 34.2 (1.3) |
| Target feeding volume | 0.02 | 0.40 | |||||
| ≤ 120 ml/kg/day | 12 (8%) | 5 (5%) | 11 (7%) | 6 (6%) | 17 (7%) | ||
| 140 ml/kg/day | 8 (6%) | 12 (11%) | 11 (7%) | 9 (10%) | 20 (8%) | ||
| 150 ml/kg/day | 51 (35%) | 25 (23%) | 45 (28%) | 32 (34%) | 77 (31%) | ||
| 160 ml/kg/day4 | 65 (45%) | 65 (60%) | 88 (55%) | 42 (45%) | 130 (51%) | ||
| Depends on clinical status and gestational age | 7 (5%) | 1 (1%) | 4 (3%) | 4 (4%) | 8 (3%) | ||
| Average days to target feeding volume from birth | 0.08 | >0.99 | |||||
| < 7 days | 18 (13%) | 15 (14%) | 22 (14%) | 12 (13%) | 34 (14%) | ||
| 7–10 days | 79 (57%) | 72 (69%) | 95 (61%) | 56 (63%) | 151 (62%) | ||
| 11–14 days | 37 (27%) | 16 (15%) | 34 (22%) | 19 (21%) | 53 (22%) | ||
| > 14 days | 5 (4%) | 1 (1%) | 4 (3%) | 2 (2%) | 6 (2%) | ||
| Human milk fortification | 144 (100%) | 108 (100%) | >0.90 | 159 (100%) | 94 (100%) | >0.99 | 253 (100%) |
| Product used for fortification | >0.99 | >0.99 | |||||
| Bovine-derived human milk fortifier | 87 (60%) | 62 (57%) | 93 (59%) | 56 (60%) | 149 (59%) | ||
| Donor human milk-derived fortifier | 48 (33%) | 38 (35%) | 56 (35%) | 31 (33%) | 87 (34%) | ||
| Patient-specific5 | 7 (5%) | 4 (4%) | 7 (5%) | 4 (4%) | 11 (4%) | ||
| Other product | 1 (1%) | 2 (2%) | 2 (1%) | 1 (1%) | 3 (1%) | ||
| Intended caloric density after fortification | 0.40 | 0.70 | |||||
| 22 kcal/oz | 38 (27%) | 31 (29%) | 41 (26%) | 28 (30%) | 69 (27%) | ||
| 24 kcal/oz | 74 (52%) | 50 (47%) | 81 (51%) | 44 (47%) | 125 (50%) | ||
| 26 kcal/oz | 22 (16%) | 15 (14%) | 22 (14%) | 15 (16%) | 37 (15%) | ||
| Other5 | 7 (5%) | 11 (10%) | 13 (8%) | 5 (5%) | 18 (7%) | ||
| Volume of feeding at fortification | 0.20 | 0.20 | |||||
| < 60 ml/kg | 12 (9%) | 16 (15%) | 15 (10%) | 13 (15%) | 28 (12%) | ||
| 60–80 ml/kg | 46 (34%) | 40 (38%) | 61 (40%) | 25 (29%) | 86 (36%) | ||
| 80–100 ml/kg | 74 (54%) | 44 (42%) | 71 (46%) | 47 (54%) | 118 (49%) | ||
| > 100 ml/kg | 4 (3%) | 5 (5%) | 7 (5%) | 2 (2%) | 9 (4%) | ||
| Average days from birth to fortification | 0.04 | >0.99 | |||||
| < 7 days | 93 (67%) | 80 (75%) | 112 (71%) | 62 (70%) | 174 (71%) | ||
| 7–10 days | 35 (25%) | 26 (24%) | 39 2(5%) | 22 (25%) | 61 (25%) | ||
| 11–14 days | 8 (6%) | 0 (0%) | 4 (3%) | 4 (5%) | 8 (3%) | ||
| > 14 days | 2 (2%) | 1 (1%) | 2 (1%) | 1 (1%) | 3 (1%) | ||
| Formula type used after discontinue donor breast milk. | 0.60 | 0.50 | |||||
| Term formula | 9 (7%) | 4 (4%) | 7 (5%) | 6 (7%) | 13 (5%) | ||
| Transitional formula | 114 (81%) | 87 (81%) | 130 (83%) | 71 (77%) | 201 (81%) |
(%): Numbers may not add up to the total due to non-responses;
One center did not provide the affiliation;
Pearson’s Chi-squared test; Fisher’s exact test; Wilcoxon rank sum test;
Two centers target >160ml/kg/day;
Fortification target and product used differently between patients with the most common use of donor milk-derived products and higher calories/oz in more immature infants.
Most NICUs (87%) had established feeding protocols, with centers commonly dividing the infants by weight into three categories, most frequently <750 g, 750–1000 g, and >1000 g. Almost all centers reported using donor human milk, with the most common change to transitional formula occurring at 34–35 weeks’ postmenstrual age. The usual goal target feeding volume varied considerably. Over 80% of NICUs defined full feeding as 150–160 ml/kg/day. A minority of the centers consider lower volume targets with 3% reported volumes depending on clinical status and gestational age. The reported time to achieve target enteral feeds varied, with most centers (76%) reaching this goal after day 7 after birth.
Bovine-derived human milk fortifiers were used in most centers, and human milk-derived fortification products were used in a third of NICUs; 5% used patient-specific fortification, reserving the human milk-derived products for the more immature infants. The intended caloric density and initiation of milk fortification also varied. The most common fortification target was 24 kcal/oz, with a higher calorie target if using human milk-derived fortification products. The most common volume used for initiating fortification was 80–100 ml/kg/d.
There were a few significant differences between level III and IV NICUs. However, compared to academic centers, non-academic centers set higher volume targets for full feeding (p = 0.02), began fortification earlier (p = 0.04), and tended to advance feeds more rapidly (p = 0.08).
DISCUSSION
Our survey describes substantial variation in feeding practices for EP infants across U.S. NICUs. While feeding protocols, donor milk and human milk fortification are used nearly universally, considerable heterogeneity exists in defining target feeding volumes, fortification products, time and volume for fortification, and caloric densities. Our findings emphasize the need for further research in a foundational area of neonatal care.
The variability in target feeding volumes (ranging from <120 to 160 ml/kg/day) and calorie intake (22–26 kcal/oz) reflects the ongoing debate about optimal nutrition for EP infants [1]. Regarding advancement of feeds, while 76% of centers take at least seven days to achieve full enteral feeding, evidence suggests that neither slow nor faster advancement of feed volumes significantly impacts necrotizing enterocolitis rates or mortality [4]. This lack of definitive evidence regarding optimal feeding advancement rates may contribute to the practice variations we observed between different types of centers. The widespread use of bovine-derived and donor human milk-derived fortification products aligns with evidence supporting fortification for improved short-term weight gain, linear and head growth [5]. However, the optimal timing and method of fortification remain unclear, likely contributing to the observed variations in fortification initiation (ranging from <60 to >100 ml/kg/day) and caloric density targets (22–26 kcal/oz). This evolving evidence base may explain why practices vary significantly between centers.
Limitations
Our survey relied on self-reported data regarding protocols and did not measure actual practices. Survey responses may have varied based on the respondents’ role and experience level within each NICU. While the study achieved a high representation of academic centers (82%), non-academic and level 3 representation is limited.
CONCLUSION
We highlight the heterogeneity in enteral feeding practices for EP infants in U.S. NICUs. Significant variation exists in target feeding volume, fortification practices, and feeding advancement strategies. Our results highlight the need for large pragmatic trials to establish evidence-based practices that advance enteral nutrition practices and clinical outcomes for EP infants.
Supplementary Material
FUNDING
National Center for Advancing Translational Sciences KL2 career development award Grant #: 5KL2TR003168. Project #: 0014743. Gerber Foundation National Research Grants. Project #:10287.
Footnotes
COMPETING INTERESTS
The authors declare no competing interests.
ETHICS APPROVAL
The study protocol was granted approval by the Institutional Review Board (IRB) at the University of Texas Health Science Center at Houston. The study involved a survey of healthcare providers in the NICU across the U.S., and participation was voluntary. The survey was designed to be anonymous, ensuring that no personal data was collected. The research posed no identifiable risks to the participants, and no compensation was provided for their involvement. No compensation was given to participate in the study.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41372-024-02198-6.
REFERENCES
- 1.Dutta S, Singh B, Chessell L, Wilson J, Janes M, McDonald K, et al. Guidelines for feeding very low birthweight infants. Nutrients. 2015;7:423–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Romero-Lopez M, Naik M, Holzapfel LF, Salas AA, Ahmad KA, Rysavy MA, et al. Survey of vitamin D supplementation practices in extremely preterm infants. Pediatr Res. 2024. 10.1038/s41390-024-03514-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pineda R, Knudsen K, Breault CC, Rogers EE, Mack WJ, Fernandez-Fernandez A. NICUs in the US: levels of acuity, number of beds, and relationships to population factors. J Perinatol. 2023;43:796–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev. 2021;8:CD001241. 10.1002/14651858.CD001241.pub8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Brown JVE, Lin L, Embleton ND, Harding JE, McGuire W. Multi-nutrient fortification of human milk for preterm infants. Cochrane Database Syst Rev. 2020;6:CD000343. 10.1002/14651858.CD000343.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
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