Progression of Enteral Feeding Volumes in Extremely Low Birth Weight Infants in the “Connection Trial”

Abstract

Objective Investigate daily feeding volumes and their association with clinical variables in the early postnatal care of premature infants of the “Connection Trial.”

Study Design A total of 641 infants of 510 to 1,000-g birth weight (BW, mean: 847 g) and mean 27 weeks' gestational age at birth (GA) were analyzed for total daily enteral (TDE) feeding volumes of 10, 20, 40, 80, and 120 mL/kg/d and their association with 24 clinical variables. Uni- and multivariable Cox regression models were used to calculate hazard ratios (HR) with 95% confidence intervals as a measure of the chance of reaching each of the TDE volumes.

Results Daily feeding volumes were highly variable and the median advancement from 10 to 120 mL/kg/d was 11 mL/kg/d. Univariable analyses showed the lowest chance (HR, 0.22–0.81) of reaching the TDE volumes for gastrointestinal (GI) serious adverse events (SAEs), GI perforation, GI obstruction, and necrotizing enterocolitis, as well as respiratory SAEs, persistent ductus arteriosus, and hypotension. Each GA week, 100-g BW, and point in 5-minute Apgar score at birth associated with 8 to 20% increased chance of reaching the TDE volumes. Multivariable analyses showed independent effects for BW, GA, Apgar score, GI SAEs, abdominal symptoms/signs, respiratory SAEs, days on antibiotics, and hypotension.

Conclusion This observational analysis demonstrates the variable and cautious progression of enteral feedings in contemporary extremely low BW infants and the extent to which clinical variables associate with this progression.

Key Points

• Total feedings of 10 and 120 mL/kg/d were reached at median 4 and 14 day of age, respectively, and at a daily increase of 11 mL/kg.

• Each incremental GA week, 100-g BW, and point in 5-minute Apgar score associated with 8 to 20% increased chance of reaching enteral feedings of 10 to 120 mL/kg/d.

• Progression of enteral feeding associated with several clinical events and was slower than advocated in common feeding protocols.

Keywords

premature infants - enteral feeding - feeding progression - feeding volumes - adverse clinical events

Enteral feeding is critical to the well-being, growth, and development of premature infants.[1] [2] [3] Several factors may affect the progression of enteral feeding volumes, such as the risk of inducing necrotizing enterocolitis (NEC) and clinical signs attributable to feeding intolerance.[4] [5] [6] Full enteral feeding is an important treatment goal in these infants and usually identified as a total daily intake of 120 to 150 mL/kg body weight for up to a couple of days, which sometimes is coupled to the discontinuation of parenteral nutrition.[5] [7] [8] [9] [10] Arguments have been raised that early initiation and rapid progression of enteral feedings in accordance with standardized feeding protocols may shorten the time to full enteral feeding without increasing the risk of serious complications.[1] [2] [11]

The time to a strict definition of full enteral feeding is a primary endpoint in the “Connection Trial,” a phase 3 study of IBP-9414 (Lactobacillus reuteri) under U.S. Investigational New Drug (IND) application and European Union (EU) Clinical Trial Exemption (CTX). This definition of sustained feeding tolerance (SFT) involves 10 consecutive days with at least 120 mL/kg/d of enteral feeding and an average body weight increase of at least 10g/kg/d without the use of parenteral nutrition.[12] SFT defined in this way was reached at mean 18 days in a treatment-blind analysis of extremely low birth weight (ELBW) infants of the “Connection Trial.”[13] This study also detailed the extent by which a range of gastrointestinal (GI) complications associated with the time to reach SFT in addition to, e.g., respiratory compromise, cardiac events, late-onset sepsis (LOS), and hypotension.

Our observation of an unexpectedly long time to reach SFT in the contemporary ELBW infants[12] initiated analysis of the early phases of enteral nutrition.[1] [2] [11] The objective of the present study is to describe total daily enteral (TDE) intakes in the infants recruited into the “Connection Trial” and to quantify the extent by which clinical variables associate with TDE volumes of 10, 20, 40, 80, and 120 mL/kg.

Materials and Methods

The “Connection Trial”

The “Connection Trial” is a phase 3, placebo-controlled study on the safety and efficacy of IBP-9414 (ClinicalTrials.gov ID: NCT03978000) with approval of institutional review boards/ethical committees as appropriate for the participating neonatal intensive care units. Recruitment will end and randomization codes will be broken when 2,168 very low birth weight (BW) infants have been reached. The infants are randomized 1:1 to a single daily enteral dose of IBP-9414 (L. reuteri) or sterile water placebo, within 48 hours of birth until a postmenstrual age (PMA) of 34 weeks + 6 days. Follow-up is conducted at PMA 40 weeks ± 7 days. The primary endpoints of the “Connection Trial” are the time to reach SFT and the incidence of NEC confirmed by independent adjudication of abdominal X-rays, laparotomy, or autopsy.

The “Connection Trial” is the first clinical study on the safety and efficacy of a probiotic under U.S. IND and EU CTX. IBP-9414 is of pharmaceutical grade with quality standards equivalent to drug products. Manufacturing requires full compliance with Good Manufacturing Processes from cell banking to final drug product, which include rigorous controls of raw materials, ingredients, and excipients as well as verified absence of a range of potential contaminants, batch control, shelf-life determination, and validated dosing procedures. This contrasts to currently available probiotics that are classified as food additives and administered to premature infants despite limited verification of their quality, efficacy, and safety.[14] [15] [16]

Patient Cohort

The presently investigated 641 infants were included into a second, independent safety evaluation, as per the “Connection Study” protocol, and they have previously been analyzed for the time to reach SFT.[13] The infants had mean BW of 847 g (SD, 113) and mean gestational age (GA) of 27 weeks (SD, 2) at birth ([Table 1]). The total enteral feeding volumes received by the infants were recorded daily up to PMA 34 weeks + 6 days (median duration, 55 days) and the duration of hospitalization for up to 40 weeks ± 7 days (median duration, 82 days). Details on the composition of enteral feeds were not gathered within the study protocol, except for any daily inclusion of any human milk. The variables analyzed for association with enteral feeding volumes were gathered under Good Clinical Practices and International Council of Harmonization guidelines.[17] They were based on reports from the investigators managing the infants with maintained blinding as to treatment group allocation of the infants. The investigated study safety events relied on investigators' assessments with respect to diagnosis criteria and classification of an adverse event (AE) as serious (SAE) or not. The safety events analyzed for an association with the TDE feeding volumes were selected from nearly 500 reported events and some were gathered into groups for ease of interpretation. The diagnosis of NEC, however, relied on independent adjudication of abdominal X-rays demonstrating intestinal pneumatosis and/or portal venous gas or verification of NEC at laparotomy or autopsy (confirmed NEC).

Table 1 Basic characteristics for the 641 investigated infants

Characteristic	Number of Infants	Median (IQR)	Mean (SD)
BW, g all	641	860 (777–940)	847 (113)
510–749	102	650 (605–700)	650 (63)
750–1,000	539	880 (825–950)	884 (75)
GA, weeks all	641	27 (26–28)	27 (2)
510–749 g	102	25 (24–27)	26 (2)
750–1,000 g	539	27 (26–29)	27 (2)
Gender, female 510–749 g	49	–	–
750–1,000 g	287	–	–
Male 510–749 g	53	–	–
750–1,000 g	252	–	–
Apgar 5-min score, points	641	7 (6–8)	7 (2)
Race Caucasian	367	–	–
African American	197	–	–
Other/multiple/unknown	77		–
Study duration[a], days	640	55 (45–64)	53 (14)
In-hospital stay, days	641	82 (67–95)	84 (32)

Abbreviations: BW, birth weight; GA, gestational age at birth; IQR, interquartile range; SD, standard deviation.

^a Number of days during which daily recordings were gathered.

Descriptive and Quantitative Statistics

The frequency of events and event groups explored for an association with the TDE feeding volumes is shown in [Table 2]. Association of these events and some basic variables of the infants with the time from birth to the TDE feeding volumes of at least 10, 20, 40, 80, and 120 mL/kg/d were analyzed with Cox proportional hazard models. Each volume was first analyzed univariably for all the clinical variables. Those with p-value <0.05 (defined as statistically significant) were subsequently entered into multivariable analyses, where the optimal model was determined using the Akaike Information Criteria (AIC) with a stepwise approach.[18] AIC balances the trade-off between accuracy of the fit and the complexity of the model. It quantifies the quality of the model by considering the data fit while penalizing models using a higher number of parameters. The output is presented as the hazard ratios (HR) with 95% confidence intervals, and nominal p-values. HR refers to the relative difference in the chance of reaching the specified TDE volume at each day related to a one-unit change in the specific variable, and HR < 1.0 indicates a reduced chance of reaching the TDE volumes. Adjustment for multiplicity was not performed due to the exploratory character of the analyses.

Table 2 Characteristics and frequency of analyzed clinical events

Event	Frequency
	n (infants)	% (infants)	Mean (median)
Any SAE	133	20.7
SAE GI	42	6.6
Confirmed NEC as per independent adjudication of abdominal radiographs and surgery/autopsy	61	9.5
SAE GI perforation, i.e., SIP, esophageal perforation, gastric perforation	17	2.7
SAE GI obstruction, i.e., ileus, bowel obstruction, and volvulus	13	2.0
AE abdominal signs, e.g., distension, discoloration, vomiting, reflux, disturbed motility, impaired gastric emptying, hematochezia, hematemesis	150	23.4
SAE respiratory, i.e., BPD, respiratory failure, apnea, pulmonary hemorrhage, pulmonary hypertension, pulmonary emphysema, pneumothorax, tracheomalacia	48	7.5
AE BPD (including chronic respiratory insufficiency/failure)	204	31.8
AE pneumonia, e.g., pneumonia, tracheitis, lower respiratory tract infection, pneumonitis, bronchiolitis	63	9.8
AE clinically suspected or verified LOS	117	18.3
SAE blood culture-positive LOS	72	11.2
Days with IV antibiotic use per infant			11(5)
AE PDA	238	37.1
SAE cardiac, i.e., bradycardia, cardiac or cardiopulmonary failure, cardiac congestion	6	0.9
AE bradycardia	75	11.7
AE hypotension	34	5.3
AE intracranial, intraventricular, and periventricular hemorrhage	154	24.0
AE ROP	188	29.3
SAE metabolism, e.g., metabolic acidosis/alkalosis, or electrolyte disturbance incl. hyper- or hypoglycemia	4	0.6
SAE renal, i.e., anuria, acute kidney injury, renal failure/impairment	3	0.5
AE renal, e.g., impairment, oliguria, anuria, hydronephrosis, nephrocalcinosis, hematuria	40	6.2

Abbreviations: AE, adverse event of any seriousness, i.e., also including SAEs; BPD, bronchopulmonary dysplasia; Confirmed NEC, necrotizing enterocolitis; GI, gastrointestinal; IV, intravenous; LOS, late-onset sepsis (>72 hours of age); PDA, persistent ductus arteriosus; ROP, retinopathy of prematurity; SAE, serious adverse event defined as, e.g., life-threatening, prolonging hospitalization or causing significant incapacity; SIP, spontaneous intestinal perforation.

Results

Daily intake reported as enteral feeding received by the infants was highly variable during the first month after birth ([Fig. 1A]). First feeds were reported to occur at the first day of life (median day 2) with the limitation that no feeding data were collected prior to randomization, which must occur within 48 hours of age. The overall difference between infants was the greatest during the more progressive feeding phases around 2 to 3 weeks of age, stabilized gradually over time and with outliers (outside 1.5 times the interquartile range [IQR]) being more common during the latter part of the first month. Low GA and body weight at birth associated with a generally slower increase in daily feeding volumes throughout the study period ([Fig. 1B and C]). Confirmed NEC was recognized at median 15 days of age, and the numerically lower enteral intake of these infants, compared with those without confirmed NEC, was already discernible during the first week of life ([Fig. 1D]). GI perforation occurred at median 6 days of age and the dramatically lower intake in these infants was discernible already shortly after birth and never recovered during the first month ([Fig. 1E]). The limited enteral intake in infants with pneumonia (diagnosed at median 21 days of age) was also notable early and maintained throughout the first month ([Fig. 1F]). Overall, the infants were fed with any amount of human milk during median 95% of days (IQR, 85–100%) in the study, received parenteral nutrition during median 31% of the days (IQR, 17–59%), and increased their body weight by median 132 g/kg/wk (IQR, 104–160 g/kg/wk).

Fig. 1 A–F. Box plots showing total daily enteral feeding volumes (mL/kg) over age (days) from birth. The box shows median values and 25th and 75th percentiles with extensions of extreme values within 1.5 times of the interquartile range as bars and outliers further away as dots. (A) Total daily enteral feeding volumes for all 641 infants. (B) Total daily enteral feeding volumes split by the median gestational age of 27 weeks at birth. (C) Total daily enteral feeding volumes split by the median birth weight of 860 g. (D) Total daily enteral feeding volumes for infants with (n = 61) and without necrotizing enterocolitis confirmed by independent adjudication of abdominal radiographs, laparotomy, or autopsy. (E) Total daily enteral feeding volumes for infants with (n = 17) and without gastrointestinal perforation. (F) Total daily enteral feeding volumes for infants with (n = 63) and without adverse event pneumonia as defined in [Table 2].

When analyzing the time to the TDE volumes, it was evident that few infants (17.5%) reached 10 mL/kg/d on day 2 of life ([Fig. 2]) and that the median time to this volume was 4 days ([Table 3]). Conversely, the shortest time to 120 mL/kg/d was 5 days ([Fig. 2]) and one-fourth of infants attained this volume at or beyond 20 days of age ([Table 3]). Using the observed median times from 10 to 120 mL/kg/d, the daily increase in total feeding volume was calculated to 11 mL/kg/d.

Fig. 2 Time (days) from birth to total daily enteral feeding volumes of ≥10 to 120 mL/kg for the 641 infants. Please note that feeding data were not collected prior randomization into the study (must occur within 48 hours after birth).

Table 3 Median age (days) at attainment of total enteral feeding volumes of at least 10, 20, 40, 80, and 120 mL/kg/d

mL/kg/d	≥10	≥20	≥40	≥80	≥120
25th percentile	3.0	4.0	5.0	8.0	11.0
Median	4.0	5.0	7.0	11.0	14.0
75th percentile	5.0	7.0	10.0	15.0	20.0

Univariable Regression

When the HR for the TDE volumes was analyzed with univariable regression ([Table 4]), all 24 variables showed statistically significant association (p < 0.001 to <0.05) with one or more of the TDE volumes, except for bronchopulmonary dysplasia (BPD), bradycardia, as well as metabolic, cardiac, and renal SAEs. The HRs across all the volumes were 1.08 to 1.20 for every increase in 100-g BW, GA week, and point in 5-minute Apgar score at birth. Occurrence of any SAE, GI SAEs and GI perforation associated with HR 0.22 to 0.78, which represent a 22 to 78% reduced chance of attaining any of the TDE volumes during the entire study period. The corresponding, statistically significant HR values were 0.63 to 0.81 for respiratory SAEs and persistent ductus arteriosus (PDA), and 0.993 to 0.997 for 1 day on antibiotics for systemic use. Confirmed NEC, GI obstruction, and abdominal signs had significant HRs of 0.43 to 0.76 to the TDE volumes of 20 to 120 mL/kg/d, whereas LOS irrespective of blood culture-positive or negative and pneumonia showed significant associations (HR, 0.68–0.74) with 80 and 120 mL/kg/d.

Table 4 Hazards ratios and color-coded statistical significance levels^a with 95% confidence intervals in the univariable regression model for the association of clinical variables with the TDE volumes of 10 to 120 mL/kg

mL/kg/d	≥10		≥20		≥40		≥80		≥120
Variable	HR	CI	HR	CI	HR	CI	HR	CI	HR	CI
BW (100-g interval)	1.13	1.06–1.21	1.15	1.07–1.23	1.20	1.12–1.29	1.18	1.10–1.26	1.20	1.12–1.29
GA (wk)	1.10	1.06–1.14	1.15	1.10–1.19	1.16	1.12–1.21	1.15	1.11–1.20	1.17	1.12–1.22
Apgar 5-min score	1.08	1.03–1.13	1.09	1.04–1.14	1.10	1.05–1.16	1.11	1.06–1.16	1.11	1.06–1.17
In-hospital stay (day)	0.997	0.99–1.00	0.995	0.99–0.99	0.992	0.99–0.99	0.991	0.99–0.99	0.990	0.99–0.99
Any SAE	0.78	0.64–0.95	0.71	0.58–0.86	0.63	0.51–0.77	0.66	0.54–0.81	0.69	0.56–0.84
SAE GI	0.62	0.45–0.86	0.47	0.34–0.66	0.39	0.27–0.55	0.39	0.27–0.55	0.48	0.34–0.68
Confirmed NEC	0.89	0.68–1.16	0.77	0.59–1.00	0.72	0.55–0.94	0.73	0.55–0.95	0.70	0.53–0.92
SAE GI perforation	0.49	0.30–0.82	0.28	0.16–0.48	0.22	0.13–0.38	0.24	0.14–0.41	0.29	0.17–0.51
SAE GI obstruction	0.95	0.55–1.65	0.54	0.16–0.48	0.54	0.30–0.96	0.43	0.24–0.78	0.48	0.26–0.90
AE abdominal sign	0.84	0.70–1.01	0.76	0.63–0.91	0.76	0.63–0.91	0.74	0.62–0.89	0.74	0.61–0.89
SAE respiratory	0.63	0.46–0.85	0.65	0.49–0.88	0.68	0.50–0.91	0.70	0.52–0.95	0.65	0.40–0.68
AE BPD	0.90	0.76–1.06	0.91	0.77–1.08	0.90	0.73–1.07	0.91	0.77–1.08	0.86	0.72–1.02
AE pneumonia	0.81	0.62–1.05	0.80	0.62–1.04	0.79	0.61–1.02	0.74	0.57–0.92	0.70	0.53–0.92
AE clinical sepsis	1.20	0.98–1.47	0.89	0.73–1.10	0.82	0.67–1.00	0.72	0.58–0.88	0.70	0.57–0.87
SAE LOS culture pos	1.17	0.91–1.49	0.93	0.73–1.20	0.87	0.68–1.11	0.73	0.57–0.94	0.68	0.53–0.88
IV antibiotics (day)	0.993	0.99–0.99	0.990	0.99–0.99	0.989	0.98–0.99	0.981	0.98–0.99	0.977	0.97–0.98
AE PDA	0.81	0.69–0.95	0.71	0.60–0.83	0.68	0.58–0.80	0.67	0.57–0.79	0.70	0.59–0.83
SAE cardiac	0.71	0.22–2.11	0.78	0.35–1.74	0.62	0.28–1.40	0.72	0.32–1.61	0.65	0.29–1.46
AE bradycardia	1.13	0.88–1.43	1.003	0.79–1.28	1.10	0.87–1.40	1.07	0.84–1.36	0.987	0.77–1.26
AE hypotension	0.60	0.42–0.84	0.42	0.29–0.59	0.42	0.29–0.60	0.40	0.28–0.58	0.47	0.33–0.68
AE cranial bleeding	0.98	0.81–1.17	0.86	0.72–1.03	0.82	0.69–0.99	0.85	0.71–1.03	0.88	0.73–1.06
AE ROP	0.87	0.73–1.03	0.78	0.66–0.92	0.76	0.64–0.90	0.85	0.72–1.01	0.86	0.72–1.02
SAE metabolic	1.07	0.40–2.86	1.39	0.52–3.71	1.27	0.47–3.39	1.58	0.59–4.23	1.63	0.61–4.36
SAE renal	0.68	0.22–2.11	0.56	0.17–1.73	0.70	0.22–2.17	0.83	0.28–2.59	0.77	0.25–2.39
AE renal	0.79	0.58–1.09	0.68	0.50–0.94	0.74	0.54–1.02	0.74	0.54–1.03	0.67	0.48–0.93

Abbreviations: AE, adverse event; BW, birth weight; BPD, bronchopulmonary dysplasia; CI, confidence interval; LOS, late-onset sepsis; Confirmed NEC, necrotizing enterocolitis confirmed by independent adjudication of abdominal radiographs; GA, gestational week at birth; GI, gastrointestinal; HR, hazard ratio; IV, intravenous; p, probability with <0.05 considered statistically significant; PDA, persistent ductus arteriosus; ROP, retinopathy of prematurity; SAE, serious adverse event defined as, e.g., life-threatening, prolonging hospitalization or causing significant incapacity.

Note: HR refers to the relative difference in the chance of reaching the specified enteral feeding volume at each day related to a one-unit change in the specific variable.

aColor-coded p-values

< 0.001

0.001–0.01

> 0.01–0.025

> 0.025– < 0.05

≥0.05

Abbreviations: AE, adverse event; BW, birth weight; BPD, bronchopulmonary dysplasia; CI, confidence interval; LOS, late-onset sepsis; Confirmed NEC, necrotizing enterocolitis confirmed by independent adjudication of abdominal radiographs; GA, gestational week at birth; GI, gastrointestinal; HR, hazard ratio; IV, intravenous; p, probability with <0.05 considered statistically significant; PDA, persistent ductus arteriosus; ROP, retinopathy of prematurity; SAE, serious adverse event defined as, e.g., life-threatening, prolonging hospitalization or causing significant incapacity.

Note: HR refers to the relative difference in the chance of reaching the specified enteral feeding volume at each day related to a one-unit change in the specific variable.

Multivariable Regression

Stepwise multivariable analysis associated 12 variables with the time to the TDE volumes ([Table 5]). BW, GA, and 5-minute Apgar score at birth had HRs of 0.99 to 1.14, and GI SAEs, GI perforation, respiratory SAEs, abdominal signs, and hypotension had HR 0.32 to 0.80. Also, days on intravenous (IV) antibiotics and PDA showed association with the TDE volumes. In contrast, e.g., confirmed NEC, GI obstruction, LOS, and pneumonia appeared to coexist with other events to such a degree that the multivariable model rejected them as independent determinants for the time to the TDE volumes.

Table 5 Hazards ratios with color-coded statistical significance levels^a and 95% confidence intervals in the stepwise selected multivariable model for the association of clinical variables with the chance of reaching total daily enteral feeding volumes of 10 to 120 mL/kg

mL/kg/d	≥10		≥20		≥40		≥80		≥120
Clinical variable	HR	CI	HR	CI	HR	CI	HR	CI	HR	CI
BW (100-g interval)	1.06	0.98–1.15	NS	–	1.12	1.03–1.21	1.14	1.06–1.23	1.127	1.04–1.23
GA (wk)	1.05	1.00–1.10	1.10	1.05–1.14	1.06	1.01–1.12	1.07	1.01–1.12	1.05	1.00–1.10
Apgar 5-min score	1.05	1.00–1.10	NS	–	1.06	1.01–1.11	0.987	0.98–0.99	1.06	1.01–1.11
In-hospital stay (d)	NS	–	NS	–	NS	–	NS	–	0.996	0.99–1.0
SAE GI	0.70	0.51–0.98	NS		0.64	0.42–0.98	0.54	0.35–0.83	0.71	0.46–1.01
SAE GI perforation	NS	–	0.32	0.19–0.56	0.33	0.17–0.64	0.48	0.25–0.93	0.54	0.27–1.07
AE abdominal sign	NS	–	0.73	0.61–0.88	0.68	0.57–0.83	0.67	0.55–0.81	0.65	0.54–0.79
SAE respiratory	0.76	0.55–1.03	0.69	0.51–0.94	0.78	0.58–1.07	0.79	0.58–1.08	0.80	0.58–1.10
IV antibiotics (day)	NS	–	0.997	0.99–1.00	0.997	0.99–1.00	0.998	1.00–1.01	0.983	0.98–0.99
AE PDA	NS	–	NS	–	0.85	0.72–1.01	0.82	0.69–0.97	NS
AE hypotension	0.73	0.51–1.04	0.51	0.35–0.73	0.54	0.37–0.78	0.56	0.38–0.80	0.66	0.46–0.95
AE renal event	NS	–	0.77	0.55–1.06	NS	–	NS	–	NS	–

Abbreviations: AE, adverse event of any seriousness; BW, birth weight; CI, confidence interval GA, gestational week at birth; GI, gastrointestinal; IV, intravenous; NS, not selected in the multivariable stepwise analyses; PDA, persistent ductus arteriosus; p, probability; SAE, serious adverse event defined as, e.g., life-threatening, prolonging hospitalization or causing significant incapacity.

Notes: HR refers to the relative difference in the chance of reaching the specific enteral feeding volume at each day related to a one-unit change in the specific clinical variable. Variables without HR values are those not recognized as relevant in the stepwise model analysis.

aColor-coded p-values

< 0.001

0.001-0.01

> 0.01-0.025

> 0.025- <0.05

≥0.05

Abbreviations: AE, adverse event of any seriousness; BW, birth weight; CI, confidence interval GA, gestational week at birth; GI, gastrointestinal; IV, intravenous; NS, not selected in the multivariable stepwise analyses; PDA, persistent ductus arteriosus; p, probability; SAE, serious adverse event defined as, e.g., life-threatening, prolonging hospitalization or causing significant incapacity.

Notes: HR refers to the relative difference in the chance of reaching the specific enteral feeding volume at each day related to a one-unit change in the specific clinical variable. Variables without HR values are those not recognized as relevant in the stepwise model analysis.

Discussion

The present study is part of an early analysis of the enteral feeding pattern of ELBW infants recruited into the “Connection Trial.” These treatment-blind analyses started with the evaluation of alternate definitions of SFT with selection of a period of 10 consecutive days during which the infants must receive at least 120 mL/kg/d without parenteral macronutrients and with an average weight gain of at least 10g/kg/d.[12] A 1-day shift in the time to this strict definition of SFT associated with clinical events such as confirmed NEC, GI and respiratory AEs, LOS, BPD, ROP, and days with IV antibiotics. Subsequent analysis showed that the mean time to SFT was 18 days.[13] This was longer than previously reported for the time to full enteral feeding,[7] [8] [9] [10] which potentially related to the underlying requisite of a consecutive 10-day period. This study also substantiated that a GI perforation, a cardiac SAE, and a hypotensive event increased the mean time to SFT with 5.7 to 15.4 days and that the corresponding values for pneumonia, clinical sepsis, and abdominal signs were 2.5 to 4.1 days. The present analysis extends these findings by demonstrating the age at which the infants first received TDE feedings of at least 10 to 120 mL/kg/d and the clinical variables associated with these volumes. The study was not designed to address an optimal enteral feeding regimen nor any relationship to body growth, but rather to describe current practices and complications in the early phases of enteral feedings of importance to the shorter- and longer-term development of ELBW infants.[1] [2] [3]

The infants described herein were included in a second safety analysis as per the “Connection Trial” protocol, whereby quality-controlled study data became available for analysis. All the investigated data are based on reports by the neonatology teams managing the infants, except for confirmed NEC that required the identification of intestinal pneumatosis and/or postal venous gas at adjudication of abdominal X-rays or at laparotomy or autopsy. This requisite related to NEC being an efficacy endpoint of the trial and recent evidence on the diversity of this disorder.[19] The reporting requirements and treatment standardizations of the study protocol were as limited as possible to minimize interference with the routines of the 80+ involved neonatal intensive care units across 10 countries. The gathering of daily feeding data was limited to total enteral volumes as well as any inclusion of human milk and any use parenteral nutrition. A standardized feeding protocol was not prescribed, whereby the enteral feedings can be assumed to reflect contemporary practices across the units. The process of reporting safety events followed the safety regulations conventional to pivotal drug development trials and any requisites for diagnosing safety events were not provided.[17] As the analyses were performed blinded, it is worth noting that L. reuteri has been claimed in nonpivotal clinical studies to, e.g., abbreviate the time to full enteral feeds and improve the feeding tolerance of premature infants.[20-23]

The variation in daily feeding volumes was present within the first days after birth and persisted during the first postnatal month. Qualitative analysis the infants with GI perforation, confirmed NEC, and pneumonia showed great variability in daily feeding volumes, which seemed to separate these infants from those without such complications early after birth. Further analysis indicated that this separation related to the infants having these complications at an early age. Recognition of confirmed NEC before the 15-day median age of this diagnosis associated with a median delay of 0.5 to 2.0 days to reach 10 to 40 mL/kg/d in comparison with the infants without NEC. In contrast, confirmed NEC occurring at a latter age showed no such separation. Similarly, the infants with pneumonia recognized before the median age of 21 days showed delayed (median, 2.0 days) attainment of the TDE feedings of 20 to 40 mL/kg/d.

Overall, one-fourth of the infants required 5 or more days to reach 10 mL/kg/d despite that feeding was reported to commence at median 2 days of age. Moreover, the same proportion of infants achieved 120 mL/kg/d at or beyond 20 days of age. The daily increase in total feeding volume was calculated to median 11 mL/kg/d. Many standardized enteral feeding protocols recommend initial feedings of 5 to 10 mL/kg, increasing 20 to 30 mL/kg/d during subsequent days, to reach 120 mL/kg/d around 1 week of age.[1] [2] [11] The observations on the modest progression of enteral feedings in the contemporary ELBW infants prompted the quantitative analyses on the association of clinical variables with the chance of reaching the TDE volumes. Cox proportional hazards models were selected for this comparison in consistency with the substantial time interval at which the TDE volumes were attained as well as the great variation in postnatal age at which the safety events were recognized. These associations should not be regarded as predictions for the attainment of the TDE volumes nor as evidence of a causal coupling of the feeding volumes to the risk of infants developing the investigated safety events.

Univariate analysis showed the chance of reaching the TDE volumes with no adjustment for the effect of events occurring in parallel in the ELBW infants, which should be considered representative of the clinical situation. In this analysis, every 100-g BW, 1-week GA, and 5-minute Apgar score at birth associated with 8 to 20% increased chances of reaching any of the TDE volumes. This association persisted beyond 120 mL/kg/d and coincides with previous notions of the difficulty of feeding especially the smallest premature infants as well as the observation that such changes in BW and GA associate with a 3-day shortening in the time to SFT.[13] [24] [25] The analysis also showed the expected, strong influence of GI complications that was evident already at total daily intakes of 10 mL/kg and persisted up to 120 mL/kg/d.[25] [26] A GI perforation associated with down to 22% chance of reaching the TDE volumes, which was lower than for confirmed NEC and GI obstruction. The reduced chance of attaining all the TDE volumes was also evident throughout the study time for PDA, hypotension, and respiratory SAEs, whereas the associations of pneumonia and LOS became significant toward the higher TDE volumes. In contrast, intracranial hemorrhages as well as BPD demonstrated no association of statistical significance despite both event categories occurred with substantial frequency.

Multivariable analysis was utilized to limit the effect of co-occurring events and the Akaike stepwise model to show the best fit of variables (including those not statistically significant) as an explanation for total variability in time to reach the TDE volumes. Using these models, the effect of BW, GA, and Apgar score essentially persisted. It also was evident that abdominal signs and serious GI complications, such as perforation, independently associated with a reduced chance of reaching the investigated volumes with up to 68%. Similarly, a hypotensive event can, after median 5 days, almost half this chance. The model also associated respiratory SAEs and to a lesser extent PDA and renal events to the TDE volumes.

Numerous factors occurring in the intensive care treatment of premature infants have been linked to the difficulty of adhering to common feeding protocols. Besides abdominal and other signs attributable to feeding intolerance, such events have included low BW, GI morbidities, metabolic acidosis, cardiovascular instability, and symptomatic PDA.[1] [2] [4] [10] Such factors also include a variety of events like hypoxia, electrolyte disturbances, hyperglycemia, hyperbilirubinemia, as well as concerns based on dogma (gastric residuals, transfusions, indomethacin use, etc.) rather than on a scientific basis.[4] [27] The present findings show the strength of association for 24 clinical variables to the feeding progression of ELBW infants, which to our knowledge has not been detailed previously. An unusually high incidence of clinical complications could be a potential explanation for the modest speed of feeding progression in the examined infants. However, this seems unlikely as the “Connection Study” protocol excludes randomization of infants “in extremis” and those with early-onset sepsis or recognized GI conditions, whereby a selection toward healthier infants as compared with unselected cohorts of ELBW infants seems probable.[28] [29] The present analysis of current practices across a substantial number of high-level, neonatal intensive care units show an unexpectedly slow progression of enteral feeding volumes in ELBW infants and suggest that a stricter adherence to commonly advocated feeding regimens may abbreviate the time to full enteral feeds in these infants.[1] [2] [3] [4] [11] [30]

Conflict of Interest

J.N. is the global coordinating investigator of the Connection Trial sponsored by Infant Bacterial Therapeutics. P.A., V.C., A.L., P.P., R.R., B.S. are principal investigators of the Connection Trial sponsored by Infant Bacterial Therapeutics Inc. M.T. is a consultant statistician employed by Infant Bacterial Therapeutics Inc. A.K., S.S., and J.R. are all employees of Infant Bacterial Therapeutics Inc. sponsoring the Connection Trail.

Acknowledgments

We are greatly indebted to all families and staff at the neonatal intensive care units making this study possible. The following contributors are gratefully acknowledged for their contribution to this study and membership of the “Connection Study Group”: K. Ahmad, MD, The Women's Hospital of Texas, Houston, TX; Ashley P., MD, Duke University, Durham, NC; V. Atanasova, MD, University Hospital, Pleven, Bulgaria; A. Avasiloaiei, MD, University of Medicine and Pharmacy, Grigore T. Popa, Romania; D. Batra, MD, Nottingham University Hospitals, Nottingham, England; B. Batton, MD, Southern Illinois University School of Medicine, Chicago, IL; M. Biniwale, MD, Keck School of Medicine of USC, Los Angeles, CA; A. Blake, MD, Baystate Children's Hospital, Springfield, MA; H. Chaaban, MD, Children's Hospital at OU Health, Oklahoma, OK; I. Chandrasekar, MD, Valley Children's Hospital, Madera, CA; V. Chowdhary, Arkansas Children's Hospital, Little Rock, AR; T. Del Moral, MD, University of Miami, Miami, FL; P. Delmore, MD, Medical Research and Endowment Foundation, Wichita, KS; M. Demetrian, MD, Clinical Hospital “Filantropia”, Bucuresti, Romania; L. Desfrere, MD, Assistance Publique-Hôpitaux de Paris, Louis Mourier Hospital, Colombes, France; F. Dicso, MD, Jósa András Hospital, Svent, Hungary; B. Doctor, MD, Spectrum Health- Helen Devos Children's Hospital, Grand Rapids, MI; M.E. Famuyide, MD, University of Mississippi Medical Center, Jackson, MS; Fayard E., MD, LOMA Linda University Children's Hospital, Anderson St, CA; L. Fazilleau, MD, Centre Hospitalier Universitaire de Caen Normandie, Cean, France; J. Ferry, MD, Pediatrix Medical Group of Florida, St. Joseph's Women's Hospital, Tampa, FL; J. Flores-Torres, MD, Tampa General Hospital, University of South Florida, Tampa, FL; R. Fonseca, MD, University of Texas Medical Branch, Galveston, TX; B. Frost, MD, North Shore University Health System, Evenston, IL; M. Garg, MD, Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA; R. Georgieva, MD, Specialized Hospital in Active Treatment of Pediatric Diseases, Sofia, Bulgaria; S.O. Guthrie, MD, Vanderbilt University School of Medicine and Jackson-Madison County General Hospital, Jacksonville, TN; I. Hand, MD, Kings County Hospital Center, Brooklyn, New York, NY; T. Havranek, MD, Children's Hospital at Montefiore, New York, NY; R. Hayes, DO, Geisinger Medical Center, Danville, PA; M. Hudak, MD, University of Florida College of Medicine, Jacksonville, FL; A. Katheria, MD, Hospital for Women & Newborns, San Diego, CA; R. Kylathu, MD, University of Arizona & Banner University Medical Center, Tucson, AZ; B. Królak-Olejnik, MD, Medical University, Wroclaw Borowska, Poland; Kordek, MD, Pomeranian Medical University, Szczecin, Poland; A. Lampland, MD, Children's Minnesota St. Paul Clinic, Saint Paul, MN; B. Loniewska, MD, Pomorski University Medyczny, Powstańców Wielkopolskich, Szczecin, Poland; J. Lua, MD, Hutzel Women's Hospital, Detroit, MI; M. del Mar Albujar Font, MD, Hospital Juan XXIII, Tarragona, Spain; M. Molad, MD, Carmel Medical Center, Haifa, Israel; R. Moores, MD, Children's Hospital of Richmond at VCU, Richmond, VA; F. Moya, MD, New Hanover Regional Medical Center, Wilmington, NC; S. Perveen, MD, Northwell Health Cohen Children's Medical Center of New York, New York, NY; L. Parton, MD, Maria Fareri Children's Hospital- Westchester Medical Center, Valhalla, NY; D. Pillers, MD, University of Illinois at Chicago, Chicago, IL; P. Quyen, MD, Augusta University, Augusta, GA; R. Ramanathan, MD, PH Good Samaritan Hospital, Los Angeles, CA; B. Reyburn, MD, North Central Baptist Hospital, San Antonio, TX; M. Riszter, MD, University of Debrecen Institute of Pediatrics, Debrecen, Hungary; G. Romera, MD, Hospital Universitario HM Monteprincipe, Madrid, Spain; A.C. Rudine, MD, St. David's HealthCare, Austin, TX; A. Santiago, MD, Texas Health Presbyterian Hospital, Plano, TX; D. Sharkey, MD, University of Nottingham, Nottingham, England; R. Singh, MD, Tufts Children's Hospital, Boston, WA; N. Spillane, MD, Hackensack Medical Center, Hackensack, NJ; A.J. Talati, MD, University of Tennessee Health Science Center, Memphis, TN; G. Talosi, MD, Bács-Kiskun County Teaching Hospital, Kecskemėt, Hungary; C. Tapia, MD, Hospital General Universitario de Alicante, Alicante, Spain; L. Vakrilova, MD, Medical University for Treatment for Obstetrics and Gynecology, Sofia, Bulgaria; C. Wagner, MD, Medical University of South Carolina, Shawn Jenkin's Children's Hospital, Charleston, SC; R. White, MD, Beacon Children's Hospital, South Bend, IN; L. Wolkoff, MD, Connecticut Children's Medical Center- School of Medicine, Hartford, WA; G. Zaharie, MD, UMF Iuliu Hatieganu, Cluj Napoca, România.

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Publication History

Received: 03 March 2023

Accepted: 01 August 2023

Article published online:
08 September 2023