Extended minimal enteral feeding and time to regain birth weight in extremely low-birth-weight infants

Abstract

BACKGROUND:

Minimal enteral feeding after birth has been developed as a strategy to enhance the functional maturation of the gastrointestinal tract. This study aimed to examine the relationship between the duration of minimal enteral feeding and time to regain birth weight in extremely low-birth-weight infants.

METHODS:

This retrospective study included all extremely low-birth-weight infants born between January 2018 and December 2020. Infants with major congenital anomalies and conditions requiring surgery and those who died or received palliative care in the first 10 days of life were excluded from the analysis. Minimal enteral feeding courses were categorized as extended if the feeding was continued for > 72 hours and short if the feeding was < 72 hours. The primary measured outcome was the time taken to regain birth weight.

RESULTS:

Of 217 study infants, 180 received an extended minimal enteral feeding for > 72 h. The median time to regain birth weight was not significantly different between the extended and short minimal enteral feeding groups, median (IQR) was 10 (7–13) versus 8 (6–11), respectively (p = 0.15). Extended minimal enteral feeding is associated with a significant increase in the mean duration of the total parenteral nutrition, (21.3±10 versus 17.2±9.3 days; p = 0.021). Infants with prolonged minimal enteral feeding courses experienced non-significantly higher levels of necrotizing enterocolitis, late-onset sepsis, and retinopathy of prematurity.

CONCLUSIONS:

Extended minimal enteral feeding in extremely low-birth-weight infants may not affect the time taken to regain birth weight.

Keywords

Intraventricular hemorrhage minimal enteral feeding necrotizing enterocolitis preterm infants retinopathy of prematurity time to full feed time to regain birth weight

1 Introduction

Minimal enteral feeding (MEF) is defined as a small volume of milk that is fed to preterm infants to prepare its gut for the subsequent advancement of enteral feeds. MEF for some period after birth has been developed as a strategy to enhance the functional maturation of the gastrointestinal tract and facilitate a smooth and rapid transition from parenteral to enteral nutrition [1].

Minimal enteral nutrition (MEN) stimulates gut hormones, promotes structural and functional intestinal maturation, and decreases indirect hyperbilirubinemia and cholestatic jaundice. MEF supports gastrointestinal disaccharidase activity, blood flow, and microbial flora [2].

Early MEF in preterm infants can result in decreased feeding intolerance and a shorter parenteral nutrition period, enhancement of the postprandial response, better weight gain, and improved bone mineralization [3].

Nevertheless, several studies have shown beneficial effects, but the results could not be confirmed in a meta-analysis [4]. However, it is important to emphasize that a meta-analysis did not suggest any harmful effects or increased incidence of necrotizing enterocolitis, while the lack of enteral nutrition causes gut atrophy and bacterial translocation [5].

Though there is no well-established practice for MEN, some studies suggest that physiological benefits occur at volumes less of than 24 ml/kg/day [6]. However, there is uncertainty about the best time to start MEF [7]. Current data support that MEN should be initiated within the first two days of a preterm infant’s life [5]. There is no general agreement about the optimal duration of MEN and the best time to advance feeding, particularly in extremely low-birth-weight infants.

Prescriber- and patient-related factors may be involved in the decision about the duration of MEF. The length of time needed to regain birth weight depends on early nutritional management [8]. We assumed that extended minimal enteral feeding might increase the length of time to transition to enteral feeding and thus decrease immediate postnatal growth. Prior studies have reported that an increase in time required to regain birth weight was associated with a greater reduction in weight for age Z-scores between birth and discharge in extremely low birth weight patients [8].

A recent retrospective study showed that time to regain birth weight was consistently the strongest predictor of neonatal growth velocity, which correlated with a decreased postnatal growth velocity [9]. Another retrospective study concluded that time to regain birth weight could be a predictor for development of ROP [10]. A meta-analysis of nine randomized trials compared early and delayed progressive feeding in predominantly moderate-preterm infants with 29–32 weeks of gestation [11]; and a retrospective study compared short and extended periods of trophic feeding in extremely preterm infants [12]. These two studies provided clinicians with evidence that early progressive feeding (small increments of feeding volumes between 1 and 4 days after birth) reduces the time to establish full enteral feeding without increasing the risk of NEC. However, many clinicians consider this evidence insufficient for standardizing the practice of early progressive feeding in extremely preterm infants. Retrospective studies have introduced selection bias mediated by the severity of illness [13], and randomized trials often exclude extremely preterm infants [14].

The relationship between the duration of MEF and the time to regain birth weight has not been addressed, particularly in extremely low-birth-weight infants. In this study, we will examine whether an extended duration of MEF has any impact on the time to regain birth weight in extremely low-birth-weight infants.

2 Methods

A retrospective chart review was performed for all infants born with birth weights less than or equal to 1000 g between January 1, 2018, and December 31, 2020, and admitted to the neonatal intensive care unit (NICU) in the Women’s Wellness and Research Center (WWRC), in Doha, Qatar. The study was approved by the Hamad Medical Corporation Research Center (MRC-01-21-412), and the requirement for informed consent was waived.

In total, 264 extremely low-birth-weight infants were admitted to the NICU during the study period. Thirty-three infants (12.5%) died, had a cardiovascular compromise, or received palliative care in the first 10 days of life, and 11 infants (4.16%) required surgery in the first 10 days of life—these infants were excluded from further analysis. There were missing data for three infants (1.13%), who were also excluded from the study. Therefore, the final study group consisted of 217 infants.

Maternal and neonatal characteristics were collected from medical records, including birth weight, gestational age, Apgar score at 1 and 5 min, singleton, premature rupture of membrane, maternal GBS status, maternal chorioamnionitis, antenatal steroids, preeclampsia, gestational diabetes, absent or reversed end-diastolic flow velocities on antenatal Doppler studies, small for gestational age (<3rd percentile), and outborn versus inborn patients.

The prediction of mortality and duration of stay in the NICU was estimated using the SNAPPE II (Score for Neonatal Acute Physiology with Perinatal Extension-II). The WWRC NICU feeding guidelines recommend starting MEF at 10–20 ml/kg/day immediately after birth if expressed breast milk (EBM) is available, and no later than 24 h if the formula will be initiated, unless clinically contraindicated. These can be maintained for up to seven days and are not intended to contribute to nutrition. The guideline recommends to progress feeding as early as possible if the preterm infant is not acutely ill. Furthermore, the guidelines call for the initiation of total parental nutrition within 24 hours of birth. We have a standardized feeding protocol for extremely low birth weight (ELBW) infants; we begin with a slow advance rate 10–20 ml/kg/day in the first 4 days then increase to 20–30 ml/kg/day thereafter. However, our unit does not currently routinely use probiotics for preterm infants, and we do not have access to a donor breast milk bank due to cultural and religious challenges.

The start time and total duration of MEF, as well as the time to regain birth weight were recorded for all eligible infants.

The primary outcome was the time taken to regain birth weight. Secondary outcomes were: the time to discontinue total parenteral nutrition which was used as a surrogate marker for feeding tolerance; LOS; early onset sepsis (EOS); NEC; severe intraventricular hemorrhage (IVH) grade III/IV; ROP diagnosed during the hospital stay; the number of days on mechanical ventilation; the length of the hospital stay; neonatal death before discharge; and feeding intolerance (abdominal distension, vomiting and gastric residuals > 50% of last feed).

2.1 Data analysis

MEF courses were categorized as extended if MEF was continued for > 72 hours and short if MEF was < 72 hours. We summarized the distribution of variables using numbers and percentages, means and standard deviations, or medians and interquartile ranges (IQR), as appropriate. We examined differences in outcomes and other covariates between the two groups using the chi-square test, Fisher’s exact test, t-test, or Mann-Whitney U test, as appropriate. Statistical analyses were performed using IBM SPSS version 26 (IBM Corp., Armonk, NY, USA) with statistical significance set at p < 0.05.

3 Results

The final study group of 217 infants had a mean gestational age of 26.1±1.6 and a mean birth weight of 780±123.6 g. Extended MEF course for > 72 hours was recorded for 180 infants (82.9%). Birth weight (779±123 versus 785.1±128.1 g; p = 0.79) and gestational age (26±1.5 versus 26.1±1.7 weeks; p = 0.21) were similar between those who received extended MEF course and those who did not. Furthermore, the maternal and neonatal characteristics were not significantly different between the groups (Table 1).

Table 1
Neonatal and maternal demographic data

MEF>72 hoursN = 180 MEF≤72 hoursN = 37 P value

Gestational age (weeks) 25.7±1.5 26.1±1.7 0.21

Birth weight (g) 779.0±123.0 785.1±128.1 0.79

Male 93 (51.7%) 20 (54.1%) 0.79

Singleton 112 (62.2%) 26 (70.3%) 0.35

1-min Apgar score 5.0±2.2 5.0 (2.1) 0.93

5-min Apgar score 7.4±1.6 7.5±1.5 0.74

Cesarean birth 101 (56.1%) 22 (59.5%) 0.71

Clinical chorioamnionitis 14 (7.8%) 1 (2.7%) 0.27

Maternal GBS positive 13 (7.2%) 6 (16.2%) 0.078

Preeclampsia/HELLP 35 (19.4%) 6 (16.2%) 0.65

Antepartum hemorrhage 39 (21.7%) 10 (27.0%) 0.48

Gestational diabetics 29 (16.1%) 9 (24.3%) 0.23

Abnormal Doppler 33 (18.3%) 3 (8.1%) 0.13

Severely Small for Gestational age 15 (8.3%) 5 (13.5%) 0.33

2 doses antenatal steroids 127 (70.6%) 23 (62.2%) 0.31

SNAPPE score 31.5±15.3 31.5±17.2 0.99

Outborn 5 (2.8%) 1 (2.7%) 1.0

	MEF>72 hoursN = 180	MEF≤72 hoursN = 37	P value
Gestational age (weeks)	25.7±1.5	26.1±1.7	0.21
Birth weight (g)	779.0±123.0	785.1±128.1	0.79
Male	93 (51.7%)	20 (54.1%)	0.79
Singleton	112 (62.2%)	26 (70.3%)	0.35
1-min Apgar score	5.0±2.2	5.0 (2.1)	0.93
5-min Apgar score	7.4±1.6	7.5±1.5	0.74
Cesarean birth	101 (56.1%)	22 (59.5%)	0.71
Clinical chorioamnionitis	14 (7.8%)	1 (2.7%)	0.27
Maternal GBS positive	13 (7.2%)	6 (16.2%)	0.078
Preeclampsia/HELLP	35 (19.4%)	6 (16.2%)	0.65
Antepartum hemorrhage	39 (21.7%)	10 (27.0%)	0.48
Gestational diabetics	29 (16.1%)	9 (24.3%)	0.23
Abnormal Doppler	33 (18.3%)	3 (8.1%)	0.13
Severely Small for Gestational age	15 (8.3%)	5 (13.5%)	0.33
2 doses antenatal steroids	127 (70.6%)	23 (62.2%)	0.31
SNAPPE score	31.5±15.3	31.5±17.2	0.99
Outborn	5 (2.8%)	1 (2.7%)	1.0

Data are presented as mean (standard deviation) or number (percentage). SNAPPE II, Score for Neonatal Acute Physiology with Perinatal Extension II.

Infants in the extended group received their first MEF at 50.8±31 hours and lasted for 139.3±52.7 hours, whereas infants in the short group received their first MEF at 54.3±36.3 and lasted for 60±16.9 hours. Both groups had similar types of milk, with 74.4% having breast milk in the extended group and 73% in the short group (Table 2). Both groups had similar SNAPPE II score (31.5±15.3 versus 31.5±17.2); therefore, the duration of MEF was not related to infant sickness. Both groups were required to have feeding increment as protocol. No statistically significant difference was observed in feeding intolerance between the two groups (13.9% versus 8.1%, P = 0.35).

Table 2

Minimal enteral feeding

	MEF>72 hoursN = 180	MEF≤72 hoursN = 37	P value
MEF start time (hours)	50.8±31	54.3±36.3	0.55
Expressed breast milk	134 (74.4%)	27 (73%)	0.85
MEF duration (hours)	139.3±52.7	60±16.9	<0.001

Data are presented as mean (standard deviation) or number (percentage).

However, the mean time taken to discontinue total parenteral nutrition (time to full feed) was significantly longer in the extended group than in the short group (21.3±10 versus 17.2±9.3 days; p = 0.021).

There was no statistically significant difference in the time to regain birth weight between those who received an extended MEF and those who did not; the median (IQR) was 10 (7–13) versus 8 (6–11), respectively (p = 0.15) (Fig. 1).

Fig. 1

MEF course comparison. The time to regain birth weight was similar between those who received an extended MEF and those who did not.

Moreover, there was no significant difference in the mean weight at discharge between the extended group and the short group (2945±282 g vs 3252±317 g; P = 0.32).

Extended MEF was accompanied by an increase in NEC, ROP, LOS, and the length of hospital stay; however, the differences were not statistically significant. Furthermore, EOS, IVH, death rates before discharge, and days on mechanical ventilation did not differ between the groups (Table 3).

Table 3

Major outcomes

	MEF>72 hoursN = 180	MEF≤72 hoursN = 37	P value
TPN duration (hours)	21.3±10	17.2±9.3	0.021
NEC	17 (9.4%)	1 (2.7%)	0.18
ROP	40 (23.8%)	7 (18.9%)	0.52
IVH	9 (5.0%)	2 (5.4%)	0.92
LOS	43 (23.9%)	5 (13.5%)	0.17
EOS	3 (1.7%)	1 (2.7%)	0.93
Mech. Vent (days)	23.9±34.0	24.0±39.5	0.98
Died in hospital	18 (10%)	3 (8.1%)	0.78
Feeding intolerance	25 (13.9%)	3 (8.1%)	0.35
Weight at discharge (g)	2945±282	3252±317	0.32

Data are presented as mean (standard deviation) or number (percentage).

4 Discussion

In this retrospective study, we showed that there was no difference in the time to regain birth weight between an extended MEF course at > 72 h and a short MEF course. Further, we did not find a difference in the development of NEC, ROP, LOS, and feeding intolerance between the groups. However, there was a significant increase in the number of days of parenteral nutrition with an extended MEF.

Our results corroborate the conclusion of a previous retrospective study by Salas et al. who compared short and extended periods of trophic feeding in 192 extremely preterm infants [12]. After adjusting for birth weight, gestational age, SGA status, race, sex, type of enteral nutrition, and the day of initiating the trophic feeding, they found that a short period of trophic feeding was associated with the early establishment of full enteral feeding.

This study confirms the results of Arial et al., who compared early progressive feeding with delayed progressive feeding after a four-day course of MEF in extremely low-birth-weight infants [15]. They found that early progressive feeding reduced the use of parenteral nutrition without increasing the risk of NEC, mortality, and postnatal growth restriction at 36 weeks of postmenstrual age.

Furthermore, our findings are consistent with the results of a recent meta-analysis of 1551 very low-birth-weight infants, which found that delaying the introduction of progressive enteral feeds beyond four days after birth may not reduce the risk of NEC or death [16]. We also could not detect a significant difference in NEC development or death before the discharge between an extended MEF at > 72 h and early progressive feeding. However, none of the trials recruited predominately ELBW or extremely preterm infants.

A systematic review and meta-analysis have recently been published by Chitale et al. (2022), which included 14 randomized controlled trials (RCTs) (n = 1505) comparing early initiation of enteral feeding (<72 hours) versus late initiation (≥72 hours) in preterm infants or low birth weight infants. They reported no significant difference in time to regain birth weight, NEC, or feeding intolerance [17].

On the other hand, our results contradict the results of a randomized trial of 199 preterm infants weighing≤1250 g that compared prolonged MEF for five days with early progressive feeding, and found that an extended MEF does not increase the time to reach full enteral feed and might increase the development of NEC in extremely preterm infants [18].

Another randomized trial favored MEF over progressive feeding in predominantly formula-fed infants with limited exposure to antenatal steroids [19]. Early initiation of enteral feeding is recommended in the current era of antenatal steroid use.

Therefore, there is no consensus on the proper duration of MEF. Practices extending MEF vary significantly at the institutional and provider levels. Few data exist regarding the reasons for this variation and the extent to which they can be explained by differences in patient-related factors. In our study, the mean SNAPPE II scores, which assess the severity of illness and predict mortality, were similar between groups. This finding reinforces the observation of a weak relationship between MEF duration and infant sickness.

Our feeding guidelines call for the early initiation of MEF for a maximum of 24 hours. However, this study showed the initiation of MEF for more than 24 h of age and less than 72 h in both groups. Sallakh et al. demonstrated a significant reduction in time to regain birth weight with early initiation of MEF for less than 72 h [20]. This could explain our study’s finding: no difference in time between groups to gain birth weight, as they had a similar initiation time of MEF of less than 72 hours.

The major outcomes did not differ between extended MEF and early progressive feeding. However, this study was not designed to demonstrate differences in outcomes, which would have required a much larger sample size.

The main strength of this study is that it is the first to examine the relationship between the duration of MEF and the time to regain birth weight in extremely low-birth-weight infants.

However, our study is limited because of its retrospective design. Furthermore, the study population was relatively small, preventing a thorough investigation of outcomes and meaningful multivariable analyses. We did not study weight gain velocity after the neonates reached birth weight. Moreover, we could not compare the results with consideration to the efficacy of mothers’ milk and formula.

5 Conclusion

In summary, this study showed that an extended MEF at > 72 h did not appear to influence the time to regain birth weight in ELBW infants. Prolonged MEF is associated with a delay in achieving full enteral feeding. There was no significant difference in the prevalence of common preterm complications, such as NEC, feeding intolerance, ROP, LOS, IVH, and death before discharge.

Footnotes

Acknowledgments

The authors acknowledge the contributors: Mrs. Tawa Olayemi Olukade.

Disclosure Statements

We have nothing to disclose.

Financial Disclosures

We have no potential or actual interests to disclose.

Human Research Statement

The study was approved by the Hamad Medical Corporation Research Center (MRC-01-21-412), and the requirement for informed consent was waived. The study was conducted in accordance with the ethical standards of all applicable national and institutional committees and the World Medical Association’s Helsinki Declaration.

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