Three-Hourly Feeding Intervals are Associated with Faster Advancement in Very Preterm Infants

Abstract

Objective:

To compare the effect of two-hourly (Q2H) vs. three-hourly (Q3H) feeding on time to achieve full enteral feeding, growth metrics and respiratory tolerance in very preterm infants with birth weight ≤1,250g.

Study Design:

Retrospective study review of 18 months before and after a change in our feeding guideline from Q3H to Q2H feedings.

Results:

113 infants were included, 59 in Q3H and 54 in Q2H groups. Q2H infants required 10% more days to achieve full enteral feeding, however it was not statistically significant (P = 0.054). Q2H feeding was associated with 16% more central catheter days (P = 0.02) and 17% more parenteral nutrition days (P = 0.019). There were no differences in respiratory outcomes or growth metrics between the groups.

Conclusion:

Very preterm infants fed Q3H had less central catheter and parenteral nutrition days when compared to those fed Q2H, without significant differences in growth or respiratory outcomes.

Introduction

Nutritional support for preterm infants is a major contributor to long term neurodevelopmental and growth outcomes for this fragile population. [1–5] Developmental intestinal immaturity in terms of absorptive surface area, hormonal regulation, and motility are challenges to achieve optimal nutritional support causing a high rate of extrauterine growth restriction in preterm infants. [6–8] Delays in establishing full enteral feeding may also increase the risk of invasive infection. [9] Therefore, several strategies have been employed in an attempt to shorten time to full enteral feeding, while trying to minimize the risk of feeding intolerance or other complications.

Four studies compared two-hourly (Q2H) vs. three-hourly feeding (Q3H) intervals in the preterm infant and provided conflicting data. [10–13] In 2008, Rudiger [10] found Q3H feeding in extremely low birth weight neonates was associated with faster advancement to full enteral feeding in comparison to Q2H feeding (median 26 days vs. 20 days), however it was not statistically significant (p=0.15). They did, however, find a significantly longer duration of continuous positive airway pressure (CPAP) support and phototherapy for hyperbilirubinemia in the Q3H feeding group. They hypothesized that Q2H feeding was associated with less gastric distension, resulted in improved respiratory tolerance and increased intestinal motility with increased fecal bilirubin excretion [10]. In another retrospective study, DeMauro [12] showed that infants who were fed Q2H achieved full enteral feeding 3.7 days sooner, were less likely to receive total parenteral nutrition for >28 days, and were less likely to have feeds withheld for ≥7 days. Two randomized controlled trials by Dhingra [11] and Ibrahim[13] showed there was no difference in the number of days to achieve full enteral feeding comparing Q2H vs. Q3H intervals, but the subjects in both studies had a greater mean birth weight of 1,300g [11, 13].

Therefore, there is insufficient evidence to choose between two-hourly versus three-hourly feeding intervals for very preterm infants.[14] We conducted this study to compare the effect of Q2H vs. Q3H feeding intervals on duration to achieve full enteral feeding, growth metrics and respiratory tolerance in very preterm infants with birth weight ≤1,250g.

Methods

This was a retrospective study of infants who were admitted to the neonatal intensive care unit (NICU) at the Children’s Hospital of Orange County (CHOC), Orange, CA, a quaternary level referral NICU. The study was approved by the hospital institutional review board (IRB).

Feeding Guidelines:

Standardized feeding guidelines have been utilized at our NICU since 2005. The guidelines undergo periodic review and updates related to new evidence on nutritional practices and local data analysis. Enteral feedings of preterm neonates with birth weight ≤1,250g were initiated at 10 ml/kg/day and remained at the same volume for 3 to 5 days, then incrementally advanced by 10 ml/kg/day until full feeding, defined as 150 ml/kg/day. Discrepancies in individual assessment of feeding intolerance were mitigated by the utilization of a feeding tolerance assessment tool which consists of abdominal exam findings, emesis and change in clinical status, without routine gastric residual assessment prior to feeding. Infants were fed human milk only, either mother’s own or pasteurized donor breast milk. The guideline included planned fortification using a commercial liquid bovine fortifier. Breast milk was fortified to 22 calorie per ounce (cal/oz) at a volume of 60 ml/kg/day and to 24 cal/oz when volume reached 80 ml/kg/day. The guideline recommended discontinuation of total parenteral nutrition (TPN) and central catheter when neonates achieved 110 ml/kg/day. In July 2015 the guideline was modified to change feeding intervals from Q3H to Q2H once volume of 40 ml/kg/day was achieved, in hope for faster feeding advancement as a result of reduced gastric distention and possibly improved respiratory tolerance.

Study Population:

Subjects included were neonates with birth weight ≤1,250g who were admitted from January 2014 through December 2016. This timeframe encompasses two epochs of 18 months each, one before and one after the change in feeding intervals to compare outcomes between neonates who were fed Q3H and those who were fed Q2H.

Subjects who met any of the following criteria were excluded from the analysis: death prior to reaching 20ml/kg/day of enteral feeds, development of spontaneous intestinal perforation (SIP) or necrotizing enterocolitis (NEC) prior to reaching 20ml/kg/day or prior to transfer to our NICU, reaching 20 ml/kg/day after 30 days of life or prior to transfer to our NICU, congenital gastrointestinal anomalies, or if infants were not fed according to the feeding guideline.

Outcomes of Interest:

Primary outcomes were the number of days required to advance from 20ml/kg/day to 150 ml/kg/day, duration of TPN and number of central catheter days after achieving 20ml/kg/day until catheter removal.

Respiratory outcomes:

We compared respiratory outcomes including incidence of physiologic bronchopulmonary dysplasia (BPD) [15]; defined as oxygen requirement at 36 weeks corrected gestational age (CGA), severe BPD; defined as requiring positive pressure ventilation or fraction of inspired oxygen ≥ 30% at 36 weeks CGA [16], and CGA when infants were weaned off all respiratory support for >24 hours. To assess respiratory status during feeding advancement, we compared respiratory severity scores (RSS- the product of mean airway pressure and fraction of inspired oxygen x 100) [17], and the daily number of apnea, bradycardia or desaturation (ABD) events requiring intervention, on the days when each infant reached 30, 60, 90, 120, and 150ml/kg/day of enteral feeding.

Growth outcomes:

Growth metrics including time to regain birth weight, body weight over time, growth velocities at day of life (DOL) 14, 21, 28 and 42 (weight gain in g/kg/day averaged over the prior 7 days) and discharge anthropometric measurement percentiles were also analyzed.

Additionally, the volumes of enteral feeding at DOL 7, 14, 21, and 28 as a surrogate for feeding tolerance, peak serum bilirubin levels, incidence of pharmacological treatment of gastroesophageal reflux, incidence of NEC (Bell’s staging criteria II or greater)[18], and the occurrence of death prior to hospital discharge or prior to reaching full enteral feeding were compared between the two groups.

Statistical Methods:

For baseline characteristics, t-test was used for continuous variables and Chi-square test for categorical variables. Wilcoxon rank sum test was done for TPN and central catheter days due to the skewness. The difference in number of days to advance from 20 to 150ml/kg/day between the groups was examined by a multivariate linear regression with a log transformation. Baseline variables that showed significant difference were adjusted in the multivariate model as confounding covariates.

For the longitudinal outcomes (feeding volume and growth velocity at different postnatal age, respiratory severity score and apnea/bradycardia/desaturation events at different feeding volume), a linear mixed effect (LME) model was used with a covariance structure of autoregressive AR(1) to adjust for with-in subject correlation. Likelihood ratio test was then performed to assess the group effect in the LME model.

Results

Study population:

During the study period, 255 neonates with birth weight ≤1,250g were admitted to our NICU. 113 neonates were included, 59 were in the first epoch fed every 3 hours (Q3H) and 54 were in the second epoch with feeding every 2 hours (Q2H). 142 neonates were excluded, out of whom 65 (45%) achieved 20 ml/kg/day of feeds or greater and 21 (15%) had NEC or SIP prior to transfer to our NICU, 17 (12%) died prior to reaching 20 ml/kg/day and 12 (8%) were not fed according to feeding guideline. Other reasons for exclusions included; transfer out prior to reaching full feeds (7%), SIP or NEC prior to reaching 20 ml/kg/day (5%), congenital gastrointestinal anomalies (5%) and reaching 20 ml/kg/day after the first month of life (3%).

There were no significant differences upon comparing subjects’ maternal, perinatal and neonatal characteristics (Table 1) with the exception that the Q2H group included a higher percentage of males compared to Q3H (59.3% vs. 40.7%, P = 0.048). There were no differences in the DOL or CGA when neonates achieved 20 ml/kg/day of enteral feeding (Table 1).

Table 1.

Subjects maternal, perinatal and neonatal characteristics comparison

		Q3H (N = 59)	Q2H (N = 54)	P value
Gestational age, weeks		27.4 ± 2.3	26.7 ± 1.9	0.09
Birth weight, g		905 ± 217	884±212	0.59
Small for gestational age		11 (18.64)	4 (7.41)	0.09
Male sex		24 (40.7)	32 (59.3)	0.048
Maternal age, years		30.02 (7.21)	30.85 (4.85)	0.47
Maternal race				0.08
	White	21 (35.6)	14 (25.9)
	Black	1 (1.7)	7 (13)
	Hispanic	25 (42.4)	19 (35.1)
	Asian	3 (5)	7 (13)
	Other	9(15.3)	7 (13)
Maternal illicit drug abuse		1 (1.7)	6 (11.1)	0.053
Antenatal steroids		45 (76.27)	43 (79.63)	0.67
Antenatal magnesium
sulfate		38 (64.41)	32 (59.26)	0.57
Cesarean delivery		46 (78)	41 (76)	0.91
Prolonged rupture of
membranes		12 (20.3)	11 (20.4)	0.93
5-minutes Apgar score*		7(5–9)	8(6–8)	0.09
Patent ductus arteriosus
Treatment				0.62
	Medical	7 (11.9)	4 (7.4)
	Surgical	6 (10.2)	9 (16.7)
Intraventricular hemorrhage
grade III or higher		7 (11.9)	6 (11.1)	0.9
DOL at 20 ml/kg/day, days*		9(7–15)	9(7–19)	0.19
CGA at 20 ml/kg/day, weeks		28.8 (2.2)	28.35 (1.6)	0.21

Data are means ± SD. Data are number of subjects with a presenting variable, and values in parentheses are percent of each group.

^*Data are medians and interquartile range

Primary outcomes and multivariate analysis:

Sex was adjusted in the multivariate linear regression and log-transformation was used on the outcome to reduce skewness. The Q2H group required an average of 10% more days to advance from 20 to 150 ml/kg/day in comparison to the Q3H group, however it was not statistically significant with P = 0.054 (Table 2). Moreover, the Q2H group had an average of 16% more central catheter days (P = 0.02) and 17% more TPN days (P = 0.019) in comparison to the Q3H group (Table 2). Three neonates in the Q2H group were excluded from this analysis due to death prior to reaching full feeding.

Table 2.

Primary outcomes comparison

	Q3H (N = 59)	Q2H (N = 51)	P Value	Adjusted for gender P Value
Days to advance to full feeds	14 (14–16)	15 (14–20)	0.052	0.054
Central catheter days	10(10–13)	11 (10–18)	0.09	0.02
TPN days	10 (9–11)	10 (10–16)	0.027	0.019

Data are medians and interquartile range

Respiratory outcomes:

Comparing respiratory severity score (RSS) as a proxy for respiratory support level, Q2H feeding was associated with higher RSS at feeding volumes of 30, 60 and 90 ml/kg/day with an overall P= 0.01. After adjusting for gender, birthweight and gestational age, there was only a statistically significant difference in RSS between the two groups at feeding volume of 30 ml/kg/day (Table 3). There were no differences in the number of ABD events requiring intervention between the groups (P = 0.49). The model-based estimate with 95% confidence interval for RSS and ABD at different feeding volumes is shown in Figure 1. There were also no differences in physiologic BPD (Q3H vs. Q2H, 30% vs. 48%, P= 0.1), severe BPD (Q3H vs. Q2H, 8.5% vs. 14.8, P= 0.4) or CGA when neonates weaned off any respiratory support (Q3H vs. Q2H, 35 ± 2.9 weeks vs. 35.1 ± 2.5 weeks, P= 0.8).

Table 3.

Comparisons of respiratory severity scores (RSS) at different feeding volume between Q3H and Q2H.

Feeding volume	Q3H RSS	Q2H RSS	P Value	Adjusted P Value*
30 ml/kg/day	115 (93–138)	167 (132–201)	0.013	0.0412
60 ml/kg/day	118 (91–145)	164 (119–209)	0.028	0.0909
90 ml/kg/day	115 (84–147)	145 (121–170)	0.022	0.0960
120 ml/kg/day	108 (83–132)	130 (109–150)	0.089	0.3840
150 ml/kg/day	101 (77–125)	127 (106–148)	0.079	0.3293

Data are mean and 95% confidence interval

^*Adjusted for gender, birth weight and gestational age

Figure 1.

Longitudinal trend of respiratory severity score (A) and apnea/bradycardia/desaturation events (B) for Q3H and Q2H at different feeding volumes

Growth outcomes:

Time to regain birthweight was identical at 12 ± 4 days. There were no differences in weight, length and head circumference percentiles upon hospital discharge between the Q3H and Q2H groups (Table 4). There were also no significant differences in growth velocity at DOL 14 to 42 (Figure 2) represented by model-based average weekly weight gain in gm/kg/day (P= 0.62). Comparing body weight at DOL 14 to 42 (Figure 2) also showed no differences (P= 0.3–0.9).

Table 4.

Anthropometric measurements percentiles comparison between Q3H and Q2H

	Q3H (58)	Q2H (54)	P Value
Weight percentile	18.5 ± 18.7	26.1 ± 23.1	0.058
Length percentile	9.6 ± 16.8	10.4 ± 15.5	0.79
Head circumference percentile	26.2 ± 24.3	27.9 ± 26.8	0.73

Data are means ± SD.

Figure 2.

Growth velocity (A) and body weight (B) for Q3H and Q2H groups DOL 14 to 42

There was no difference in feeding tolerance when volumes of enteral feeding were compared at DOL 7, 14, 21, and 28 (P = 0.078). Peak bilirubin levels (mean ± SD) for Q3H vs. Q2H were 7.1 ± 2.4 mg/dL vs. 6.9 ± 2.5 mg/dL, P=0.12. There were 17 (28.8%) neonates in the Q3h group and 11 (20.4%) in the Q2H who required pharmacological treatment of gastroesophageal reflux, P=0.38. NEC rate was not different (Q3H vs. Q2H, 3.4% vs. 5.6%, P=0.7). There were no differences in incidence of death prior to hospital discharge (Q3H vs. Q2H, 1.7% vs. 9.3%, P=0.1) or prior to reaching full feeds (Q3H vs. Q2H, 0% vs. 5.6%, P=0.1).

Discussion

A limited number of studies have attempted to analyze outcomes related to different feeding intervals for preterm infants [10–13]. In our cohort of 113 neonates with birth weight ≤1,250g, feedings were introduced through a standardized feeding guideline with a change in feeding interval from every 3 hours to every 2 hours in July 2015 resulted in two epochs of 18 months each before and after the change.

We found that two-hourly feeding was associated with a greater number of days to advance from 20ml/kg/day to 150 ml/kg/day, however this difference was not statistically significant (P= 0.054). Similarly, Rudiger et al[10] reported that full enteral feeding in a cohort of 74 extremely low birth weight infants was achieved at a median age of 20 and 26 days in the Q3H and Q2H group respectively (p = 0.15). They concluded that 100 subjects were likely needed per group to show a decrease in number of days to reach full enteral feeding in the Q3H group with statistical difference.

In healthy adults there is post-prandial increase in the superior mesenteric artery (SMA) blood flow with a latency of approximately 1 hour [19, 20]. Similar findings in term neonates have been described [21, 22]. For preterm neonates, it was reported that there is an effect of feeding interval on the latency of SMA blood flow with the more frequent the feeds, the more sustained is the inter-feed hyperemia[23]. Could the persistent hyperemic state in the splanchnic bed of the preterm neonate fed at Q2H predispose to less tolerance of feeding advancement?

Two randomized controlled trials [11, 13] compared between Q2H and Q3H feeding intervals in preterm neonates reported no differences in number of days to achieve full enteral feeding. However, both studies’ subjects had greater birth weight with mean 1,300g [11, 13] in comparison to our report and the study by Rudiger [10] with mean birth weight 900g.

In contrast to our data, DeMauro [12] reported that very low birth weight infants fed every 2 hours reached full feeding 3.7 days sooner than the Q3H group (95% confidence interval (CI) 1.6, 5.9). Infants fed Q3H were more likely to receive >28 days of TPN (odds ratio (OR) 4.7; 95% CI 1.5, 14.4), and were more likely to have feeds held for 7 days (OR 4.7, 95% CI 1.9, 11.7). Their study however has limitations as there was no protocol dictating the choice of feeding interval or the process of feeding advancement. There was also crossover between the Q2H and Q3H groups, and the feeding composition was not standardized i.e. both human milk and formula were used. Interestingly the Q2H group had better feeding advancement tolerance despite subjects being smaller, younger, required longer days of trophic feeds and utilized less human milk [12], all are potential factors that should have contributed into longer time to reach full feedings. We wonder if the Q2H group faster feeding advancement reported by the authors [12] was caused by practice variation.

In our study Q3H feeding was associated with less TPN and central catheter days. Rudiger [10] reported that Q3H in comparison to Q2H feeding interval was associated with shorter duration of umbilical venous catheter (median 4 vs. 5 day, P= 0.045). Peripherally inserted central catheter duration was also shorter but not statically significant (median 14 vs. 32 days, P= 0.23). The number of subjects in each category was different with obvious crossover, however the authors did not report on combined central catheter days.[10]

Rudiger et al[10] reported Q2H feeding was associated with less CPAP days. They speculated that lower volume administered Q2H did not alter lung mechanics as much as a higher volume administered Q3H. We had changed our feeding protocol from Q3H to Q2H based on the hypothesis that less gastric distention would be associated with better respiratory tolerance and faster feeding advancement. To test this hypothesis, we compared several metrics between the groups to assess respiratory tolerance during feeding advancement such as RSS and ABD events at different feeding volumes. The RSS is a previously validated metric to assess the degree of respiratory support.[17, 24–26] We also compared longer term outcomes such as physiologic BPD, severe BPD and CGA when neonates weaned off respiratory support. There were no differences between the groups in any of the respiratory related variables. The higher RSS for the Q2H group at 30 ml/kg/day reflects a difference in the severity of respiratory illness between groups, as infants in both groups were fed every 3 hours at 30 ml/kg/day. The change to 2 hours interval feeding in the Q2H group occurred when volume of 40 ml/kg/day was achieved.

Another hypothesis introduced by Rudiger et al [10] was that every 2 hours feeding intervals promoted intestinal motility more than every 3 hours intervals and thus may increase fecal bilirubin excretion and could explain fewer days of phototherapy among the Q2H group in their cohort. We found no difference in peak bilirubin level among the groups which complement the results from other studies. [11, 13]

The study’s limitations include being a retrospective study performed at single center with relatively small numbers of subjects (N=113). However, our report has unique strengths including a standardized feeding guideline which detailed feeding advancement, fortification timing, universal human milk use and a feeding tolerance assessment tool. In our NICU breastmilk handling and preparation is centralized at the hospital nutrition lab with barcoding system as an additional layer of accuracy and safety. [27] From inception, the guidelines were designed to incorporate nursing autonomy to advance feeding with a systematic feeding tolerance assessment tool. Adherence to the guidelines has limited practice variability and has resulted in less interruption in enteral feeding nutrition, thus promoting efficient advancement to full feedings.

The present study supports that every three hours feeding in very preterm neonates is associated with less TPN and central catheter days in comparison to every two hours feeding, with no difference in respiratory tolerance, growth metrics or other outcomes. After 18 months period of Q2H feedings, our group reviewed the perceived advantages and disadvantages associated with Q2H feeding. Nursing hours and costs to the centralized nutrition lab preparing 12 feedings per day were notable. We felt there were no compelling outcomes observed to offset these concerns. Based on the local review and subsequently the study results we have changed our standardized feeding guideline from every 2 hours back to every 3 hours feeding intervals.

Highlights.

• Three-hourly feeding was associated with faster advancement to full enteral feeding in very preterm infants.

• Two-hourly feeding was associated 16% more central catheter days and 17% more parenteral nutrition days.

• There were no differences in respiratory outcomes or growth metrics between the two feeding intervals.

Abbreviations:

GA

gestational age

Q2H

every two hours feeding

Q3H

every three hours feeding