PLoS ONE
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Impact of introducing a standardized nutrition protocol on very premature infants’ growth and morbidity
DOI 10.1371/journal.pone.0232659 , Volume: 15 , Issue: 5

Table of Contents

Highlights

Notes

Abstract

BackgroundInappropriate nutritional intake in premature infants may be responsible for postnatal growth restriction (PGR) and adverse long-term outcomes.ObjectiveWe evaluated the impact of an updated nutrition protocol on very premature infants’ longitudinal growth and morbidity, and secondly the compliance to this new protocol.DesignAll infants born between 26–32 weeks gestation (GA) were studied retrospectively during two 6-month periods before (group 1) and after (group 2) the introduction of an optimized nutrition protocol, in a longitudinal comparative analysis.Results158 infants were included; 72 before and 86 after the introduction of the protocol (Group 1: (mean±SD) birthweight (BW) 1154±276 g, GA 29.0±1.4 weeks; Group 2: BW 1215±332 g, GA 28.9±1.7 weeks). We observed growth improvement in Group 2 more pronounced in males (weight z-score) at D42 (−1.688±0.758 vs. −1.370±0.762, p = 0.045), D49 (−1.696±0.776 vs. −1.370±0.718, p = 0.051), D56 (−1.748±0.855 vs. −1.392±0.737, p = 0.072), D63 (−1.885±0.832 vs. −1.336±0.779 p = 0.016), and D70 (−2.001±0.747 vs. −1.228±0.765 p = 0.004). There was no difference in females or in morbidities between the groups. We observed low compliance to the protocol in both groups: similar energy intake but higher lipid intake in Group 1 and higher protein intake in Group 2.ConclusionThe quality of nutritional care with a strictly-defined protocol may significantly improve weight gain for very preterm infants. As compliance remained low, an educational reinforcement is needed to prevent PGR.Clinical trial registrationThis retrospective study was registered by ClinicalTrials.gov under number NCT03217045, and by the CNIL (Commission Nationale de l’Informatique et des Libertés) under study number R2015-1 for the Maternity of the CHRU of Nancy.

Wittwer, Hascoët, and Ehrhardt: Impact of introducing a standardized nutrition protocol on very premature infants’ growth and morbidity

Introduction

Inappropriate nutrition is an issue for premature infants as it may be responsible for postnatal growth restriction (PGR) and increased morbidity [14]. Embleton [2] demonstrated that 55% of PGR [5] were related to a cumulative deficit in energy and protein intake. Malnutrition in the first weeks of life is associated with short stature and adverse outcomes in adulthood [68]. The goal of nutrition is to allow body composition and outcomes similar to those of infants born at term [3,9]. Optimizing nutrition needs to start from birth as the window for PGR prevention and catch-up growth is rather narrow [10]. The prevention of nutrient deficits may be achieved through the implementation of optimized nutritional policies. More recent studies also demonstrated benefits on growth with the implementation of nutritional strategies [1113].

We decided therefore to introduce a standardized nutritional protocol in our NICU and study outcomes on premature infants (including growth and morbidity).

In our unit, parenteral and enteral nutrition used to be adjusted according to the 2004 guidelines defining global nutritional intakes [14,15]. From May 1st , 2014, we decided to update our policy according to more recent ESPGHAN and other recommendations [1619] available at the time of the study, and to follow a strict nutritional protocol rather than only global guidelines.

The objective of this study was to evaluate the longitudinal impact of implementing this strictly-defined nutrition protocol on very premature infants’ growth and morbidity using a before/after comparison design, with a 6-months wash-out period. The secondary objective was to evaluate physicians’ compliance to the standardized protocol.

Patients and methods

Study design

All infants born at the maternity hospital and hospitalized in our NICU were studied retrospectively during two 6-month periods, separated by a 6-month washout period, from May 1 to October 31, 2013 (group 1) then from May 1 to October 31, 2014 (group 2), which occurred before and after the introduction of an optimized nutrition protocol. We performed a longitudinal comparative analysis between these two independent groups. Collection of data from the infants’ files was standardized.

Methods

This retrospective study was registered by ClinicalTrials.gov under number NCT03217045, and by the French ethic committee “Commission Nationale de l’Informatique et des Libertés” (CNIL) under study number R2015-1 for the Maternity of the CHRU of Nancy. Parents’ consent for using the collected clinical data of their infant was obtained and signed at admission.

Infants born between 26 to 32 weeks gestation (GA) and admitted to our NICU were included in the study. Infants who died before discharge or presented with any congenital malformation were excluded. The primary outcome measure was to evaluate the impact of introducing a well-defined nutrition protocol on the longitudinal growth of the infants up to the time of discharge. Weight was assessed by daily measurements, every morning, as defined in our routine policy of care. To account for variations in gestational and postnatal age, body weight was converted into a z-score using the Olsen preterm infants’ reference growth chart [20].

In order to account for the infants’ size at birth, we also analyzed each point z-score difference from birth z-score. PGR was defined by a weight z-score <-1,5 DS before 36 post conceptual age (PCA) or discharge [21].

Secondary outcomes were the incidence of necrotizing enterocolitis (NEC) as defined by Bell [22]; interruption of nutrition and its duration; duration of parenteral nutrition; incidence of late onset sepsis; patent ductus arteriosus (PDA) requiring treatment; bronchopulmonary dysplasia (BPD) defined as the use of supplemental oxygen at 28 days of life; and chronic lung disease (CLD) defined as the need for supplemental oxygen at 36 weeks PMA. Antenatal steroids rate, ibuprofen, caffeine, and doxapram treatment were also recorded in the infants’ files.

Finally, we evaluated weekly actual nutritional intake of the infants fed according to the guidelines compared to the new protocol to define the compliance of our team to the 2 policies. Enteral and parenteral nutrition were modified according to ESPGHAN recommendations. Proteins were prescribed at a higher rate in group 2, with a onset at birth, of 1.5 vs. 0.5 g/kg/d, and a goal of 3.5 vs. 2.5 g/kg/d. Lipids were prescribed earlier in group 2 and at higher rate of 1 g/kg/d on day 1 vs. 0.5 g/kg/d starting on day 2, with a goal of 3.5 vs. 3 g/kg/d. Enteral nutrition was initiated from day 1 in both groups but with an increase of 15–20 in group 2 vs.10-15 ml/kg/d in group 1 (Table 1).

Table 1
Old guidelines compared to new protocol.
  Day of lifeD0D1D2D3D4D5D10D15
Fluids (mL/kg/d)Old guidelines7090160160–180
New protocol8090+10–20+10–20+10–20130–160160160
Carbohydrates (g/kg/d)Old guidelines6–6,510–1220–24 
New protocol68–10+1+1+112–141818
Proteins (g/kg/d)Old guidelines0,50,5222–3.5
New protocol1,52+0,5+0,5+0,52,53,53,5
Lipids (g/kg/d)Old guidelines00,5 à 11 to 222–3.5
New protocol01+0,5+0,5+0,533,53,5
Sodium(mEq/kg/d)Old guidelines01+0.5+0.5+0.51,5 to 23 to 43 to 4
New protocol01+1–2+1–2+1–22 to 444
Enteral NutritionOld guidelines01–2 mL/kg/d+ 8–10 mL/kg/d+ 8–10 mL/kg/d+ 8–10 mL/kg/d+ 8–10 mL/kg/d100–150 mL/kg/d150 mL/kg/d
New protocol06x 1 to 2 mL+20 mL/kg/d+20 mL/kg/d+20 mL/kg/d80 mL/kg/d160 mL/kg/d160 mL/kg/d
+1% Fortifier+3% Fortifier+3% Fortifier
Energy (kcal/kg/d)Old guidelines 50    100
New protocol 50   90120 

Use of mother’s own milk was promoted, but when it was not available banked donor’s milk was used. Milk fortification was initiated from 80 ml/kg/d in both groups.

The parenteral solutions were prepared by the hospital pharmacy according to medical prescription.

In order to evaluate compliance to the protocol, energy, protein, lipid, carbohydrate, and sodium intake were reported weekly for each patient after collection of the raw data in the patient’s individual daily file. Human milk content was assumed to be an average of 70 kcal/100 mL with 1.2 g protein, 4.2 g fat, and 7 g/100 mL carbohydrate[23]. Milk fortification and preterm infant formulas were also used and their formula compositions and nutritional content were based on the product labels.

Each intake (protein, carbohydrate, lipid) was compared to the theoretical recommendations of each nutritional protocol in use for the period. When the intake was out of the range of the recommendations, it was considered as not compliant to the protocol for the period.

Compliance to guidelines for each intake in the two groups was calculated by the average of compliant prescriptions compared with recommendations for each nutritional protocol in use for the period (in percentage +/- standard deviation).

Statistics

Normally distributed data, assessed by a Shapiro-Wilk test of normality, are presented as mean values with SD; non-normally distributed data are presented as medians with the range of values. To evaluate differences between groups, we used the Student t test for continuous variables and the Chi2 test or Fisher exact test when appropriate for categorical variables. For continuous variables not normally distributed, we used the Mann-Whitney U test. Categorical data are presented as actual numbers or percentages. Postnatal evolution of growth variables was assessed longitudinally by z-score. Observed differences were considered statistically significant if P < 0.05. All analyses were performed with SYSTAT 13 software (2009, Systat Software Inc®, San Jose CA, USA).

Results

Demographic and clinical characteristics of the population

From May to October 2013, 85 eligible infants were included in the study. Thirteen were excluded: twelve died, and one file was lost. The remaining 72 infants (Group 1) had a mean birthweight (BW) of 1154 ± 276 g, and a mean GA of 29.0 ± 1.4 weeks. From May to October 2014, 90 eligible infants were included in the study. Four were excluded: two died and two files contained missing data. The remaining 86 infants (Group 2) had a mean BW of 1215 ± 332 g and a mean GA of 28.9 ± 1.7 weeks.

The clinical characteristics of the study population are displayed in Table 2. The groups were similar, with no significant differences for sex, birth weight, GA, prenatal steroids, PDA, or BPD. We observed a significant difference for PDA requiring surgery and for the duration of treatment with doxapram which did not impact the results (Table 2).

Table 2
Clinical characteristics and outcomes of the study population.
Group 1 (n = 72)Group 2 (n = 86)Total population (n = 158)p
Males, n (%)37 (51.39)44 (51.16)81 (51.27)0.977
Mean birth weight (SD), g1154 (±276)1215 (±332)0.21
Mean birth weight z-score (SD)−0.494 (±0.140)−0.426 (±1.096)0.705
Mean gestational age (SD), weeks29.0 (±1.4)28.9 (±1.7)0.69
Any prenatal steroids, n (%)66 (91.67)76 (88.4)142 (89.9)0.632
Complete course29 (40.3)38 (44.2)67 (42.4)0.266
PDA, n (%)17 (23.6)13 (15.1)30 (19)0.187
PDA surgically closed05 (5.8)5 (3.16)0.008
PDA medically closed15 (20.8)13 (15.1)28 (17.7)0.705
Doxapram, n (%)21 (29.2)28 (32.6)49 (31)0.611
Mean duration, (SD) (days)10.8 (±11.54)22.89 (±11.73)0.001
BPD, n (%)35 (48.6)35 (40.7)70 (44.3)0.7
CLD, n (%)18 (25)20 (23.3)38 (24.1)0.622
NEC, n (%)18 (25)14 (16.3)33 (20.9)0.17
Stage 2 of Bell, n (%)13 (18)8 (9.3)21 (13.3)0.13
Stage 2B of Bell, n (%)03 (3.5)3 (1.9)0.13
Stage 3 of Bell, n (%)01 (1.2)1 (0.6)0.13
Alimentation withdrawal, n (%)43 (59.7)42 (48.8)85 (53.8)0.196
Duration of alimentation stop, days6.4 (±6.1)5.9 (±5.4)0.642
CVL, n (%)70 (97.2)74 (86.0)144 (91.1)0.051
CVL duration, days15.7 ±10.515.3 ±9.40.803
Infection, n (%)32 (44.4)40 (46.5)72 (45.6)0.743
Parenteral alimentation duration, days15.8 (±9.1)14.1 (±8.3)0.254
Hospitalization duration, days54.9 (±27.1)51.5 (±31.7)0.314
Age at discharge, WGA36.8 (±3.5)36.1 (±3.7)0.166
BPD: bronchopulmonary dysplasia; CLD: chronic lung disease; CVL: central venous line; NEC: necrotizing enterocolitis; PDA: patent ductus arteriosus; SD: standard deviation; WGA: weeks of gestational age.

Primary outcome: Impact on longitudinal raw weight and weight z-score

Postnatal weight loss occurred in both groups during the first week of life, with no difference in the minimal global weight on day 7 (1121±233 g in Group 1 vs. 1159±305 g in Group 2; p = 0.385). Mean weight loss was 2.8% in Group 1 and 4.9% in Group 2 (NS). There was no significant difference in raw weight between the two groups from birth to day 77. However, when looking at weight z-scores, we observed significant differences between the 2 periods from day 42 up to day 70 (Fig 1). Of note, z-score decrease was significantly smaller (about 0.5 z-score) and delayed in Group 1 as compared to Group 2 (day 70 vs. day 21, respectively) (Fig 1).

Longitudinal weight z-score evolution from birth to day 77.
Fig 1
D = day, *p <0.05.Longitudinal weight z-score evolution from birth to day 77.

Looking at weight z-score evolution with regards to gender, we observed a significant difference between male and female infants: there was a significant difference in males from day 42 to day 70 (Fig 2A), but not in females (Fig 2B). However, when taking into account the weight z-score at birth, the analysis of each time point difference from birth was always above -1 for boys (Fig 3A) and without significant difference between groups or sex (Fig 3A and 3B).

A: Longitudinal weight z-score evolution from birth to day 77 in males. D = day, *p <0.05. B: Longitudinal weight z-score evolution from birth to day 77 in females. D = day, p > 0.05 for all values.
Fig 2
A: Longitudinal weight z-score evolution from birth to day 77 in males. D = day, *p <0.05. B: Longitudinal weight z-score evolution from birth to day 77 in females. D = day, p > 0.05 for all values.
A: Longitudinal weight delta z-score evolution from birth to day 77 in males. D = day, p > 0.05 for all values. B: Longitudinal weight delta z-score evolution from birth to day 77 in males. D = day, p > 0.05 for all values.
Fig 3
A: Longitudinal weight delta z-score evolution from birth to day 77 in males. D = day, p > 0.05 for all values. B: Longitudinal weight delta z-score evolution from birth to day 77 in males. D = day, p > 0.05 for all values.

Secondary outcomes

We evaluated the potential impact of our new standardized protocol on population morbidity (Table 2). We evaluated the tolerance of enteral nutrition because of a faster increase in enteral nutrition volume, but found no difference between the two groups for the rate of NEC.

While our new protocol allowed for faster achievement of full enteral nutrition, there was no significant difference in the duration of hospitalization, central venous line and parenteral nutrition duration (which correspond with full enteral feeding), or the rates of infection (Table 2).

Compliance to guidelines or standardized protocol

We observed low compliance to the protocol in both groups with regards to protein, lipid, and caloric intakes with a high variability. Fig 4 presents the nutrition data up to D42. There were no further differences between the groups from D42 onwards.

Median and variability (IQR) for (A) energy, (B) protein, and (C) lipid intakes from birth to day 42.
Fig 4
D = day, *p <0.05.Median and variability (IQR) for (A) energy, (B) protein, and (C) lipid intakes from birth to day 42.

Concerning caloric intakes, there was low compliance in both group throughout the observation period, but no significant differences in the median caloric intake between the 2 groups (Fig 4A). Compliance for caloric intake was 27.9%+/-19.8 in group 1 and 23%+/- 26.1% in group 2. Of note, Group 2 received a significantly higher protein intake and Group 1 received a significantly higher lipid intake from day 0 to day 42. The median protein intake varied from 1.2 to 3.1 g/kg/d at day 42 in Group 1 and from 1.5 to 3.5 g/kg/d at day 42 in Group 2, with significant differences between the two groups from day 7 to day 42 (Fig 4B and 4C). Compliance to guidelines was also low for protein intakes (53% +/-35.2 in group 1 and 38.6% +/- 26.4 in group 2), and for lipid intakes (26.9% +/- 25.6 in group 1 and 36.6% +/- 31 in group 2).

Discussion

In this study, we showed that the introduction of a strict nutritional protocol, designed according to the most recent recommendations, led to a higher weight gain velocity from the sixth to the eleventh week of life with a limitation of PGR in very preterm infants. We observed a significantly attenuated drop in weight z-score compared with infants receiving nutrition based on the older recommendations. The difference was not statistically significant after 40 weeks PCA because the number of infants discharged from the hospital increased, thus the analysis lacked power. Our results also showed that the minimal z-score was higher and occurred earlier in Group 2 than in Group 1, with a catch-up effect after day 35 not observed in Group 1. These results suggest that a strictly implemented nutritional protocol may indeed improve growth in very preterm infants, limiting PGR severity before discharge Roggero et al.[12] studied 102 very low birth weight infants prospectively after the implementation of a new nutritional practice, compared to 69 infants from an historical cohort. They showed that discharged weight z-score was significantly higher in the intervention group (-1.7 vs 2.2 p = 0.001) which is consistent with our study. Likewise, Rochow et al. [13] introduced a set of evidence-based strategies in 123 premature infants, compared to 115 controls in a pre/post study design. They showed that optimization of early nutrition was associated to birth weight return 3 days earlier than the control group and an increased weight at 36 weeks PCA (delta = 260g, p<0.05) [13].

Of note, there was no difference in raw weight between the two groups, confirming that raw weight is not a good indicator for following infants’ growth in daily practice. Indeed, weight z-score is a better predictor to diagnose growth restriction and adjust nutrition [24].Using raw weight trajectory in 396 patients, after introduction of improved nutritional guidelines, Andrews et al. [11] found that the median change between birth and 36 weeks PCA was -0.27 SD score which is consistent with our findings.

Early nutritional deficits were not regained before hospital discharge in our study. This could be explained by poor compliance to the protocol. A significant part of PGR in preterm infants has been linked to nutritional deficit, which is mainly caused by fear of metabolic intolerance or NEC [2,3]. Looking at individual infant’s files to verify their actual nutrition intake with regards to guidelines (Group 1) or the strict protocol (Group 2), we observed low compliance in both groups for the first month of life and throughout the observation period. This is consistent with Lapillonne et al [25]. Of note, we observed a significantly higher protein intake in Group 2, as expected when using the new protocol, but a significantly higher lipid intake in Group 1, with no differences in caloric intake between both groups. Maybe this low compliance was due to higher expectations, so despite higher intakes, compliance was not reached.

Thus, our two groups were demographically and clinically comparable, but their nutritional intake was qualitatively different. This point raises the question about the quality of growth in formerly premature infants [26]. We can speculate that more protein intake is better because growth velocity is increased in our study. Previously published studies confirm that earlier and higher protein intake by preterm infants may increase weight gain velocity. Also they may achieve a leaner mass closer to that of full term infants [24]. We need to improve our practice and strictly follow the nutritional protocol. Early growth improvement is very important because there seems to be a window, in the first weeks of life, when interventions may have an impact [27,28]. We showed that despite appropriate energy intake and more protein intake, there is a catch-up growth but delayed by about one month. We speculate that lower protein intake may have a delayed maturation effect due to cumulative deficit during the first month [2].

Evaluating weight z-score, there was a significant growth improvement between the two periods for males only. This difference observed in growth trajectory is consistent with Christmann and Hack long term observations [29, 30]. However, this difference may also be due in part to the fact that males had lower weight z-scores at birth than females in our population. Therefore, we further analyzed the data accounting for the weight of the infants at birth using delta z-score from birth. We did not find significant differences anymore but delta z-score were stable with time and always above -1, without significant difference between sex but with a trend of a worse evolution in female from Day 56 (Fig 3B).

This suggests that the introduction of a nutrition protocol updated on the last guidelines had an impact on nutrient delivery, but the impact on growth was not what we expected because of low compliance to the protocol. In addition, as we worked on a cohort we might have had a lack of power.

We evaluated the effects of our new protocol on clinical outcomes other than growth and did not find any difference except a higher rate of surgery for PDA in Group 2, and longer doxapram treatment in Group 2. These differences may be explained by a better availability of pediatrics surgeons from 2014, and by a modification in our protocol for doxapram treatment between the two periods. Unfortunately, due to the retrospective design of our study, no data were available on respiratory support (mechanical ventilation and/or continuous positive airway pressure) to confirm this speculation.

The rate of NEC was lower in group 2 but not statistically different despite that enteral nutrition was increased faster using the new protocol. This is consistent with good tolerance of early “aggressive” nutrition for preterm infants [2].

The two groups were similar for the duration of central venous line and parenteral nutrition. We expected a shorter duration with the new protocol because enteral feeding was increased faster and the central venous line should be removed earlier than before (140 ml/kg/day of enteral feeding after versus 160 ml/kg/day before). This part of the protocol was obviously not fulfilled. These results demonstrate that when a new protocol is introduced in a unit, medical caregivers must be trained and that a time for adaptation is needed, as a recent study suggested it [31].

The strengths of the study include the extensive retrospective standardized collection of data as well as the routinely measured weight values throughout the study period.

Conversely, our study has limitations. It was not a randomized trial; however, it would not be ethical to voluntarily limit nutritional support in some infants. Confounding factors, such as medical treatment and mechanical ventilation could have affected the results, but were not investigated in this cohort study. However, we may speculate that a 6-month washout period was short enough to prevent significant modifications in our practice and allow for a comparison of both cohorts. Other limitations include the retrospective collection of nutritional data and a high dropout rate due to hospital discharge. Thus, we cannot exclude that the lack of difference observed from D70 onwards may be related to a lack of power. There is also variability in the protein and the fat composition of human milk that we were not able to determine at the time of the study [32].

Conclusion

Feeding preterm neonates is extremely challenging. Optimal nutrition with a low incidence of complications requires a well-organized structure. Hospital staff must acknowledge that preterm birth is also a nutritional emergency which could result in serious short- and long-term detrimental effects. Our data suggest that the quality of nutritional care using a strictly-defined protocol may improve weight gain for very preterm infants. The results are promising since this policy was able to limit PGR at discharge.

This study was based on an internal audit and we noted that what we think we are doing is not always what we are really doing. That kind of evaluation may be recommended to all units to point out what improvements can be made for optimizing nutritional care for these vulnerable infants.

Abbreviations

BPD

bronchopulmonary dysplasia

BW

birth weight

CLD

chronic lung disease

CVL

central venous line

DGOS

Direction générale de l’offre de soins

ESPGHAN

European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee

GA

gestational age

HM

human milk

IUGR

intra uterine growth restriction

MOM

mother’s own milk

NEC

necrotizing enterocolitis

NICU

neonatal intensive unit care

PCA

post conceptual age

PDA

patent ductus arteriosus

PGR

postnatal growth restriction

PMA

post menstrual age

SD

standard deviation

WGA

weeks of gestational age

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    C Maas, CF Poets, AR Franz. . Avoiding postnatal undernutrition of VLBW infants during neonatal intensive care: evidence and personal view in the absence of evidence. Arch Dis Child Fetal Neonatal Ed. 2015;100(1):, pp.F76–81. , doi: 10.1136/archdischild-2014-306195

29 

    V Christmann, N Roeleveld, R Visser, et al. The early postnatal nutritional intake of preterm infants affected neurodevelopmental outcomes differently in boys and girls at 24 months. Acta Paediatr2017;106(2):, pp.242–9. , doi: 10.1111/apa.13669

30 

    M Hack, M Schluchter, S Margevicius, et al. Trajectory and correlates of growth of extremely-low-birth-weight adolescents. Pediatr Res2014;75(2):, pp.358–66. , doi: 10.1038/pr.2013.209

31 

    BM Stefanescu, M Gillam-Krakauer, AR Stefanescu, et al. Very low birth weight infant care: adherence to a new nutrition protocol improves growth outcomes and reduces infectious risk. Early Hum Dev2016;94:, pp.25–30. , doi: 10.1016/j.earlhumdev.2016.01.011

32 

    JM Hascoet, M Chauvin, C Pierret, et al. Impact of Maternal Nutrition and Perinatal Factors on Breast Milk Composition after Premature Delivery. Nutrients2019;11:, pp.E366, doi: 10.3390/nu11020366

9 Jan 2020

Submitted filename: 200109 WITTWER et HASCOET Plos one highlight correction.doc

7 Feb 2020

PONE-D-19-35465

Impact of introducing a standardized nutrition protocol on very premature infants’ growth and morbidity

PLOS ONE

Dear Dr. WITTWER,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I kindly ask you to address all points raised by both reviewers in a revised version of the ms including a detailled point-by-point response to each comment addressing the changes in the revised version. Please pay special attention to the SDS and z-score discrepancies and the proper and detailled inclusion of congruencies and disparities of the presented results in comparison to the published literature. 

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper has been improved by the responses the authors have made to the reviewer comments, and I am appreciative of their efforts. However, there are a few more issues which would improve the paper further if they were to be addressed.

The main issue is that, whilst they have now added in something about the changes in SDS from birth in their groups (line 139-140), they have not shown this data properly, nor integrated well into the paper. It seems there were not significant differences between the groups with regard to change in SDS from birth, and this is an important finding. As change in SDS from birth takes into account the differences in birth weight in each group, the fact that the authors could not demonstrate a significant improvement in the fall in SDS from birth to each time point, means that their intervention perhaps was not as effective at improving growth as they suggest it is. The change in SSD is more meaningful that raw SDS, so for me this non-significant difference supersedes the significant findings between the two groups in terms of raw z score. The authors need to better integrate and acknowledge the new results in to the paper (as a table or figure) and need to comment more on this non-significant finding in the results. This is not to say that the work here is not important- they demonstrated that their intervention had a significant impact on nutrient delivery, and this is important. The fact it doesn’t to appear to have made an impact on growth may fit with their finding that compliance with the new practices were poor, and is again important and needs further thought and comment. In relation to this, the authors compared group using t-tests or mann-whitney tests. If the growth and nutrition data is normally distributed, then they should use linear regression where possible rather than t tests, as this would enable them to adjust for baseline factors between groups such as sex, gestational age and weight at birth. This may also impact on their results

My other main comment, is that whilst the authors have now included some pertinent references of similar studies (Andrews et al. Rogerro et al and Rochow et al), they have only included these in the introduction and not the discussion, which needs to be addressed. In the discussion, the authors need to comment on how their findings are similar to or differ from these earlier studies, and where there are differences, what are they and why do the authors think this occurred?

There other some other, more specific, minor issues which need to be addressed:

Abstract- this is fine though the results section is packed with dense figures and is a little hard to read, The authors need to make their headlines clear here

Line 73- this should read SDS and not DS. Also, WOG (week of gestation) would be better replaced with the term Post-conceptual Age (PCA). Figures 1 and 2 should also use SDS and not DS in the y axis labels

Line 136- the authors still use the term ‘significantly more important’ and I’m not sure what they mean by this. Looking at the results I think they mean ‘significantly smaller’, but this needs to be amended

Reviewer #2: The authors have addressed most of my comments as far as available.

As with many retrospective studies some relevant data are missing which is addressed in the discussion.

I have a few minor comments to be addressed.

Page 11 line 209 I think it should read We speculate that lower protein intake may have a delayed maturation effect......

Page 11 line 218. I would add a sentence here that unfortunately there were no data available on respiratory support (echanical ventilation and/or CPAP). I expect that that would be the most important factor why longer doxapram was given?

The references are still inconsistent including some french words and eg ref 33 is incomplete.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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26 Mar 2020

Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files

As requested, we included the tables as part of the main manuscript

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policyhttp://www.plosone.org/static/policies.action#sharing requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper has been improved by the responses the authors have made to the reviewer comments, and I am appreciative of their efforts. However, there are a few more issues which would improve the paper further if they were to be addressed.

The main issue is that, whilst they have now added in something about the changes in SDS from birth in their groups (line 139-140), they have not shown this data properly, nor integrated well into the paper. It seems there were not significant differences between the groups with regard to change in SDS from birth, and this is an important finding. As change in SDS from birth takes into account the differences in birth weight in each group, the fact that the authors could not demonstrate a significant improvement in the fall in SDS from birth to each time point, means that their intervention perhaps was not as effective at improving growth as they suggest it is. The change in SSD is more meaningful that raw SDS, so for me this non-significant difference supersedes the significant findings between the two groups in terms of raw z score. The authors need to better integrate and acknowledge the new results in to the paper (as a table or figure) and need to comment more on this non-significant finding in the results. This is not to say that the work here is not important- they demonstrated that their intervention had a significant impact on nutrient delivery, and this is important. The fact it doesn’t to appear to have made an impact on growth may fit with their finding that compliance with the new practices were poor, and is again important and needs further thought and comment.

As requested, we added in the Results section additional Figures (Fig 3A for boys and Fig.3B for girls) to illustrate the delta z-score analysis;

In addition, we developed the comments on this non-significant finding in the discussion.

In relation to this, the authors compared group using t-tests or Mann-Whitney tests. If the growth and nutrition data is normally distributed, then they should use linear regression where possible rather than t tests, as this would enable them to adjust for baseline factors between groups such as sex, gestational age and weight at birth. This may also impact on their results

As stated in the Method section, we tested the normality of the data with a Shapiro-Wilk test of normality. Unfortunately, the fit is poor for several variables and significant for one of them indicated a lack of normal distribution. Therefore it is not appropriate to perform a linear regression for these data. In addition, the difference observed between each time point is rather low which allow us to speculate that a linear regression would not show any significant correlation.

Using weight z-score adjusted for sex may be considered as a substitute for the impact of sex, gestational age and post-natal age. The analysis of delta weight z-score from birth should cope for weight at birth.

My other main comment, is that whilst the authors have now included some pertinent references of similar studies (Andrews et al. Rogerro et al and Rochow et al), they have only included these in the introduction and not the discussion, which needs to be addressed. In the discussion, the authors need to comment on how their findings are similar to or differ from these earlier studies, and where there are differences, what are they and why do the authors think this occurred?

As requested, we developed the 3 studies whose findings are consistent with our own data in the discussion section of the manuscript.

There other some other, more specific, minor issues which need to be addressed:

Abstract- this is fine though the results section is packed with dense figures and is a little hard to read, The authors need to make their headlines clear here

Line 73- this should read SDS and not DS. Also, WOG (week of gestation) would be better replaced with the term Post-conceptual Age (PCA). Figures 1 and 2 should also use SDS and not DS in the y axis labels

Line 136- the authors still use the term ‘significantly more important’ and I’m not sure what they mean by this. Looking at the results I think they mean ‘significantly smaller’, but this needs to be amended

All these points have been corrected.

Reviewer #2: The authors have addressed most of my comments as far as available.

As with many retrospective studies some relevant data are missing which is addressed in the discussion.

I have a few minor comments to be addressed.

Page 11 line 209 I think it should read We speculate that lower protein intake may have a delayed maturation effect......

Page 11 line 218. I would add a sentence here that unfortunately there were no data available on respiratory support (echanical ventilation and/or CPAP). I expect that that would be the most important factor why longer doxapram was given?

All these points have been corrected and a sentence added in the discussion as requested

The references are still inconsistent including some french words and eg ref 33 is incomplete.

We thoroughly revised the referent format to make it consistent throughout the manuscript. We corrected and completed the incomplete reference. We apologize for that problem.

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policyhttps://www.plos.org/privacy-policy.

Reviewer #1: No

Reviewer #2: No

Submitted filename: renamed_24f03.docx

21 Apr 2020

Impact of introducing a standardized nutrition protocol on very premature infants’ growth and morbidity

PONE-D-19-35465R1

Dear Dr. WITTWER,

We are pleased to inform you that you have carefully addressed all items raised and that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Harald Ehrhardt

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The reviewers have addressed my remaining comments.

I have no remaining comments except for the legend for figure 3A and B is now missing

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No


5 May 2020

PONE-D-19-35465R1

Impact of introducing a standardized nutrition protocol on very premature infants’ growth and morbidity

Dear Dr. Wittwer:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

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on behalf of

Dr. Harald Ehrhardt

Academic Editor

PLOS ONE

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

https://www.researchpad.co/tools/openurl?pubtype=article&doi=10.1371/journal.pone.0232659&title=Impact of introducing a standardized nutrition protocol on very premature infants’ growth and morbidity&author=&keyword=&subject=Research Article,Biology and Life Sciences,Nutrition,Medicine and Health Sciences,Nutrition,People and Places,Population Groupings,Age Groups,Children,Infants,People and Places,Population Groupings,Families,Children,Infants,Biology and Life Sciences,Biochemistry,Lipids,Medicine and Health Sciences,Health Care,Health Statistics,Morbidity,Biology and Life Sciences,Physiology,Physiological Parameters,Body Weight,Birth Weight,Medicine and Health Sciences,Physiology,Physiological Parameters,Body Weight,Birth Weight,Biology and Life Sciences,Nutrition,Diet,Beverages,Milk,Medicine and Health Sciences,Nutrition,Diet,Beverages,Milk,Biology and Life Sciences,Anatomy,Body Fluids,Milk,Medicine and Health Sciences,Anatomy,Body Fluids,Milk,Biology and Life Sciences,Physiology,Body Fluids,Milk,Medicine and Health Sciences,Physiology,Body Fluids,Milk,Biology and Life Sciences,Physiology,Physiological Parameters,Body Weight,Weight Gain,Medicine and Health Sciences,Physiology,Physiological Parameters,Body Weight,Weight Gain,Medicine and Health Sciences,Pediatrics,Child Development,Child Growth,Growth Restriction,