Review for 10.1186/s12876-015-0369-0 (2015)

Reviewer's report
Title:Systematic review on the impact of protein in infant formula on gastric
emptying in children
Version:2Date:25 June 2015
Reviewer: Sharon Perrella
Reviewer's report:
Thank you for the opportunity to review this systematic review on the impact of
protein in infant formula on gastric emptying (GE) in children. As identified by the
authors, despite limited evidence, different formula types are often recommended
with the belief that they empty more rapidly than others. Evaluation of published
studies will assist in informing clinical decision-making when choosing enteral
nutrition for infants and children.
This review groups studies from a wide range of paediatric subsets including
preterm infants, infants both healthy and with gastro-oesophageal reflux, and
older children both healthy and with neuro-developmental disorders and/or
dysmotility. It is not known whether patterns of GE and the enteroendocrine
response to protein are similar between preterm infants, older infants and
children with and without medical conditions. There is some evidence of slower
GE in infants and children with gastro-oesophageal reflux. Further, while both
scintigraphy and the stable isotope breath test have been validated in adults,
scintigraphy has not been validated and neither method has been standardised
in the paediatric population. These important points need to be made clear within
the manuscript as they influence interpretation of the data.
With the limited number of published paediatric scintigraphic and stable isotope
breath test GE studies available, methodological issues, and included studies
representing diverse paediatric subgroups, I agree with the finding that only
limited conclusions can be drawn.
A similar review was published in 2008 with similar conclusions to this review
(see Woodley FW & Mousa H. Revisiting the effect of casein and whey on gastric
emptying: Do differences in protein source really matter?” Journal of
Neonatal-Perinatal Medicine 2008, 1: 111-117) However as this manuscript
offers a comparison between GE of intact and hydrolysed protein formulas that is
not explored in the previous review, it may have something new to offer. I
recommend the manuscript may be reconsidered for publication after major
revisions and editing to improve the clarity of the paper.
Sincerely,
Sharon Perrella PhD
Major Compulsory Revisions
Introduction
1. Please revise the literature review. As there is limited evidence for the effect of
liquid meal composition on GE in infants and children, it is important to state what
is known about this population. Evidence from the adult literature may not apply
to the paediatric population; much of this is yet to be confirmed.
2. Please briefly review all of the considered GE methods and clarify which of
these have been validated in the paediatric population.
Methods
The Methods are appropriate, however a more detailed description of the study
selection process is required.
3. Details of the screening process are duplicated with the same details provided
in Figure 1 and in the manuscript. Please describe the process more fully in the
manuscript, and refer to Figure 1.
4. Please clarify why some of the final 10 full text articles excluded from the
review were not excluded earlier in the process. It is stated that 108 were
excluded “due falling outside of inclusion criteria [sic]”, but of the final 18 articles
evaluated some of the 10 were removed due to “…using techniques outside of
inclusion criteria.”
5. It is not clear why the Pozler study has been included in the review as the
study does not address the influence of protein type / hydrolysis level on GE but
reports on the effects of meal volume and postnatal age. The test meals were
pasteurized breast milk and there was no comparison with GE of formula. Please
justify its inclusion or remove it from the review.
6. It is not clear from the Methods section why the following publications were not
included in the review; a more detailed explanation of your study selection
technique is needed to clarify this.
Thorkelsson T, Mimouni F, Namgung R, Fernandez-Ulloa F, Krug-Wispe S &
Tsang RC. Similar gastric emptying rates for casein- and whey-predominant
formulas in preterm infants. Pediatric Research 1994, 36(3), 329-33.
Tolia V, Lin CH & Kuhns LR. Gastric emptying using three different formulas in
infants with gastroesophageal reflux. Journal of Pediatric Gastroenterology &
Nutrtion 1992, 15(3), 297-310.
Fried MD, Khoshoo V, Secker D, Gilday DL, Ash JM & Pencharz PB. Decrease
in gastric emptying time and episodes of regurgitation in children with spastic
quadriplegia fed whey-based formula. Journal of Pediatrics 1992, 120(4 Pt 1),
569-72. (although it has some 18yr subjects and you have defined adults as >16
years rather than the commonly accepted #18 years)
Results
7. Across the results, a more robust reporting and critique of study factors such
as the reported sample sizes and justification / appropriateness of these, age
range of subjects (if preterm, report both birth gestation and postnatal age),
heterogeneity of the sample, and control of composition factors that influence
GE.
8. Please remove the Khoo study from the Results as it did not address the aims
of the study.
Discussion
9. A review of the impact of protein type on GE in children was published in 2008
(details as previously mentioned) –please discuss your findings with relation to
this review.
10. Limitations are clearly stated but need to be more succinct.
11. A limitation of this review is the wide age range of paediatric populations,
both healthy and with medical conditions, which limits comparisons of the
available study findings
12. Please reference your statement that amylase influences GE
Minor Essential Revisions
Clarity and sentence structure require attention throughout the manuscript.
13. The title of the study does not clearly reflect the aim of the systematic review,
and is a little confusing as it suggests that the review assesses GE of infant
formula in children. Please consider rewording it to reflect the aim and selected
population of the review eg.
“Systematic review of the impact of milk formula protein type and degree of
hydrolysis on gastric emptying in infants and children”
Abstract
14. The introduction refers only to the comparison of effect of protein type on GE;
there is no mention of degree of hydrolysis yet this is one of the stated aims of
the review.
Introduction
15. The aims of the review should be stated at the end of the Introduction rather
than in the Methods section.
16. Table 2 is difficult to read. Please simplify the table so it is less wordy, and
adopt a consistent reporting style eg. currently RCT (n=13) and “RCT on 10
children.” Age range of subjects would be a useful addition
Results
17. As the effect of protein composition is the focus of the review please report
details of the protein composition of all tested feeds within the manuscript. If
details are reported for breastmilk protein, state whether the compositions were
measured or assumed.
When stating casein:whey ratios please be consistent ie. ratio or %
18. Regarding Van den Driessche’s study, you have identified that there were
differences between the formula fed and breastmilk fed infants with regard to
birth gestation and postnatal age. Please note that there were also differences in
postnatal age. It is important to note that the effects of both birth gestation and
postnatal maturation on GE are not known, and it is possible that these may have
confounded the results.
19. Regarding the Billeaud study, several feed types are tested and so it is
mentioned in three of the four results sections. The manuscript will be easier to
read if, after introducing the study, only the relevant test feeds are discussed in
each results section.
20. Details and critiques of each of the Brun studies are required, and discussion
of Billeaud study should relate only to comparison of GE of intact whey and intact
casein formulas.
21. Regarding reference to the Perrella (2015) study, please note that the test
meals fortified with extensively hydrolysed whey emptied more slowly than
unfortified breastmilk, while that containing partially hydrolysed whey emptied
similarly to unfortified whey.
Discretionary Revisions
Introduction
For clarity I suggest changing the wording of the study aims to
We aimed to compare GE of
Breast milk and formula
Casein dominant and whey dominant formulas (intact proteins)
Intact and hydrolysed protein formulas
Hydrolysed casein and hydrolysed whey formula
Please note that there are two ultrasound methods for assessing GE in infants;
serial measurements of the antral cross sectional area (ACSA), (which has not
been validated) and more recently a direct ultrasound method for calculating
gastric volume, which has been validated in the preterm population (see Perrella
et al, Validation of ultrasound methods to monitor gastric volume changes in
preterm infants. 2012 JPGN 57(6); 741-9)
Methods It would be useful to state how many studies were included for each of
the study aims.
The studies include formulas containing both casein and whey of differing
degrees of hydrolysis. It would be useful to describe the differing degrees of
hydrolysis in the introduction, and in the results section discuss why it might be
difficult to interpret the GE results for feeds of such different compositions.
Hydrolysed casein versus hydrolysed whey: This comparison was an aim of the
review, however no suitable published studies were found. This could be stated
at the start of the review section when outlining how many studies were included
for each aim of the review (instead of as a concluding sentence for the previous
results section).
It may be useful to cite the Khoo study as an example of the potential impact of
protein dose on GE within the Introduction.
Regarding Perrella (2015) paper, an honest mistake was made in misreporting
casein as a component of the S-26 HMF – an erratum is to be published with the
next issue of JPGN.
Discussion
Consider critically examining why breast milk empties faster than formula eg
structural differences between bovine and human caseins as well as the
enterogastrone response to these.
Suggested edits
Consider shortening 13C octanoic acid breath test to “13C-OABT” as is
commonly used in the literature, rather than “13C-Octanoic Acid BT.”
Consider replacing “whole” with “intact” when referring to protein/casein/whey
that has not been hydrolysed.
Please remove the hyphen from “breast-fed” and “formula-fed”
Abstract
Background
“The choice of infant formula plays an important role” suggest replace with
“The choice of infant formula is thought to play an important role…”
because, as identified in this review, the effect of different protein compositions in
formula on GE is not well established.
Introduction
“Human breast milk” please delete “human” as other mammalian milk is not
referred to as breast milk
Please delete hyphen from “gastro-paresis”
Please provide full wording for DTPA
Please change “13CO2 in expired” to “a stable isotope in serial expired” (as there
are a few different isotopes that may be used)
Please change “13C- enriched” to “isotope labeled”
Please change “has shown to correlate well in…” to “has been shown to correlate
well with…”
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare that I have no competing interests