Fortification of Human Milk With Infant Formula for Very Low Birth Weight Preterm Infants: A Systematic Review

Abstract

Background:
Off-label fortification of expressed human milk (HM) with infant milk formula (IMF) is common in developing countries, though its benefits and safety are unclear.

Objectives:
To study the effects of IMF fortification of HM on growth of very low birth weight (VLBW) preterm infants.

Design:
Systematic review and meta-analysis of randomized and quasi-randomized controlled trials (RCTs).

Data sources and selection criteria:
MEDLINE, EMBASE, CINAHL, CENTRAL and other databases were searched for articles published in English language from inception to December 2019, evaluating the effects of HM fortified with IMF as intervention, compared to unfortified HM or HM fortified with human milk fortifier (HMF).

Participants:
Five RCTs including 423 VLBW preterm infants.

Intervention:
Feeding with HM fortified with IMF compared to unfortified or HMF-fortified HM.

Outcome measures:
Primary outcome measure was assessment of growth as weight, length and head circumference (HC) gain velocity. Secondary outcome measures were incidences of feed intolerance (FI), necrotizing enterocolitis (NEC), time to reach full feeds, concentration of nutritional biomarkers, duration of hospital-stay and cost of intervention.

Results:
Of the five studies included in the review, pooled effects regarding weight gain velocity (SMD 0.27 g/day; 95% CI 0.08 to 0.62), length gain (MD 0.07cm/week; 95% CI 0.02 to 0.16) and HC gain (MD 0.05 cm/wk; 95% CI 0.01 to 0.11), were not statistically significant. Sensitivity analysis by pooling studies using unfortified milk as comparator yielded a statistically significant result for all growth parameters. Risk of FI or NEC was comparable. Length of hospitalstay was reduced in the intervention group.

Conclusion:
A very-low quality evidence suggested that IMF fortification of HM is superior to unfortified milk and may be a safe alternative for HMF for short term growth of VLBW preterm infants.

Full text

INDIAN PEDIATRICS 253 VOLUME 58__MARCH 15, 2021
Every year, approximately14.9 million neonates,
representing a birth rate of 11.1%, are born
preterm, globally [1]. Though substantial
advancement in medical care has led to an
improved survival of preterm infants [2], significant
morbidity during the hospital stay and adverse long-term
neurological consequences remain major areas of
concern.
Deprived of the third trimester accretion of macro and
micronutrients, along with the inability to meet the
increased postnatal demand due to prematurity-related
illnesses and poor nutritional intake, more than half of
these infants have extra-uterine growth restriction, which
in turn has long-term adverse cardiovascular and
metabolic consequences [3,4]. Nutritional optimization is
considered vital for survival, growth, and improved
neurodevelopmental outcome [5-8].
Though breastmilk is the nutrition of choice for very
Fortification of Human Milk With Infant Formula for Very Low Birth
Weight Preterm Infants: A Systematic Review
MANISH KUMAR,1 J AYA U PADHYAY2 AND S RIPARNA B ASU2
From Departments of 1Pediatrics and 2Neonatology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India.
Correspondence to: Sriparna Basu, Department of Neonatology, All India Institute of Medical Sciences, Rishikesh,
Uttarakhand -249203, India. sriparna.neonat@aiimsrishikesh.edu.in
Received: July 10, 2019; Initial review: November 05, 2019; Accepted: October 29, 2020.
Background: Off-label fortification of expressed human milk
(HM) with infant milk formula (IMF) is common in developing
countries, though its benefits and safety are unclear.
Objective: To study the effects of IMF fortification of HM on growth
of very low birth weight (VLBW) preterm infants.
Design: Systematic review and meta-analysis of randomized and
quasi-randomized controlled trials (RCTs).
Data sources and selection criteria: MEDLINE, EMBASE,
CINAHL, CENTRAL and other databases were searched for ar-
ticles published in English language from inception to December
2019, evaluating the effects of HM fortified with IMF as interven-
tion, compared to unfortified HM or HM fortified with human milk
fortifier (HMF).
Participants: Five RCTs including 423 VLBW preterm infants.
Intervention: Feeding with HM fortified with IMF compared to un-
fortified or HMF-fortified HM.
Outcome measures: Primary outcome measure was assess-
ment of growth as weight, length and head circumference (HC)
gain velocity. Secondary outcome measures were incidences of
feed intolerance (FI), necrotizing enterocolitis (NEC), time to
reach full feeds, concentration of nutritional biomarkers, duration
of hospital-stay and cost of intervention.
Results: Of the five studies included in the review, pooled effects
regarding weight gain velocity (SMD 0.27 g/day; 95% CI 0.08 to
0.62), length gain (MD 0.07cm/week; 95% CI 0.02 to 0.16) and HC
gain (MD 0.05 cm/wk; 95% CI 0.01 to 0.11), were not statistically
significant. Sensitivity analysis by pooling studies using unfortified
milk as comparator yielded a statistically significant result for all
growth parameters. Risk of FI or NEC was comparable. Length of
hospitalstay was reduced in th intervention group.
Conclusions: A very-low quality evidence suggested that IMF for-
tification of HM is superior to unfortified milk and may be a safe al-
ternative for HMF for short term growth of VLBW preterm infants.
Keywords: Human milk, Human milk fortification, Preterm, Very
low birth weight infant
low birth weight (VLBW) preterm neonates [9],
exclusive human milk (HM) feeding, does not meet their
nutritional targets [10,11]. Moreover, after two weeks,
the protein content of milk of mothers delivering preterm
decreases further [12]. Multi-nutrient fortification of HM
results in increased rate of gain in weight, length and head
circumference of VLBW preterm infants [13-16].
Unfortunately, in low- and middle-income countries
(LMICs), the concept of individualized and targeted
fortification is far from implementation. Commercially
available human milk fortifiers (HMF) are low in protein
content (<1g/100 mL) and expensive, prohibiting routine
supplementation [17]. An alternative and more econo-
mical strategy, commonly employed off-label in various
neonatal units, is to enrich EBM by adding infant milk
formula (IMF) to achieve the required level of protein for
improved growth outcomes [18-22]. However, IMF
fortification may result in increased osmolarity, non-
uniform protein content and risk of contamination leading
PROSPERO Registration Number: CRD42019138122 Early online: January 02, 2021; PII: S097475591600277
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INDIAN PEDIATRICS 254 VOLUME 58__MARCH 15, 2021
KUMAR, ET AL.FORMULA-FORTIFIED MILK IN VLBW INFANTS
to feeding intolerance (FI), sepsis and necrotizing
enterocolitis (NEC). In addition, the quantity needed for
optimum fortification and measuring technique is not
validated.
This systematic review intended to evaluate the role
of fortification of HM with IMF for growth in VLBW
preterm infants.
METHODS
This systematic review and meta-analysis was conducted
in accordance to PRISMA guidelines [23].
Search strategy and search criteria: All authors
independently searched the databases including PubMed,
Embase, Cochrane Central Register of Controlled Trials,
other clinical trial registries, Google Scholar, Scopus, Web
of Science and hand searching of conference proceedings
from inception to December 2019 for peer-reviewed
publications in English language. The electronic search
strategy included a combination of keywords along with
their representative medical subjects headings (MeSH)
terms. Details of search strategy are provided in Web
Appendix 1. Reference list of all articles whose full texts
were screened, was also checked to find additional articles.
We included randomized or quasi-randomized
controlled trials (RCT) evaluating the effects of HM
fortified with IMF as intervention, compared to unforti-fied
or HMF-fortified HM on growth rate, duration of hospital-
stay and other clinically relevant outcomes in VLBW
preterm infants. Non-English publications were excluded.
The primary outcome was assessment of velocity of
gain in weight, length, and head circumference (HC).
Secondary outcomes were duration of hospital stay,
incidences of FI and NEC, time to reach full feeds,
concen-tration of nutritional biomarkers (calcium,
phosphorous, blood urea nitrogen, prealbumin, albumin,
alkaline phos-phatase) and cost of intervention.
Data extraction and quality assessment: Two authors
independently extracted data using a pre-designed pro-
forma. Disagreement, if any, was resolved by discussion
with third author. Study details including location and year
of study, number of infants and their characteristics, details
of feeding including fortification and outcomes relevant to
the study were noted. Quality of studies were assessed
independently by all authors, for each study, using the risk
of bias (ROB) criteria outlined in the Cochrane Handbook
for Systematic Reviews of Interventions [24] in the
domains of random sequence generation, allocation
concealment, blinding of partici-pants and personnel,
blinding of outcome assessment, incomplete outcome data,
selective outcome reporting, and other bias.
Statistical analysis: Statistical analysis was performed
using Review Manager version 5.4 (The Cochrane Colla-
boration, 2020). Out-come variables were calculated as
risk ratio (RR) with 95% confidence interval (CI) for
dichotomous data and mean differences (MD) with 95% CI
for continuous data. Standardized mean differences
(SMDs) were calculated where outcomes had different
measurement instruments. Studies reporting dispersion of
outcomes in range was converted to standard deviation
using established mathematical models [25]. Results were
pooled using either fixed or random effects model based on
hetero-geneity which was assessed using the I² statistic.
Grading of recommendations assessment, development
and evaluation (GRADE) approach [26] was applied to
assess the quality of evidence for predefined outcomes.
RESULTS
Screening and inclusion of studies are summarized in
Fig.1. Four full-text articles [18-21] and one abstract [22]
were selected for this systematic review including a total
of 423 VLBW preterm infants.
The characteristics of included studies are summarized
in Table 1. The birth weight of the preterm VLBW infants
included in the studies, ranged from 500g to 1499g.
Fortification of HM with IMF was the intervention in all
five trials. The time to start fortification varied from 100
mL/kg/d [18,19,22] to150 mL/kg/d of enteral feed [21].
Willeitner, et al. [20] introduced fortification as early as at
60 mL/kg/d, at the discretion of the treating team. In three
studies [18,20,22] the comparator was HMF, while other
two studies [19,21] used unfortified HM. Web Fig. 1
depicts ROB graph summarizing each ROB item as
percentage across all studies while Web Fig. 2 summarizes
ROB for each included study.
All included studies evaluated weight gain velocity as
primary outcome. Four studies [19,20-22], described
weight gain velocity in terms of g/kg/day, while Khorana,
et al. [18] reported weight gain as g/day. Overall, pooled
effects of all five studies on weight gain velocity was
statistically not significant (SMD 0.27 g/kg/day; 95% CI:
-0.08 to 0.62) (Fig. 2a). Sensitivity analysis was done due
to difference in comparators. IMF fortification was found
to cause a statistically significant increase in the rate of
weight gain (MD 02.03 g/day; 95% CI: 1.15 to 2.92)
compared to unfortified HM. Using HMF as comparator,
SMD of weight gain velocity was similar (SMD -0.01 g/
day; 95% CI: -0.27 to 0.25).
Four studies [18,19,21,22] with 353 participants
reported data regarding rate of increase in length and HC.
The pooled effect with respect to velocity of gain in length
was not statistically significant (MD 0.07 cm/week; 95%

INDIAN PEDIATRICS 255 VOLUME 58__MARCH 15, 2021
KUMAR, ET AL.FORMULA-FORTIFIED MILK IN VLBW INFANTS
CI: -0.02 to 0.16) (Fig. 2b). On sensitivity analysis, when
compared to unfortified HM, IMF fortification resulted in
significantly higher rate of gain (MD 0.12 cm/week; 95%
CI: 0.02 to 0.22), but failed to show difference when
compared with HMF (MD -0.03 cm/week; 95% CI: -0.15
to 0.08). Similarly, the pooled effect with respect to
velocity of gain in HC was not statistically significant (MD
0.05 cm/week; 95% CI: -0.01 to 0.11) (Fig. 2c). On
sensitivity analysis, when compared to unfortified HM,
IMF fortification resulted in significantly higher rate of
gain (MD 0.08 cm/week; 95% CI: 0.03 to 0.13), but failed
to show difference when compared with HMF (MD -0.04
cm/week; 95% CI: -0.14 to 0.06).
FI, reported in two studies [19,21] (n=208), showed
no difference in risk between IMF and HMF fortification
versus no fortification of HM (RR 2.29; 95% CI: 0.61to
8.59) (Web Fig. 3a). Though HMF fortification showed
apparently higher rates of NEC [18,20], the RR was not
statistically significant for either suspected NEC (RR
0.37; 95% CI: 0.07 to 1.95) (Web Fig. 3b) or confirmed
NEC (RR 0.25; 95% CI: 0.04 to 1.39) (Web Fig. 3c).
Three studies [18,19,21] including 231 participants,
showed that the length of hospital stay of neonates with
IMF was significantly reduced (MD -4.38 days; 95% CI:
-7.39 to -1.37) (Web Fig. 3d). Two studies [18,19]
(n=83) found no significant difference with respect to
time to achieve full enteral feeding, between those
receiving formula fortified HM and those on either HMF
fortified or unfortified HM. (Web Fig. 3e). Effect of
fortification on nutritional biomarkers were reported by
two studies [18,21]. No significant effect on BUN nor
albumin levels was observed (Web Fig.3f, 3g).
Though four of the studies favored IMF intervention
in terms of cost, this economical aspect was not studied as
an outcome in any of them. The data presentation was not
uniform and therefore, could not be pooled.
The quality of evidence pooled from included studies
was assessed using GRADE approach and summary of
findings table was generated on GRADE pro GDT
software (Evidence Prime Inc.) (Web Appendix 2).
DISCUSSION
This systematic review and meta-analysis of five RCTs,
including a total of 423 VLBW preterm infants, did not
show any significant benefit of IMF fortification of HM
over combined HMF fortification/no fortification, on
growth velocity, with respect to weight, length and HC.
On sensitivity analysis for the same parameters, IMF and
HMF fortifications were comparable, whereas IMF
fortification was significantly better than unfortified HM,
quality of evidence (QOE) being very low. No significant
difference was noted in the incidences of FI/NEC and
Fig. 1 PRISMA flow diagram.

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KUMAR, ET AL.FORMULA-FORTIFIED MILK IN VLBW INFANTS
Table I Characteristic of Studies Included
Included studies/ Fortification Outcomes Supplements Recruitment Nature of GA (wks) BW (g), Cost
Year/Place started at enteral assessed (n) fortification Mean (SD) Mean ()
feeding volume
Khorana, et al. 100 mL/kg/day Weight gain, length gain, If inadequate Intervention Post discharge 30.67 (2.32) 1206.67 605 baht per
2014 [18], HC gain, BUN, creatinine, weight gain, MCT oil was (n=15) formula (224.99) infant
Thailand albumin, alkaline phos- used as additive in both (Similac NeoSure
phatase, total calcium, phos- arms to achieve concen- Advance Powder,
phate, urine Ca/Cr, urine tration of 30 cal/oz, Iron
PO4/Cr, NEC, rectal blee- supplementation started Control HMF fortified 30.0 (1.88) 1158.61 11,655 baht
ding, BPD, IVH, ROP, at 2 wk and vitamin D (n=18) (232.94) per infant
osteopenia, sepsis, length was started on full feeds. EBM (Enfamil
of hospital stay, cost reduction Human Milk
Fortifier
El Sakka, et al. 100 mL/kg/day Weight gain, length gain, Vitamin D supple- Intervention Infant formula 32.08 (2.53) 1291.8 (105.3) Not mentioned
2016 [19], HC gain, Hb, hematocrit, mented at start of enteral (n=25) (Babelac premature
Egypt albumin, BUN, Na, K, Ca, feeding; and iron pres- formula)
PO4, length of hospital stay cribed when enteral feed- Control Unfortified EBM 31.37 (2.62) 1290.3 (177.4) Not mentioned
ing reached 150 mL/kg/day (n=25)
Willietner, et al. Started at the Weight gain, residual gastric Not mentioned Intervention CPF30 (Similac 29 (24-32) Median (Range) 7 cents less than
2017 [20], USA discretion of aspirate, erythromycin treat- (n=35) Special Care 30 1099 in HMF
attending physi- ment, NEC, blood culture, With Iron) (530-1470) fortified group
cian (not before death
a minimum of Control PHMF fortified Median Median
60 mL/kg/day) (n= 35) breastmilk(Similac (range) (range)
HMF Park, 29 (24-34) 1100
(570-1490)
Gupta, et al. 150 mL/kg/day Weight gain, linear growth, All newborn in both Intervention Infant milk 31.2 (1.5) 1242.3 (170.9) Rs.190/ infant
2018 [21], India HC, sepsis, FI, hospital stay, groups were supple- (n=75) formula (Simyl
time in trial, apneic spells, mented with extra calcium, LBW
BPD, ROP, IVH, PVL, phosphate, iron and multi-
anemia, biochemical vitamin drops Control Unfortified 31.2 (1.6) 1234.8 (190.8) Rs. 2000/ infant
parameters (n=73) EBM
Arunambika, et al.100 mL/kg/day Weight gain, length gain, HC Not mentioned Intervention Preterm formula 30.5 (2.2) 1161 (251) Rs 300/ infant
2019 [22], India gain, FI, NEC, sepsis, anemia, (n=59) made in hospital
MBD, late metabolic acidosis pharmacy
Control PreNAN 29.9 (2.2) 1119 (265) Rs 10,800/
(n=63) infant
BUN: Blood urea nitrogen; BW: Birth weight; BPD: Bronchopulmonary dysplasia; Ca: Calcium; CPF30: Concentrated preterm formula 20 Kcal/oz; Cr: Creatinine; EBM: Expressed breast milk; FI:
Feeding intolerance; GA: Gestational age; Hb: Hemoglobin; HC: Head circumference; HMF: Human milk fortifier; IVH: Intraventricular hemorrhage; K: Potassium; Na: Sodium; MBD: Metabolic bone
disease; NEC: Necrotizing enterocolitis; PHMF: Powdered human milk fortifier; PVL: Periventricular leukomalacia; PO4: Phosphate; RCT: Randomized controlled trial; ROP: Retinopathy of
prematurity.

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KUMAR, ET AL.FORMULA-FORTIFIED MILK IN VLBW INFANTS
levels of nutritional biomarkers like BUN and albumin
(QOE: very low). Pooled data from three trials, showed a
significant reduction in duration of hospital stay favoring
IMF fortification (QOE, very low). This reduction was
probably because the comparator in two of these studies
was unfortified HM.
There are several limitations in the included trials.
The study by El Sakka, et al. [19] was quasi-randomized
with an unclear methodology. Still this study was
included as its outcome measures met our inclusion
criteria. The gestational age varied among the studies,
with one trial [21] excluding late preterm infants. No data
were available regarding long term growth and
developmental outcome. Formulas and HMFs
preparations used were from different manufacturers,
though the protein and energy content were similar.
Another area of discrepancy was non-uniform timing of
initiation of fortification in included trials, which might
have affected growth. The most important concern for
implementation of IMF fortification in routine practice is
increase in osmolarity with risk of FI and NEC. Only one
trial [21] measured osmolarity of HM after IMF
fortification and found it below 400 mOsm/L, the
recommended upper safety limit of American Academy
of Pediatrics [27]. Though no difference in the incidences
of FI and NEC was noted, none of the studies was
adequately powered to detect the difference. None of the
trials had individualized the fortification by analysis of
HM macronutrients. IMF measurement technique for
fortification was described by only one study [22].
A relatively limited number of studies, with high ROB
and statistical heterogeneity in this systematic review
limit the generalizability of this meta-analysis. Variability
in the time of initiation of feed, the maximum feeding
volume and continuation of IMF as ‘bridge feeding’ when
EBM was unavailable [20] probably limited the impact of
the intervention on growth outcomes. Further, subgroup
analysis based on gestation or birth weight could not be
done because of unavailability of raw data. Not all
biomarkers of nutrition could be evaluated due to lack of
measured values. Data regarding cost could not be pooled
as there was no uniformity in presentation.
Fig. 2 Forest plot showing meta-analysis of the effect of infant milk fortification on the velocity of weight gain (2a), length gain (2b) and
head circumference (HC) gain (2c).

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KUMAR, ET AL.FORMULA-FORTIFIED MILK IN VLBW INFANTS
To summarize, a very-low quality evidence suggests
that IMF fortification of HM is superior to unfortified
HM and may be a safe alternative for bovine HMFs for
short term growth of VLBW preterm infants, especially in
resource-limited settings. Larger well-designed studies
with strict monitoring of complications including NEC
with a focus on long-term outcomes are needed.
Acknowledgement: Dr. Poonam Singh for assistance in revising
the manuscript.
Contributors: MK: conceptualized the review, literature search,
data analysis and manuscript writing; JU: literature search, data
analysis and manuscript writing; SB: conceptualized the review,
literature search, data analysis and manuscript writing.
Funding: None; Competing interest: None stated.
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WEB APPENDIX 1 Electronic Search Strategy
Database Date Search Strategy Number of references
PubMed 28-11-19 ("growth"[MeSH Terms] AND (((("milk,
human"[MeSH Terms] OR "human
milk"[Title/Abstract]) OR "breast
milk"[Title/Abstract]) OR "human milk
fortifier"[Title/Abstract]) OR
"fortification"[Title/Abstract])) AND ((("infant,
very low birth weight"[MeSH Terms] OR "very
low birth weight infant"[Title/Abstract]) OR
"infant, premature"[MeSH Terms]) OR "preterm
infant"[Title/Abstract])
494
Embase 28-11-19 (‘breast milk’/exp OR ‘breast milk’ OR ‘human
milk fortifier’) AND (‘very low birth weight’
OR ‘prematurity’) AND ‘growth rate’
160
CENTRAL 28-11-19 “infant, premature” in Title Abstract Keyword
AND “human milk fortifier” in Title Abstract
Keyword AND “growth” in Title Abstract
Keyword
21

KUMAR, ET AL. FORMULA-FORTIFIED MILK IN VLBW INFANTS
INDIAN PEDIATRICS VOLUME 58__MARCH 15, 2021
WEB FIG. 1 Risk of bias graph showing authors’ judgement about each risk of bias item, presented as
percentages across all included studies
WEB FIG. 2: Risk of bias summary for included studies, showing authors’ judgements about each risk of
bias item for each included study.

KUMAR, ET AL. FORMULA-FORTIFIED MILK IN VLBW INFANTS
INDIAN PEDIATRICS VOLUME 58__MARCH 15, 2021
WEB FIG. 3 Forest Plot, Feed intolerance (3a), suspected necrotizing enterocolitis (NEC) (3b), definite NEC (3c), duration of
stay (days) (3d), time to reach full feeds (days) (3e), blood urea nitrogen (BUN) (3f), albumin (3g)

WEB APPENDIX 2 GRADE PROFILE
Certainty assessment Summary of findings
№ of
participant
s
(studies)
Follow-up
Risk of
bias
Inconsistenc
y
Indirectnes
s
Imprecisio
n
Publication
bias
Overall
certainty
of
evidence
Study event rates (%) Relativ
e effect
(95%
CI)
Anticipated absolute
effects
With
unfortified/HM
F fortified
With
Formul
a
fortified
Risk with
unfortified/HM
F fortified
Risk
differenc
e with
Formula
fortified
Growth velocity
423
(5 RCTs)
very
seriou
s a
very serious
b
not serious very
serious c
all plausible
residual
confounding
would
reduce the
demonstrate
d effect
⨁◯◯
◯
VERY
LOW
214 209 - - SMD
0.27
higher
(0.08
lower to
0.62
higher)
Length gain
353
(4 RCTs)
very
seriou
s a
very serious
b
not serious very
serious c
all plausible
residual
confounding
would
reduce the
demonstrate
d effect
⨁◯◯
◯
VERY
LOW
179 174 - - MD 0.07
higher
(0.02
lower to
0.16
higher)
OFC gain
353
(4 RCTs)
very
seriou
s a
very serious
b
not serious very
serious c
all plausible
residual
confounding
would
reduce the
demonstrate
d effect
⨁◯◯
◯
VERY
LOW
179 174 - - MD 0.05
higher
(0.01
lower to
0.11
higher)
Feed Intolerance
198
(2 RCTs)
very
seriou
s d
not serious very
serious e
very
serious c
all plausible
residual
confounding
would
reduce the
demonstrate
d effect
⨁◯◯
◯
VERY
LOW
3/98 (3.1%) 7/100
(7.0%)
RR
2.29
(0.61
to
8.59)
31 per 1,000 39 more
per
1,000
(from 12
fewer to
232
more)
KUMAR, ET AL. FORMULA-FORTIFIED MILK IN VLBW INFANTS
INDIAN PEDIATRICS VOLUME 58__MARCH 15, 2021

Definite NEC
103
(2 RCTs)
very
seriou
s f
not serious very
serious g
very
serious c
all plausible
residual
confounding
would
reduce the
demonstrate
d effect
⨁◯◯
◯
VERY
LOW
6/53 (11.3%) 1/50
(2.0%)
RR
0.25
(0.04
to
1.39)
113 per 1,000 85
fewer
per
1,000
(from
109
fewer to
44 more)
Duration of stay
231
(3 RCTs)
very
seriou
s h
not serious not serious very
serious c
all plausible
residual
confounding
would
reduce the
demonstrate
d effect
⨁◯◯
◯
VERY
LOW
116 115 - - MD 4.38
lower
(7.39
lower to
1.37
lower)
Time to full feeds
83
(2 RCTs)
very
seriou
s h
not serious not serious very
serious c
all plausible
residual
confounding
would
reduce the
demonstrate
d effect
⨁◯◯
◯
VERY
LOW
43 40 - The mean
time to full
feeds was 0
MD 1.29
lower
(6.33
lower to
3.75
higher)
CI: Confidence interval; SMD:Standardised mean difference; MD: Mean difference; RR: Risk ratio
Details: a. 4 studies (Arunambika 2019, El Sakka2016, Gupta 2018, Khorana 2014) were open labeled; Randomization and allocation concealment was
improper in El Sakka 2016. b. Khorana 2014 and Arunambika 2020 favored control while other studies favored intervention. c. 95% confidence intervals are
wide across studies. d. Included studies were open labeled. Randomization and allocation concealment was improper in El Sakka 2016. e. Definition of feed
intolerance varied across studies. f. In Khorana 2014 allocation concealment and blinding was not clearly defined. In Willeitner 2017, allocation concealment
was not explained properly and had incomplete outcome data bias. g. Definition of NEC varied across studies. h. Included studies were open labeled.
Randomization and allocation concealment in not proper in El Sakka 2016.
INDIAN PEDIATRICS VOLUME 58__MARCH 15, 2021
KUMAR, ET AL. FORMULA-FORTIFIED MILK IN VLBW INFANTS