Our search strategy yielded 2,830 studies (Figure 1- PRISMA flow diagram). After assessing 9 full-text articles, we included 7 studies in the meta-analysis [12–18]. While 6 studies assessed early versus delayed feeding, 1 study assessed slow versus rapid feed advancement [18]. The characteristics of included studies are provided in Table 1. The characteristics of the participants are provided in Table 2. The characteristics of excluded studies are provided in the online supplemental material.
Table 1
Characteristics of included studies
Author
|
Study setting
|
Inclusion criteria
|
Exclusion criteria
|
NEC definition
|
Feeding intolerance definition
|
Full feeds definition
|
Abdelmaaboud, 2012
|
Level 3 NICU, Doha, Qatar
|
Fulfilling all the 5 criteria: (1) 24-36+6 weeks, (2) <10th centile on Child Growth Foundation Charts, (3) Antenatal ultrasound showing IUGR with AREDF on at least 50% of the Doppler waveforms from the umbilical artery on at least one occasion during pregnancy and an evidence of cerebral redistribution, defined as occurring when both the umbilical artery pulsatility index >95th centile and the middle cerebral artery pulsatility index <5th centile for gestational age; (4) Arterial cord blood pH ≥ 7.0, base deficit ≥ -12 mmol/L and (5) 5-minute Apgar score > 5.
|
Major congenital abnormality including known chromosomal abnormality, twin-twin transfusion, intra- uterine transfusion or exchange transfusion, rhesus iso-immunisation, significant multi-organ failure and inotropic drug support prior to trial entry or if they already received any minimal enteral feeding
|
Modified Bells' staging criteria
|
Gastric residuals were checked before each feed. (1) Non-bilious residuals: 25-50% + other worrying signs; >50% gastric residuals + AG increase >2 cm. (2) Bilious aspirates. (3) Blood in stool, loose stool, metabolic acidosis and other signs of NEC
|
150-160 ml/kg/day sustained for 72 hours
|
Arnon, 2013
|
Level 3 NICU, Kafar Saba, Israel
|
Clinically & hemodynamically stable, birth wt <10th centile as per Israel National registry & gest <37 wks & AREDF
|
Systemic disease, need for mechanical ventilation, major congenital anomalies including known chromosomal abnormality, enteral feeding before study entry, use of anti-reflux medication or special diet before or during the
study period, Apgar score 0 to 3 for > 5 minutes, arterial cord blood pH < 7.0 or base deficit 12 to 16 mmol/L, need for resuscitation, or significant multi-organ failure.
|
No mention
|
Clinical signs of abdominal distension/ tenderness, visible bowel loops or emesis, gastric residuals>50% of 3hr volume
|
150 ml/kg
|
Karagianni, 2009
|
Level 3 NICU, Greece
|
27-34 weeks, Birth wt <10th centile, Abnormal Doppler (elevated PI>90th centile), arterial cord pH>7 (base deficit >-12mmol/L) and 5 min APGAR >5
|
Major congenital anomalies, infections, signs of genetic syndromes and gastrointestinal tract anomalies, exchange transfusion, inotropic support
|
Bell's criteria 2 & 3
|
Gastric residuals, bilious vomiting, abdominal distension
|
Not mentioned
|
Leaf, 2012
|
Southampton, Multicentre, UK
|
Preterm (up to 34+6 weeks of gestation), SGA (birth weight below 10th centile23), ,48 hours postnatal age, and had abnormal antenatal Doppler studies indicative of IUGR. This was defined as the following: (1) AREDFV in the umbilical artery seen on at least 50% of waveforms on at least 1 occasion during pregnancy, or (2) cerebral re- distribution (umbilical artery pulsatility index >95th centile and middle cerebral artery pulsatitility index <5th centile for gestation)
|
Major congenital anomaly, twin- twin transfusion, Rhesus iso-immunization, previous intrauterine or exchange trans- fusion, multiorgan dysfunction, inotropic drug support, or enteral feeding before trial entry
|
modified Bell’s stage 1, 2, or 3
|
Not mentioned
|
150 ml/kg/d sustained-72hrs
|
Srinivasan, 2017
|
Level 3 NICU, Mumbai, India
|
Preterm (up to 36+6 weeks of gestation), 24 hours postnatal age, and had abnormal antenatal Doppler studies indicative of IUGR. This was defined as the following: (1) AREDF in the umbilical artery seen on at least 50% of waveforms on at least 1 occasion during pregnancy, or (2) cerebral re- distribution (umbilical artery pulsatility index .95th centile and middle cerebral artery pulsatitility index ,5th centile for gestation)
|
Major congenital anomaly, twin- twin transfusion, Rhesus iso-immunization, previous intrauterine or exchange trans- fusion, multiorgan dysfunction, inotropic drug support, or enteral feeding before trial entry
|
Not mentioned
|
Not mentioned
|
Not mentioned
|
Tewari, 2017
|
Level3 NICU, Delhi, India
|
<32 weeks with AREDF on UA Doppler and birth weight below the 10th centile
|
Extramural, symmetric IUGR, antenatally suspected intestinal anomaly, lethal congenital anomaly, dysmorphic, needed invasive ventilation, inotropic support or extensive resuscitation and parent unavailable. Intramural preterm IUGR neonates < 27 weeks
|
Not defined
|
Abdominal girth >2 cm increase over baseline in 24 h; Pre-feed aspirate volume >50% of feed volume; Pre-feed aspirate color: Bilious/ altered or fresh blood; >1 vomitus with yellow or green color and/ or altered blood
|
150-180ml/kg/d allowing for weight gain consistently 3 days
|
Jain, 2015
|
Level 3 NICU, Chandigarh, India
|
AEDF who were ≥1000g and between 30-36 weeks
|
Perinatal asphyxia (Apgar score at 5 minutes <6), REDF, shock or inotrope dependency, any gastrointestinal tract or other major congenital malformation
|
Bell's criteria
|
Any two of these criteria: gastric residuals>33% of total feeds on 2 consecutive occasions (if total feed volume >8ml) or >50% on a single occasion (if total feed volume was <8ml), abdominal distension (increase in abdominal girth by >2cm from baseline), brown, bilious, or blood stained gastric aspirates, vomiting for which feeds were withheld for ≥12 hours and absent bowel sounds on auscultation in two different quadrants for two minutes confirmed by second observer.
|
150ml/kg/day
|
NEC- necrotizing enterocolitis, NICU- neonatal intensive care unit, IUGR- intrauterine growth retardation, AG- abdominal girth, AREDF- absent or reversal of end diastolic flow, UA- umbilical artery. |
Table 2: Characteristics of neonates participating in the included studies
Author,
year
|
Gestational agea
Mean (SD)
Median (IQR)
|
Birth weighta
|
Male genderb
n(%)
|
Antenatal steroid useb; n(%)
|
PIHb
n(%)
|
Cesarean sectionb
n(%)
|
Chorioamnionitisb
n(%)
|
Apgarc
Median (IQR)
|
Experimental
|
Control
|
Experimental
|
Control
|
Experimental
|
Control
|
Experimental
|
Control
|
Experimental
|
Control
|
Experimental
|
Control
|
Experimental
|
Control
|
Experimental
|
Control
|
Abdelmaaboud, 2012
|
32.5 ± 3.5
|
31.8 ± 2.9
|
740 (620–1270)
|
810 (630–1945)
|
30 (45.2)
|
33 (49.2)
|
48 (72.7)
|
52 (77.6)
|
Preeclampsia: 18 (27.3)
|
16 (23.9)
|
57 (86.3)
|
60 (89.5)
|
Not provided
|
Not provided
|
Not provided
|
Not provided
|
Arnon, 2013
|
31 (29-34)
|
32 (30-34)
|
1425 (1032-1620)
|
1542 (963-1683)
|
Not provided
|
Not provided
|
26 (87)
|
26 (87)
|
Not provided
|
Not provided
|
Not provided
|
Not provided
|
Not provided
|
Not provided
|
1 min- 6 (2-10); 5 min- 8 (4-9)
|
1 min- 6 (4-10); 5 min-8 (5-10)
|
Karagianni, 2009
|
32 (27-34)
|
31.3 (27-34)
|
1080 (680-1440)
|
1130 (440-1420)
|
17 (42.5)
|
16 (39)
|
33 (82.5)
|
32 (72)
|
9 (22.5)
|
10 (24.4)
|
39 (97.5)
|
41 (100)
|
not provided
|
not provided
|
1 min-7 (3-8) 5 min-8(5-9)
|
1 min-7(4-8); 5 min-8(5-9)
|
Leaf, 2012
|
31 (2.3)
|
31 (2.3)
|
1042 (303)
|
1021 (308)
|
104 (52)
|
112 (56)
|
Not provided
|
Not provided
|
83 (41)
|
76 (38)
|
189 (94)
|
200 (100)
|
Not provided
|
Not provided
|
9 (9-10)
|
9 (9-10)
|
Srinivasan, 2017
|
32.1 (2.07)
|
32.8 (2.3)
|
1119 (181.26)
|
1116 (181.26)
|
8 (50)
|
5 (31)
|
Not provided
|
Not provided
|
Not provided
|
Not provided
|
15 (93)
|
15 (93)
|
Not provided
|
Not provided
|
Not provided
|
Not provided
|
Tewari, 2017
|
<30 wk-28+5 (4), >30wk-31+3 (5)
|
<30wk-28+3 (5), >30wk 31+2 (5)
|
<30 833 (121), >30-1212.38 (118.86)
|
<30-833 (119.70), >30-1232.6 (119.9)
|
<30- 6 (60), >30-12 (58)
|
<30- 5 (50), >30-11 (53)
|
<30-9 (90), >30-16 (76)
|
<30-8 (80), >30-18 (85)
|
<30-7, >30-15
|
<30-8, >30-13
|
<30-9 (90), >30-15 (72)
|
<30-8 (80), >30-18 (86)
|
Not provided
|
Not provided
|
Not provided
|
Not provided
|
Jain, 2015
|
>1250g-34 (1.4); <1250g-33 (1)
|
>1250-34(1.2); <1250g-32(1.4)
|
>1250g-1521 (205); <1250g-1135(67)
|
>1250g-1563 (391); <1250g-1110 (78)
|
24 (60)
|
25 (58)
|
25 of 34 (73.5)
|
22 of 38 (58)
|
26 (65)
|
29 (67)
|
31 (77.5)
|
32 (74.4)
|
Not provided
|
Not provided
|
5 min->1250- 9 (7-9), <1250- 9 (6-9)
|
5 min->1250- 9 (7-9), <1250- 9 (6-9)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
a- mean (SD); b- n (%); c- median (IQR)
SD- standard deviation, IQR- interquartile range, PIH- Pregnancy Induced Hypertension.
In three studies, the neonates were <37 weeks gestational age [12, 13, 16], while 3 other studies included neonates up to 32 weeks [17], 34 weeks [14], and 35 weeks [15]. In five studies, all the neonates included were small for gestational age, while in one study [16], it was not reported. In the five studies that provided data on antenatal steroid use [12–14, 17, 18], no significant differences were noted between the experimental and control arms. None of the studies provided data on the duration of doppler abnormalities, chorioamnionitis and sickness scores at admission to NICU. Jain et al have restricted study population to neonates between 30-36 weeks and weight above 1,000 grams; 60% of neonates in the experimental arm and 63% in the control arm were growth-restricted [18].
While donor human milk was provided as a second option when breast milk was unavailable in the three recent studies [15–17], infant formula was provided in the other four studies [12–14, 18]. The human milk was fortified at feed volumes of 100 – 150 ml/kg in three studies [12, 13, 15], while it was unclear in the others. None of the studies have reported the use of probiotics. The definitions used for NEC (modified Bell’s staging) and full feeds (150-180 ml/kg/day sustained for 3 days) were consistent across the studies. Feeding intolerance was variably defined in five studies [12–14, 17, 18], while it was not defined in the other two studies [15, 16]. In all the studies, >50% pre-feed volumes, blood in stool, bilious aspirates and abdominal signs were considered worrisome.
In five studies, early feeding was defined as feeding within 48 hours of birth, while in one study, it was defined as <5 days of birth [14]. The volume at feed initiation varied from 4 – 30 ml/kg/day, duration of trophic feeds from 0 – 6 days, and volume of feed advancement from 12 – 35 ml/kg/day. In 2 studies, the feed initiation and advancement were stratified according to the birth weight [15, 17]. In the study by Jain et al, rapid advancement was defined as 30 ml/kg/day in neonates weighing 1-1.25 kg, and 40 ml/kg/day in those weighing >1.25 kg [18]. Slow advancement was defined as 20 ml/kg/day and 30 ml/kg/day in the above weight ranges, respectively. Further details of feed initiation and advancement in the experimental and control arms are summarized in the online supplemental material.
When compared to delayed feeding, the strategy of early feeding did not increase the incidence of NEC stage 2 or more (odds ratio/OR 1.27, 95% confidence interval/CI 0.83, 1.96) and mortality (OR 0.79, 95% CI 0.4, 1.57). A trend was noted towards an increased incidence of feeding intolerance (OR 1.37, 95% CI 0.98, 1.92). There was a significant reduction in time to reach full feeds (mean difference/MD -3.03 days. 95% CI -3.53, -2.53 days), duration of total parental nutrition (MD -3.14 days, 95% CI -3.98, -2.3 days), and duration of hospital stay (MD -4.98 days, 95% CI -8.31, -1.65 days). There was also a significant reduction in rates of hospital-acquired infections (OR 0.67, 95% CI 0.45, 0.98). The time to regain birth weight was not different. The forest plots are shown in figure 2.
On the risk of bias assessment using RoB2 tool, 5 studies were adjudged to have some concerns [12–14, 16, 17], while 1 study had a low risk of bias [15]. For outcomes with subjectivity in assessment (i.e., feeding intolerance), 4 studies were adjudged to be at high risk of bias due to lack of blinding of outcome assessment [12, 15–17]. The assessment is shown in Table 3 and the criteria used in the online supplemental material. Heterogeneity was not noted for the outcomes studied, except the duration of hospital stay (I2 = 35%). Subgroup analysis, sensitivity analysis and publication bias assessment were not performed because of the small number of eligible studies.
Table 3
Risk of bias in the included studies
Author, year
|
Randomization process
|
Deviations from intended interventions
|
Missing outcome data
|
Measurement of the outcome
|
Selection of the reported result
|
Overall Bias
|
Overall effect
|
Abdelmaaboud, 2012
|
Some concernsa
|
Low
|
Low
|
Lowd
|
Some concernse
|
Some concernsg
|
Favours experimental
|
Arnon, 2013
|
Some concernsb
|
Low
|
Low
|
Low
|
Some concernsf
|
Some concerns
|
Favours experimental
|
Karagianni, 2009
|
Some concernsa
|
Some concernsc
|
Low
|
Low
|
Some concernse
|
Some concerns
|
Favours experimental
|
Leaf, 2012
|
Low
|
Low
|
Low
|
Lowd
|
Low
|
Lowg
|
Unpredictable
|
Srinivasan, 2017
|
Low
|
Low
|
Low
|
Lowd
|
Some concernse
|
Some concernsg
|
Unpredictable
|
Tewari, 2017
|
Low
|
Low
|
Low
|
Lowd
|
Some concernse
|
Some concernsg
|
Unpredictable
|
Jain, 2015
|
Low
|
Low
|
Low
|
Low
|
Low
|
Low
|
NA
|
a- Methods to generate random sequence and conceal allocation not mentioned. |
b- No information provided on allocation concealment |
c- Post randomization exclusions were done |
d- Outcome assessors were not blinded for the intervention. The prior knowledge can influence assessment of outcomes of feed intolerance. Hence, the assessment for this outcome is high risk of bias. For other outcomes like necrotizing enterocolitis stage 2 or more, mortality, duration of parenteral nutrition, duration of hospital stay, hospital acquired sepsis, time to reach full feeds and time to regain birth weight, prior knowledge is unlikely to influence assessment of outcomes. They were adjudged to be at low risk of bias. |
e- Trail protocol, registration details, and statistical analysis plan not available |
f- The published protocol mentions this as an observational study for electrogastrography (EGG). Hence, in effect, this protocol was not published/ or is planned as the study progressed |
g- high risk for outcomes of feeding intolerance and NEC; some concerns for other outcomes. |
On GRADE assessment, the certainty of evidence was rated high for days on parenteral nutrition; moderate for mortality, and time to reach full feeds; low for NEC 2 or more, hospital-acquired sepsis, duration of hospital stay, and time to regain birth weight; and very low for feeding intolerance (Table 4).
Table 4. GRADE evidence profile
Comparison 1: Early versus delayed initiation of feed in neonates with antenatal doppler abnormalities
Certainty assessment
|
№ of patients
|
Effect
|
Certainty
|
Importance
|
№ of studies
|
Study design
|
Risk of bias
|
Inconsistency
|
Indirectness
|
Imprecision
|
Other considerations
|
Early
|
delayed feed initiation
|
Relative (95% CI)
|
Absolute (95% CI)
|
|
|
Necrotizing enterocolitis 2A or more
|
6
|
randomised trials
|
seriousa
|
not serious
|
not serious
|
seriousb
|
none
|
54/385 (14.0%)
|
44/387 (11.4%)
|
OR 1.27 (0.83 to 1.96)
|
26 more per 1,000 (from 17 fewer to 87 more)
|
⨁⨁◯◯ Low
|
CRITICAL
|
Feeding intolerance
|
5
|
randomised trials
|
very seriousc
|
not serious
|
not serious
|
seriousb
|
none
|
112/355 (31.5%)
|
90/356 (25.3%)
|
OR 1.37 (0.98 to 1.92)
|
64 more per 1,000 (from 4 fewer to 141 more)
|
⨁◯◯◯ Very low
|
IMPORTANT
|
Time to reach full feeds
|
5
|
randomised trials
|
seriousd
|
not serious
|
not serious
|
not serious
|
none
|
345
|
346
|
-
|
MD 3.03 lower (3.53 lower to 2.53 lower)
|
⨁⨁⨁◯ Moderate
|
IMPORTANT
|
Duration of hospital stay
|
5
|
randomised trials
|
seriousd
|
not serious
|
not serious
|
seriousb
|
none
|
345
|
945
|
-
|
MD 4.98 lower (8.31 lower to 1.65 lower)
|
⨁⨁◯◯ Low
|
IMPORTANT
|
Mortality
|
3
|
randomised trials
|
not serious
|
not serious
|
not serious
|
seriousb
|
none
|
16/249 (6.4%)
|
20/249 (8.0%)
|
OR 0.79 (0.40 to 1.57)
|
16 fewer per 1,000 (from 47 fewer to 40 more)
|
⨁⨁⨁◯ Moderate
|
CRITICAL
|
Hospital acquired sepsis
|
4
|
randomised trials
|
seriouse
|
not serious
|
not serious
|
seriousb
|
none
|
63/279 (22.6%)
|
85/279 (30.5%)
|
OR 0.67 (0.45 to 0.98)
|
78 fewer per 1,000 (from 140 fewer to 4 fewer)
|
⨁⨁◯◯ Low
|
IMPORTANT
|
Days on total parenteral nutrition
|
3
|
randomised
trials
|
not serious
|
not serious
|
not serious
|
not serious
|
none
|
249
|
249
|
-
|
MD 3.14 lower (3.98 lower to 2.3 lower)
|
⨁⨁⨁⨁ High
|
IMPORTANT
|
Time to regain birth weight
|
2
|
randomised trials
|
seriousf
|
not serious
|
not serious
|
seriousb
|
none
|
97
|
98
|
-
|
MD 4.15 higher (9.57 lower to 17.86 higher)
|
⨁⨁◯◯ Low
|
IMPORTANT
|
CI: confidence interval; MD: mean difference; OR: odds ratio
Explanations
a. Of the 6 studies, 3 had "some concerns" in the randomization process, 1 due to deviation from intended intervention, and 5 studies in the selection of reported results.
b. The confidence intervals are wide
c. Of the 5 studies, 4 were adjudged to be at high risk of bias in the measurement of the outcome due to lack of blinding of outcome assessors. 2 studies had some concerns in the randomization process, 1 due to deviation from the intended intervention, and 4 in the selection of the reported result.
d. Of the 5 studies, 2 had some concerns in the randomization process and 4 in the selection of the reported result.
e. Of the 4 studies, 1 study had some concerns in the randomization process, and 3 studies in the selection of the reported outcome.
f. Of the 2 studies, 1 had some concerns in the randomization process and both in the selection of the reported outcome.
Comparison 2: Slow compared to Rapid advancement of feeds for neonates with antenatal doppler abnormalities
Certainty assessment
|
№ of patients
|
Effect
|
Certainty
|
Importance
|
№ of studies
|
Study design
|
Risk of bias
|
Inconsistency
|
Indirectness
|
Imprecision
|
Other considerations
|
Slow
|
Rapid advancement of feeds
|
Relative (95% CI)
|
Absolute (95% CI)
|
|
|
|
Necrotizing enterocolitis
|
1
|
randomised trials
|
not serious
|
seriousa
|
not serious
|
seriousb
|
none
|
3/40 (7.5%)
|
4/43 (9.3%)
|
OR 0.79 (0.17 to 3.77)
|
18 fewer per 1,000 (from 76 fewer to 186 more)
|
⨁⨁◯◯ Low
|
CRITICAL
|
|
Feeding intolerance
|
1
|
randomised trials
|
not serious
|
seriousa
|
not serious
|
seriousb
|
none
|
9/40 (22.5%)
|
11/43 (25.6%)
|
OR 0.84 (0.31 to 2.32)
|
32 fewer per 1,000 (from 160 fewer to 188 more)
|
⨁⨁◯◯ Low
|
IMPORTANT
|
|
Mortality
|
1
|
randomised trials
|
not serious
|
seriousa
|
not serious
|
seriousb
|
none
|
0/40 (0.0%)
|
5/43 (11.6%)
|
OR 0.09 (0.00 to 1.62)
|
105 fewer per 1,000 (from -- to 59 more)
|
⨁⨁◯◯ Low
|
CRITICAL
|
|
Hospital acquired sepsis
|
1
|
randomised trials
|
not serious
|
seriousa
|
not serious
|
seriousb
|
none
|
3/40 (7.5%)
|
6/43 (14.0%)
|
OR 0.50 (0.12 to 2.15)
|
65 fewer per 1,000 (from 120 fewer to 119 more)
|
⨁⨁◯◯ Low
|
IMPORTANT
|
|
Time to reach full feeds
|
1
|
randomised trials
|
not serious
|
seriousa
|
not serious
|
seriousb
|
none
|
40
|
43
|
-
|
MD 0.2 lower (0.39 lower to 0.01 lower)
|
⨁⨁◯◯ Low
|
IMPORTANT
|
|
Duration of parenteral nutrition
|
0
|
randomised trials
|
|
|
|
|
|
0
|
0
|
-
|
see comment
|
-
|
IMPORTANT
|
|
Duration of hospital stay
|
1
|
randomised trials
|
not serious
|
seriousa
|
not serious
|
seriousb
|
none
|
40
|
43
|
-
|
MD 3.4 higher (0.45 lower to 7.25 higher)
|
⨁⨁◯◯ Low
|
IMPORTANT
|
|
Time to regain birth weight
|
0
|
randomised trials
|
|
|
|
|
|
0
|
0
|
-
|
see comment
|
-
|
IMPORTANT
|
|
CI: confidence interval; MD: mean difference; OR: odds ratio
Explanations
a. Wide confidence interval
b. Small sample size
When compared to slower feed advancement, rapid feed advancement resulted in decreased time to reach full feeds (MD -0.2 days, 95% CI -0.39, -0.01). There was no difference in other outcomes. The overall risk of bias was adjudged to be low. However, because of the small sample size and wide confidence intervals, the certainty of evidence was rated low.