Journal Club

JAN 20, 2020

The New England Journal of Medicine 381;15 nejm.org October 10, 2019

Introduction(1)

• Very preterm or who have a VLBW are fed increasing volumes of milk

per day until they reach full enteral feeding volumes.

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• The approach to increasing the feeding volume per day is uncertain

because of competing concerns.

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• Observational studies have shown a higher risk of NEC with rapid

advancement of feeding volumes but are subject to bias.

Introduction(2)

• Slower advances in feeding volume might, however, increase the risk

of LOS from longer exposure to parenteral feeding, as shown in a

meta-analysis that also revealed no increase in necrotizing enterocolitis.

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• Existing trial data are insufficient to determine whether advancing

enteral feeding volumes slowly (by < 24 ml/kg/day) as compared with

more quickly (by 30-40 ml/kg/day).

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• The Speed of Increasing Milk Feeds Trial (SIFT) compared faster

(30 ml/kg) with slower (18 ml/kg) daily increments in milk feeding

volumes.

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Methods(1)

• A multicenter, parallel-group, randomized, controlled trial.

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• Approved by the East Midlands National Research and the National

Maternity Hospital Ethics Committee in Dublin.

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• Between June8, 2013 and June30, 2015 from 55 hospitals.

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• Informed consent was obtained from parents.

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Methods(2)

Inclusion criteria

I. Born before 32 weeks of gestation, had a birth weight of less than

1500 g, or both.

II. Receiving less than 30 ml/kg/day of milk at randomization.

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Exclusion criteria

Severe congenital anomaly or no realistic chance of survival or who

were unlikely to be traceable for follow-up at 24 months.

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Methods(3)

• Computerized randomization was performed through a secure

website hosted by the National Perinatal Epidemiology Unit Clinical

Trials Unit, University of Oxford.

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• A minimization algorithm balanced prognostic factors: hospital,

multiple birth, GA range and whether the BW was below 10th percentile

for gestational age, including infants from multiple births were assigned to the same treatment.

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Methods(4)

• Infants were randomly assigned to receive daily increments in

feeding volume of…

“ 30 ml/kg (faster increment) or 18 ml/kg (slower increment) ”

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• All other aspects of feeding and care followed routine clinical practice

in the individual units, including the capacity to stop or alter the rate of

increase in feeding volume if clinically indicated.

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• Data were corrected ay trial eytry, including whether the infant had

absent or reversed end-diastolic umbilical arterial blood flow identified

on any antenatal ultrasonographic scan.

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Measurement(1)

• The primary outcome was survival without moderate or severe

neurodevelopmental disability at 24 months of age, corrected for

gestational age at birth.

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• Moderate or severe neurodevelopmental disability was defined as any of the following: visual, hearing, gross motor impairment and cognitive

impairment as assessed with the use of the Parent Report of Children’s

Abilities–Revised (PARCA-R).

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PARCA-R: Screening of cognitive and language delay in preterm born infants

Ref. https://www2.le.ac.uk/partnership/parca-r/docs/parca-r-manual

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Measurement(2)

• The secondary outcome included

- death before discharge home

- microbiologically confirmed or clinically suspected LOS

- Bell’s stage 2 or 3 NEC

- time taken to reach full milk feeding volume

(150 ml/kg/day for 3 consecutive days)

- growth (change in Wt and HC z score for GA)

- duration of parenteral feeding, time in intensive care,

hospital stay to discharge home

- diagnosis of cerebral palsy

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Sample size(1)

• Estimated that 80% of infants would survive to 2 yrs and that 11% of survivors would have moderate or severe neurodevelopmental disability. We anticipated that the primary outcome would occur in 71% of the comparator (slower increment) group

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• Allowance for a questionnaire response rate of 80%, there would be 90% power to detect an absolute difference of 6.3 percentage points in the incidence of the primary outcome between the trial groups with a two-sided significance level of 5%.

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Sample size(2)

• Enrollment of 2500 infants would provide the trial with 90% power

to detect an absolute difference of 5.4 percentage points (from 25.0% in the comparator group) in the incidence of LOS and an absolute difference of 3.5 percentage points (from 6.0% in the comparator group) in the incidence of NEC (Bell’s stage 2 or 3).

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• An inflation factor of 1.12 was applied to the sample size to allow

for multiple births, since infants from a multiple birth received the same treatment and we anticipated correlated outcomes.

Sample size(3)

• This adjustment assumed the percentage of multiple births to be 25% and an intraclass correlation coefficient of 0.9 for the primary outcome at 24 months, corrected for gestational age.

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• The total target sample size was therefore increased to 2800.

Statistics(1)

• Demographic factors, clinical characteristics, and outcomes were

summarized with counts and percentages for categorical variables.

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• Means and standard deviations for normally distributed continuous

variables, or medians (interquartile or entire ranges) for other

continuous variables.

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• For primary outcome, an adjusted RR with 95% confidence were

calculated using log binomial regression, or log poisson regression

with a robust variance estimator if binomial model fails to converge.

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Statistics(2)

• Linear regression was used for normally distributed outcome,

and quantile regression for skewed continuous variables, and

Cox regression for time to event outcome.

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• 95% confidence intervals were calculated for all secondary outcome.

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• Subgroup analysis were performed on primary outcome, and the

Incidence of sepsis and NEC.

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• Pre-specified and Post hoc analysis for subgroup analysis.

i. week of GA, ii. Birth wieght (10^th centile for GA), iii. Type of milk

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Results

Participants

Results(1)

• Survival without moderate or severe neurodevelopmental disability

at 24 months occurred in

- 802 of 1224 infants (65.5%) assigned to the faster increment

- 848 of 1246 infants (68.1%) assigned to the slower increment

(adjusted risk ratio, 0.96; 95% confidence interval [CI] , 0.92 to 1.01)

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Results(2)

• Late onset sepsis occurred in

- 414 of 1389 infants (29.8%) in the faster-increment group

- 434 of 1397 (31.1%) in the slower-increment group

(adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07)

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• Bell’s stage 2 or 3 Necrotizing enterocolitis occurred in

- 70 of 1394 infants (5.0%) in the faster-increment group

- 78 of 1399 (5.6%) in the slower-increment group

(adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16)

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Complications

• Four serious adverse events that were not pre-specified as outcomes

were reported.

i. one infant in each group had an intracardiac thrombus, with one of

these extending into the superior vena cava and causing renal failure

and death (faster-increment group).

ii. one infant (faster-increment group) had conjugated hyper-

bilirubinemia, which resolved.

iii. and one infant (slower-increment group) became dehydrated briefly

with extravasation from a central venous catheter.

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Discussion(1)

• Although these feeding outcomes seem to favor faster increments,

the risk of moderate or severe motor impairment was unexpectedly

higher in the faster-increment group than in the slower-increment

group. This observation is unexplained.

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• Infants born at extremely GA or ELBW may react differently than

other infants to the speed of increasing feeding volumes. We did not

find appreciable differences in outcome according to these variables,

and trial included relatively small numbers of infants in these categories,

further research may be warranted in these groups.

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Discussion(2)

• Observational data have suggested a reduced risk of NEC among

very preterm or VLBW infants fed breast milk, but most participating

infants in SIFT were fed, at least partially, with breast milk.

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Limitation

• The trial was unblinded, because it was considered impractical for

caregivers and parents to be unaware of the trial-group assignments.

Conclusion

• SIFT — did not have a significant effect on the primary outcome of

survival without moderate or severe neurodevelopmental disability,

nor did it affect the risks of LOS or NEC in very preterm or VLBW infants.

Journal Club

JAN 20, 2020