YEARS

PROTEIN INTRAVENOUS NUTRITION ON

DEVELOPMENT (PROVIDE) TRIAL
INTRODUCTION

 A fetus receives amino acids at an estimated rate of 3 to 4 g per kilogram of body weight per day, an amount that
supports fetal growth and brain development.
 Preterm infants have impaired brain maturation after birth, which is reflected in altered brain size, structure,
connectivity, and function, as compared with the maturation in full term infants.
 Insufficient protein is known to lead to a negative nitrogen balance.
 The appropriate protein intake to support the growth and development of infants with extremely low birth weight
(<1000 g) is unknown, especially in the first few days after birth.
BACKGROUND

 Observational studies showed associations between higher levels of protein intake and better growth and
neurodevelopment. This has prompted recommendations for earlier and higher amino acid intake for ELBW.
 However, data from randomized, controlled trials that are powered to detect differences in morbidity, mortality,
and important functional outcomes are lacking.
 Of concern, trials in which parenteral nutrition was begun early in critically ill adults and children have shown
decreased survival and, in a subgroup of full-term newborns, adverse neurodevelopmental outcomes at 2 years of
age.
 Whether this outcome also occurs with parenteral nutrition in the first postnatal days in extremely preterm
neonates is not known.
PROBLEM STATEMENT

 Whether higher parenteral amino acid intake improves outcomes in infants with extremely low birth weight <
1000 gm is unclear.
 The aim of the Protein Intravenous Nutrition on Development (ProVIDe) trial was to determine whether the
administration of amino acids at an additional 1 g per day starting within 24 hours after birth and continuing for 5
days would increase the percentage of children who survived without neurodisability at an age of 2 years,
corrected for gestational age at birth.
METHODOLOGY

 Multicenter, parallel-group, double-blind, two-group, randomized, controlled trial.

 Infants with birth weights of less than 1000 g
 Intervention group - receive amino acids at a dose of 1 g per day for the first 5 days after birth.(in addition to usual
nutrition)
 Control group – received placebo
Inclusion criteria – Infants with a birth weight of less than 1000 g.
Exclusion criteria –
 admission to the neonatal intensive care unit (NICU) more than 24 hours after birth
 multiple births of more than 2 infants
 presence of a known chromosomal, genetic, or congenital disorder that affects growth
 presence of an inborn error of metabolism
 danger of imminent death
OUTCOMES
PRIMARY OUTCOME

 Survival free from neurodisability at 2 years, corrected for gestational age at birth.

Assessed using
 Bayley Scales of Infant and Toddler Development, third edition (Bayley-III)
 Neurologic examination
 Behavior Rating Inventory of Executive Function–Preschool Version
 Child Behavior Checklist

Neurodisabilities classified as severe, moderate, or mild.

SECONDARY OUTCOMES

 Secondary outcomes were the components of the primary outcome as well as the presence or absence of neonatal
disorders, the rate of growth, and nutritional intake.
 Intraventricular hemorrhage (any); cerebellar hemorrhage; periventricular leukomalacia
 Patent ductus arteriosus
 Necrotizing enterocolitis of stage II or higher on the Bell classification scale
 Chronic lung disease
 Retinopathy of prematurity of stage 3 or higher
 Sepsis
 Serum concentrations of urea, calcium, phosphate, and ammonia
 Length of neonatal unit stay
 Infant growth (weight, length, and head circumference, as absolute and z scores,at 28 days, 8 weeks, 36 weeks’
postmenstrual age, neonatal unit discharge, and 2 years corrected age)
RESULTS
RESULTS

434 infants were enrolled. 217 assigned to each group.

The mean parenteral amino acid intake in the first 7 days after birth was higher in the intervention group (3.4±0.6 g
per kilogram per day) than in the placebo group (2.6±0.6 g per kilogram per day).
PRIMARY OUTCOME
The primary outcome was available for 203 infants (93.6%) in the intervention group and 205 (94.5%) in the placebo
group.
Survival free from neurodisability at 2 yrs age was observed in
 97 of 203 children (47.8%) in the intervention group
 102 of 205 (49.8%) in the placebo group
 P value 0.56 , adjusted relative risk, 0.95 (Not significant)
PRIMARY OUTCOMES

Death before the age of 2 years occurred in

 39 of 217 children (18.0%) in the intervention group
 42 of 217 (19.4%) in the placebo group

Neurodisability occurred in
 67 of 164 children (40.9%) in the intervention group
 61 of 163 (37.4%) in the placebo group
 adjusted relative risk, 1.16
PRIMARY OUTCOMES

 Moderate-to-severe neurodisability appeared to be more common in the intervention group (27 of 164 infants
assessed [16.5%]) than in the placebo group (14 of 163 [8.6%]) (adjusted relative risk, 1.95; 95% CI, 1.09 to
3.48).
 Moderate-to-severe cognitive delay appeared to be more common in the intervention group.
 Language scores on the Bayley-III scale appeared to be lower in the intervention group.
 Other individual components of the primary outcome were similar in the two groups
PRIMARY OUTCOMES
 SECONDARY OUTCOMES
(INCREASED IN INTERVENTION GROUP)

 Patent ductus arteriosus (adjusted relative risk, 1.30)

 Serum concentrations of urea were higher in the intervention group
 Hypophosphatemia
 Refeeding syndrome (adjusted relative risk, 1.64)
 SECONDARY OUTCOMES
(SIMILAR IN BOTH GROUPS)

 Neonatal morbidity and mortality.

 Length of NICU stay for those who survived to hospital discharge.
 Serum concentrations of ammonia.
 Time to reach full enteral feeding and the type of feeding at the time of hospital discharge.
 Other measurements of growth except weight.
 SECONDARY OUTCOMES
(DECREASED IN INTERVENTION GROUP)

 Serum concentrations of phosphate and calcium

 Results suggest that infants in the intervention group had a lesser decrease in z scores for weight between birth and
4 weeks than those in the placebo group and consequently were heavier at 4 weeks.
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DISCUSSION

 Administration of amino acids at a dose of 1 g per day for 5 days after birth resulted in no significant difference in
the incidence of death or survival without neurodisability at a corrected age of 2 years.
 In analyses of secondary outcomes, the results were consistent with a possible increase in moderate to-severe
neurodisability among infants who received the intervention.
 Amino acid intake in the placebo group fell within the range of the most recent recommendations of 2.5 to 3.5 g
per kilogram per day.
 Our findings support these recommendations and suggest that intake levels higher than 2.5 to 3.5 g/kg/day are not
needed to support growth and may have adverse effects on neurodevelopment.
 Infants in the intervention group had more patent ductus arteriosus, along with refeeding syndrome and its
characteristic biochemical feature, hypophosphatemia, than infants in the placebo group, which we speculate
could have contributed to the neurodevelopmental outcomes.
 Urea concentrations were elevated in the intervention group, but ammonia concentrations were similar in the two
groups and were in the range of concentrations seen in full-term infants.
 The intervention was associated with increased early weight gain but this difference did not persist.
 The small and temporary effects on weight suggest that parenteral amino acid intake in the placebo group was
sufficient to support growth.
 Such effects also suggest that amino acid intake above those in the placebo group during the first 5 days after birth
did not enhance head growth.
CONCLUSION

 In infants with extremely low birth weight, additional parenteral amino acids administered at a dose of 1 g per day
in the first 5 days after birth did not result in a higher rate of survival without neurodisability at a corrected age of
2 years.
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