High Protein and High Energy Intakes and Physical Activity on Growth of Extremely Low Birth Weight Infants

Effect of High Protein and High Energy Intakes and Physical Activity on Growth and Body Composition of Extremely Low Birth Weight Infants: a Randomised Controlled Trial.

The aim of this study is to evaluate the effect of increasing amino acid and energy intake during parenteral and enteral nutrition with and without the stimulation of the infant's physical activity, on growth of extremely low birth weight infants .

Study Overview

• Status: Unknown
• Conditions: Infant, Very Low Birth Weight
• Intervention / Treatment: Behavioral: STIMUL +; Dietary supplement: NUTR +

Detailed Description

Increasing protein and energy intake above the anabolic capacity of a given individual may result in increased lipogenesis and excessive fat deposition. Adults with reduced mobility or with neuromuscular conditions will develop excessive fat deposition if they receive normal to high protein and energy intakes. Excessive fat deposition have been demonstrated in preterm infants receiving high energy intakes. Given that physical activity in preterms is often reduced for the prematurity itself, the associated sickness and the numerous medications, the investigators speculate that physical stimulation may have a beneficial effect on protein accretion and on lean mass accretion. The investigators further hypothesize that today's recommended daily intakes of proteins and energy cannot be fully incorporated into lean body mass without a concomitant physical activity. In spite of the fact that this notion is well accepted in adult physiology and in the elderly, it has never been tested in preterm infants.

This factorial randomised controlled trial will evaluate the effect of increasing amino acid intake (by 1 g/kg/d) and energy intake (by 20 kcal/kg/d) during parenteral nutrition and also of increasing protein intake and energy intake by an extra 1 g/kg/d during enteral nutrition, with and without the stimulation of the infant's physical activity, on growth of extremely low birth weight infants. The investigators aim at demonstrating that increasing energy and protein intake above the standard of care intakes will result in better growth only in association with adequate physical activity, in particular in relation to body composition and lean mass accretion.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Virgilio P. Carnielli, MD, PhD; Phone Number: 00390715962045; Email: v.carnielli@univpm.it
• Study Contact Backup: Name: Chiara Biagetti, MD; Phone Number: 00390715962014; Email: chiara.biagetti@ospedaliriuniti.marche.it

Study Locations

• Italy
  • Ancona, Italy, 60123
    • Recruiting
    • Ospedale G. Salesi
    • Contact: Virgilio P. Carnielli, MD, PhD; Phone Number: 00390715962045; Email: v.carnielli@univpm.it
    • Contact: Chiara Biagetti, MD; Phone Number: 00390715962014; Email: chiara.biagetti@ospedaliriuniti.marche.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 7 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 24 weeks < gestational age < 32 weeks
• inborn or outborn admitted before 24 hours of age
• parenteral or enteral nutrition start before 48 hours of age
• parental consent

Exclusion Criteria:

• difficulty in starting physical activity stimulation before 10 days of life
• death before 36 W PMA
• diagnosis of necrotising enterocolitis (before 36 W PMA)
• any major surgery (before 36 W PMA)
• congenital syndrome, severe malformations
• inborn errors of metabolism
• parental consent withdrawn

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: NUTR (Nutrition) 0_STIMUL(Stimulation) 0; Standard Nutrition and no Physical Stimulation
EXPERIMENTAL: NUTR 0_STIMUL +; Standard Nutrition and Physical Stimulation	Behavioral: STIMUL +; Physical activity stimulation consists in flexion/extension of the 4 limbs and other motion exercises of the shoulder girdle and of the hips. This stimulation will take place before the feed for a mean of 30 times a week (minimum 24- maximum 36 times a week, 10 minutes each time) and will start within the 10th day of life until 36 weeks postmenstrual age
EXPERIMENTAL: NUTR +_STIMUL 0; Enhanced Nutrition, and no Physical Stimulation	Dietary supplement: NUTR +; one extra g/kg/d of protein and lipids starting before 48 hours after birth until 36 weeks postmenstrual age
EXPERIMENTAL: NUTR +_STIMUL +; Enhanced Nutrition and Physical Stimulation	Behavioral: STIMUL +; Physical activity stimulation consists in flexion/extension of the 4 limbs and other motion exercises of the shoulder girdle and of the hips. This stimulation will take place before the feed for a mean of 30 times a week (minimum 24- maximum 36 times a week, 10 minutes each time) and will start within the 10th day of life until 36 weeks postmenstrual age; Dietary supplement: NUTR +; one extra g/kg/d of protein and lipids starting before 48 hours after birth until 36 weeks postmenstrual age

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight gain (Birth-36 Weeks PMA)	Weight gain from birth up to 36 weeks postmenstrual age (g/kg/d)	birth up to 36 weeks postmenstrual age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle ultrasound	Ultrasound measurement of mid thigh and mid arm muscle thickness (cm)	32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age(+-1d ), 36 weeks postmenstrual age(+-1d ), 40 weeks postmenstrual age(+-1d )
Adipose tissue ultrasound	Ultrasound measurement of mid thigh and mid arm adipose tissue thickness (cm)	32 weeks postmenstrual age(+-1d ), 34 weeks postmenstrual age(+-1d ), 36 weeks postmenstrual age(+-1d ), 40 weeks postmenstrual age(+-1d )
Lean body mass estimate using deuterium dilution	Urinary deuterium enrichment after 6 and 12 hours from deuterium oral administration (baseline)	36 weeks postmenstrual age (+-1d )
Skinfold thickness	Biceps and triceps skinfold thickness (both arms) (cm)	32 weeks postmenstrual age(+-1d ), 34 weeks postmenstrual age(+-1d ), 36 weeks postmenstrual age(+-1d ), 40 weeks postmenstrual age(+-1d ), between 22 and 24 months (2 years correct age)
Brain MRI	Brain injury, growth and maturation according to Kidokoro et al.	40 weeks postmenstrual age (+-1d )
Weight	weight measured by a digital infant scale (g)	birth, daily up to 36 weeks postmenstrual age; 40weeks postmenstrual age (+-1d ), between 22 and 24 months (2 years correct age)
Total body length	Total body length measured by a neonatal stadiometer (cm)	birth, weekly until 36 weeks postmenstrual age; 40weeks postmenstrual age (+-1d ), between 22 and 24 months (2 years correct age)
Head circumference	Head circumference measured by a flexible non-stretchable tape (cm)	birth, weekly up to 36 weeks postmenstrual age; 40weeks postmenstrual age (+-1d ), between 22 and 24 months (2 years correct age)
Tibial length	Knee-heel length measured by knemometry (cm)	birth, 32 weeks postmenstrual age(+-1d ), 34 weeks postmenstrual age(+-1d ), 36 weeks postmenstrual age(+-1d ), 40 weeks postmenstrual age(+-1d ), between 22 and 24 months (2 years correct age)
Weight gain (BW recovery-36W PMA)	Weight gain from the birth weight recovery until 36 weeks postmenstrual age (g/kg/d)	birth weight recovery up to 36 weeks postmenstrual age
Bayley III Cognitive Score (MDI)	Cognitive scale (range 55-145). The Scale has index mean scores of 100 (SD ± 15). An index composite score of < 70 (>2 SD below the mean) is defined to indicate severe impairment, while an index composite score of 70-84 (>1 SD below the mean) is defined to indicate mild impairment. Index composite scores ≥ 85 indicate normal development.	between 22 and 24 months (2 years correct age)
Bayley III Language Score	Language scale (range 45-155). The Scale has index mean scores of 100 (SD ± 15). An index composite score of < 70 (>2 SD below the mean) is defined to indicate severe impairment, while an index composite score of 70-84 (>1 SD below the mean) is defined to indicate mild impairment. Index composite scores ≥ 85 indicate normal development.	between 22 and 24 months (2 years correct age)
Bayley III Motor Score (PDI)	Motor scale (range 45-155). The Scale has index mean scores of 100 (SD ± 15). An index composite score of < 70 (>2 SD below the mean) is defined to indicate severe impairment, while an index composite score of 70-84 (>1 SD below the mean) is defined to indicate mild impairment. Index composite scores ≥ 85 indicate normal development.	between 22 and 24 months (2 years correct age)
Safety (metabolic tolerance)	Plasma and urinary urea (mg/dl), Plasma triglycerides (mg/dl), blood glucose (mg/dl)	At least daily during the first week of life, weekly up to 30 weeks postmenstrual age (when applicable), 30 weeks postmenstrual age (+-1d ), 32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age (+-1d ), 36 weeks postmenstrual age (+-1d )
Safety (haematology)	Complete blood count	At least daily during the first week of life, weekly up to 30 weeks postmenstrual age (when applicable), 30 weeks postmenstrual age (+-1d ), 32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age (+-1d ), 36 weeks postmenstrual age (+-1d )
Safety (gas-analysis)	Gas-analisys	At least daily during the first week of life, weekly up to 30 weeks postmenstrual age (when applicable), 30 weeks postmenstrual age (+-1d ), 32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age (+-1d ), 36 weeks postmenstrual age (+-1d )
Bone mineralisation	Plasma and urinary calcium and phosphorus, alkaline phosphatase, parathyroid hormone, osteocalcin measurements	6 weeks of age, 32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age (+-1d ), 36 weeks postmenstrual age (+-1d )
Bone ultrasound (1)	metacarpus speed of sound (m/s)	32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age (+-1d ), 36 weeks postmenstrual age (+-1d )
Bone ultrasound (2)	Metacarpus bone transmission time (ms)	32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age (+-1d ), 36 weeks postmenstrual age (+-1d )
Measurement of physical activity	Different levels of activity are assigned according to the Bruck's activity scale as described by Freymond et al. (24 hour continuous recording using a video camera). Levels of activity are defined as follows: 0, no body, arm, or leg movement, facial movement present or not with eyes closed or open; 1, arm or leg movement with eyes closed or open; 2, total body movement with eyes closed or open; 3, crying. Levels of activity in each group are expressed as percentage of time spent during the day in each level.	32 weeks postmenstrual age (+-1d ), 34 weeks postmenstrual age (+-1d ), 36 weeks postmenstrual age (+-1d ), 40 weeks postmenstrual age (+-1d) if still hospitalized
Morbidity	incidence of the main complication of prematurity	Hospital stay, on average 36 weeks postmenstrual age
Mortality	incidence of mortality	hospital stay, on average 36 weeks postmenstrual age

Collaborators and Investigators

• Sponsor: Università Politecnica delle Marche

Publications and helpful links

General Publications

• Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics. 2001 Feb;107(2):270-3. doi: 10.1542/peds.107.2.270.
• Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, Domellof M, Embleton ND, Fusch C, Genzel-Boroviczeny O, Goulet O, Kalhan SC, Kolacek S, Koletzko B, Lapillonne A, Mihatsch W, Moreno L, Neu J, Poindexter B, Puntis J, Putet G, Rigo J, Riskin A, Salle B, Sauer P, Shamir R, Szajewska H, Thureen P, Turck D, van Goudoever JB, Ziegler EE; ESPGHAN Committee on Nutrition. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010 Jan;50(1):85-91. doi: 10.1097/MPG.0b013e3181adaee0.
• Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R; Parenteral Nutrition Guidelines Working Group; European Society for Clinical Nutrition and Metabolism; European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN); European Society of Paediatric Research (ESPR). 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr. 2005 Nov;41 Suppl 2:S1-87. doi: 10.1097/01.mpg.0000181841.07090.f4. No abstract available.
• Burattini I, Bellagamba MP, Spagnoli C, D'Ascenzo R, Mazzoni N, Peretti A, Cogo PE, Carnielli VP; Marche Neonatal Network. Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial. J Pediatr. 2013 Nov;163(5):1278-82.e1. doi: 10.1016/j.jpeds.2013.06.075. Epub 2013 Aug 12.
• Bellagamba MP, Carmenati E, D'Ascenzo R, Malatesta M, Spagnoli C, Biagetti C, Burattini I, Carnielli VP. One Extra Gram of Protein to Preterm Infants From Birth to 1800 g: A Single-Blinded Randomized Clinical Trial. J Pediatr Gastroenterol Nutr. 2016 Jun;62(6):879-84. doi: 10.1097/MPG.0000000000000989.
• Biolo G, Ciocchi B, Stulle M, Piccoli A, Lorenzon S, Dal Mas V, Barazzoni R, Zanetti M, Guarnieri G. Metabolic consequences of physical inactivity. J Ren Nutr. 2005 Jan;15(1):49-53. doi: 10.1053/j.jrn.2004.09.009.
• Schulzke SM, Kaempfen S, Trachsel D, Patole SK. Physical activity programs for promoting bone mineralization and growth in preterm infants. Cochrane Database Syst Rev. 2014 Apr 22;(4):CD005387. doi: 10.1002/14651858.CD005387.pub3.
• Uthaya S, Thomas EL, Hamilton G, Dore CJ, Bell J, Modi N. Altered adiposity after extremely preterm birth. Pediatr Res. 2005 Feb;57(2):211-5. doi: 10.1203/01.PDR.0000148284.58934.1C. Epub 2004 Dec 20.
• Prado CM, Heymsfield SB. Lean tissue imaging: a new era for nutritional assessment and intervention. JPEN J Parenter Enteral Nutr. 2014 Nov;38(8):940-53. doi: 10.1177/0148607114550189. Epub 2014 Sep 19. Erratum In: JPEN J Parenter Enteral Nutr. 2016 Jul;40(5):742.
• Betto M, Gaio P, Ferrini I, De Terlizzi F, Zambolin M, Scattolin S, Pasinato A, Verlato G. Assessment of bone health in preterm infants through quantitative ultrasound and biochemical markers. J Matern Fetal Neonatal Med. 2014 Sep;27(13):1343-7. doi: 10.3109/14767058.2013.858317. Epub 2013 Nov 26.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 10, 2017
• Primary Completion (ANTICIPATED): April 3, 2020
• Study Completion (ANTICIPATED): July 30, 2022

Study Registration Dates

• First Submitted: November 13, 2017
• First Submitted That Met QC Criteria: December 10, 2017
• First Posted (ACTUAL): December 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 9, 2019
• Last Update Submitted That Met QC Criteria: May 7, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Preterm infants, growth, nutrition, physical activity
• Additional Relevant MeSH Terms: Body Weight; Birth Weight
• Other Study ID Numbers: DG-297

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No