Optimal Growth of Preterm Infants With Growth Restriction (OPTIGROW)

Body Composition, Metabolic Programming and Long Term Outcome of Growth Restricted Preterm Infants Under Different Nutritional Management A Prospective Randomized Controlled Multicenter Trial

In this prospective randomized controlled multi center trial the investigators stratify "Very Low Birthweight " (VLBW)-infants with growth retardation in small for gestational age (SGA) or intrauterine growth restricted (IUGR) - infants and aim to investigate the impact of a nutritional management with enhanced nutrients from discharge up to the 52nd week of postconceptional age on growth, body composition, metabolic programming, metabolomics, microbiome and long term neurodevelopmental outcome. In this study, the investigators will evaluate the difference in metabolic profiles of SGA and IUGR preterm infants. The investigators will further longitudinally assess, how different nutritional interventions affect the altered pathways in the first year of life and identify, in combination with data available from metabolic markers, microbiome and breast milk analysis, potential pathways resulting in increased disease risk later in life.

Study Overview

• Status: Withdrawn
• Conditions: Diabetes; Adiposity; Growth Failure; Neurologic Deficits
• Intervention / Treatment: Dietary supplement: SGA-enhanced nutrients; Other: SGA-standard nutrients; Dietary supplement: IUGR-enhanced nutrients; Other: IUGR-standard nutrients

Detailed Description

Prematurity is the leading cause for mortality and morbidity in newborns with very low birth weight (VLBW) infants (< 1500g birth weight) at highest risk. Ten to thirty percent of VLBW infants are also born too small for their gestational age defined by a birth weight below the 10th percentile. In daily neonatal intensive care, consequential long term-follow up and most studies all growth restricted premature infants are treated the same, importantly this includes the nutritional management after birth. However, different groups of patients with different causal pathologies are subsumed under the definition growth restriction or born too small. One group of growth restricted patients refers to the infants born constitutionally small or small for gestational age (SGA). The other group refers to infants with an intrauterine growth restriction (IUGR) caused by a complex antenatal pathology. Consequently, the nutritional management after birth is very important to minimize the potential risk for developing obesity, diabetes and cardiovascular diseases later in life and to achieve optimal growth. So far we do not consider the different underlying pathomechanisms of growth restriction in our nutritional concepts for preterm infants and therefore cause long-term consequences. The European society of pediatric gastroenterology, hematology and nutrition (ESPGHAN) recommends to feed enhanced nutrients up to 52nd week of gestation in all growth restricted preterm infants- regardless if they are SGA or IUGR premature. Actually, reliable data guaranteeing that the recommended "enhanced nutrients strategy" providing extra nutrients up to 52 weeks for SGA and IUGR infants is safe and effective for both groups in terms of long-term growth and metabolic programming are lacking.

A total of 348 preterm infants born and discharged below the 10th percentile at term will be included in the study and stratified according to SGA or IUGR by a combination of antenatal ultrasound parameters and growth parameters (including 10% screening failures and 20% drop out. Furthermore IUGR and SGA growth restricted preterm infants will be stratified according to breastfeeding or formula feeding and randomized in one of the following groups: Standard nutrients group (breastfeeding or starter formula) or Enhanced nutrients group (fortified breast milk or post-discharge formula. Body composition measurements will be performed by air displacement plethysmography - a non-invasive method. Anthropometric measurements will be performed by measuring weight, height and head circumference. Furthermore, parameters of metabolic programming, metabolomics, the stool microbiome and neurodevelopmental outcome will be determined. Additionally, the stool microbiome will be characterized from infant stool samples and compared between the two groups. After an interventional period of three months infants will be followed up until 2 years of age.

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 9 months (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Preterm infants with a birth weight <1500g and birth weight <10th percentile.
• Weight at term <10th percentile
• Informed consent

Exclusion Criteria:

• Genetic or metabolic diseases with the primary effect on growth
• Necrotizing enterocolitis
• Intraventricular hemorrhage (IVH) >Grade II
• Periventricular leukomalacia (PVL) Stage III
• Genetic or metabolic disorders
• Bronchopulmonary dysplasia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: SGA-enhanced nutrients; Infants will receive fortified breast milk (>50% meals/d fortified, 1,4 g protein, 85 kcal/100ml, FM85, Nestle ®) or post discharge formula (2g protein; 73-75 kcal/100ml; Aptamil PDF, Milupa® or Beba F Nestle® ) between discharge and 52nd week of gestation (three months after term)	Dietary supplement: SGA-enhanced nutrients; Infants will receive fortified breast milk (>50% meals/d fortified, 1,4 g protein, 85 kcal/100ml, FM85, Nestle ®) or post discharge formula (2g protein; 73-75 kcal/100ml; Aptamil PDF, Milupa® or Beba F Nestle® ) between discharge and 52nd week of gestation (three months after term
OTHER: SGA-standard nutrients; Infants will receive unfortified breast milk (65-70kcal/100ml) or starter formula (1,2- 1,3g protein, 66 kcal/100ml Beba Pre Pro Start, Nestle® or Aptamil Pre, Milupa ®) between discharge and 52nd week of gestation (three months after term).	Other: SGA-standard nutrients; Infants will receive unfortified breast milk (65-70kcal/100ml) or starter formula (1,2- 1,3g protein, 66 kcal/100ml Beba Pre Pro Start, Nestle® or Aptamil Pre, Milupa ®) between discharge and 52nd week of gestation (three months after term)
ACTIVE_COMPARATOR: IUGR-enhanced nutrients; Infants will receive fortified breast milk (>50% meals/d fortified, 1,4 g protein, 85 kcal/100ml, FM85, Nestle ®) or post discharge formula (2g protein; 73-75 kcal/100ml; Aptamil PDF, Milupa® or Beba F Nestle® ) between discharge and 52nd week of gestation (three months after term	Dietary supplement: IUGR-enhanced nutrients; Infants will receive fortified breast milk (>50% meals/d fortified, 1,4 g protein, 85 kcal/100ml, FM85, Nestle ®) or post discharge formula (2g protein; 73-75 kcal/100ml; Aptamil PDF, Milupa® or Beba F Nestle® ) between discharge and 52nd week of gestation (three months after term
OTHER: IUGR-standard nutrients; Infants will receive unfortified breast milk (65-70kcal/100ml) or starter formula (1,2- 1,3g protein, 66 kcal/100ml Beba Pre Pro Start, Nestle® or Aptamil Pre, Milupa ®) between discharge and 52nd week of gestation (three months after term).	Other: IUGR-standard nutrients; Infants will receive unfortified breast milk (65-70kcal/100ml) or starter formula (1,2- 1,3g protein, 66 kcal/100ml Beba Pre Pro Start, Nestle® or Aptamil Pre, Milupa ®) between discharge and 52nd week of gestation (three months after term)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fat Free Mass	Fat free mass measured by body plethysmography	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
anthropometry-length	length in cm	24 months
anthropometry-weight	weight in grams	24 months
anthropometry-HC	head circumference in cm	24 months
anthropometry-z-score	z-scores	24 months
parameters of metabolic programming- IGF1	IGF-1in ng/ml	12 months
parameters of metabolic programming-IGF3	IGF-3 in ng/ml	12 months
parameters of metabolic programming-IGF-BP	IGF-BP in ng/ml	12 months
parameters of metabolic programming-Leptin	Leptin in ng/ml	12 months
parameters of metabolic programming-Adiponectin	Adiponectin in mcg/ml	12 months
neurodevelopmental outcome	Bayley scales	24months
metabolomics	Metabolomic analysis will determine around 200 metabolites covering polar lipids (SOFIA), acylcarnitines (CARN), non-esterified fatty acids (NEFA) and amino acids (AA). Data will be acquired according to retention time and mass transition on triple quadrupole mass spectrometer, controlled by Analyst. All metabolite concentrations are reported in µmol/L	12 months
stool microbiome		24 months
macronutrients in breastmilk-fat	Fat will be analysed by modified Mojonnierether extraction (g/100ml)	6 months
macronutrients in breastmilk-Lactose	Lactose will be determined by Lactose analysis method: LC-MS/MS (g/100ml)	6 months
macronutrients in breastmilk-protein	Protein will be determined by elemental analysis (g/100ml)	6 months

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Medical University of Graz; Lund University; University of Erlangen-Nürnberg Medical School; Ludwig-Maximilians - University of Munich; Poznan University of Medical Sciences; University Hospital Tuebingen; University of Milan
• Investigators: Principal Investigator: Nadja Haiden, MD, MUW

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): March 1, 2019
• Primary Completion (ANTICIPATED): January 1, 2020
• Study Completion (ANTICIPATED): January 1, 2022

Study Registration Dates

• First Submitted: December 5, 2016
• First Submitted That Met QC Criteria: December 17, 2016
• First Posted (ESTIMATE): December 21, 2016

Study Record Updates

• Last Update Posted (ACTUAL): March 21, 2019
• Last Update Submitted That Met QC Criteria: March 19, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: growth; preterm infants; body composition; microbiome; metabolomics; neurodevelopmental outcome; metabolic programming; SGA infants; IUGR infants; adiposity markers
• Additional Relevant MeSH Terms: Nervous System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Failure to Thrive; Neurologic Manifestations
• Other Study ID Numbers: OPTIGROW

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