programming of ncds in preterm infants focus on …...programming of ncds in preterm infants focus...

Programming of NCDs in Preterm Infants Focus on Growth

Ken Ong

Programme Leader MRC Epidemiology Unit, IMS, University of

Cambridge, UK

Paediatric Endocrinologist Department of Paediatrics, University of Cambridge,

UK

Power of Programming 13th Oct 2016

Note: for non-commercial purposes only

Mean difference (95% CI) in Parent Report of Children's Abilities-Revised (PARCA-R) z scores between late and moderately preterm (32–36 weeks

gestation) and term-born (37–42 weeks gestation) infants.

Samantha Johnson et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F301-F308

Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.

• 6.7% higher 2-hour glucose • 6.7% higher fasting insulin • 40.0% higher 2-hour insulin • 18.9% higher HOMA-insulin-resistance index

Preterm-birth and later risk of Type 2 Diabetes: Systematic review and meta-analysis. Li et al. Obesity Reviews 2014

Preterm-birth and later Systolic Blood Pressure: Systematic review and meta-analysis. De Jong et al. Hypertension 2012

Rochow et al. Ped Res 2016

Physiological adjustment to postnatal growth trajectories in healthy preterm infants

Rapid Infancy Weight Gain and Subsequent Obesity

Systematic Reviews:

Monteiro & Victora (Obes Rev 2005): 13 studies

Baird et al. (BMJ 2005): 10 studies

Ong & Loos (Acta Paediatrica 2006): 21 studies

*Woo Baidal et al, (Am J Prev Med 2016) 45 / 46 studies

*Risk Factors for Childhood Obesity in the First 1,000 Days: A Systematic Review

Woo Baidal et al, Am J Prev Med 2016

Pro’s & Con’s of promoting postnatal growth

Neurocognition Adult height

Obesity Blood pressure Type 2 diabetes

Postnatal growth in preterm infants and later health outcomes: A systematic review

Ken K. Ong1, Kathy Kennedy2, Eurídice Castañeda Gutiérrez3, Stewart Forsyth4, Keith Godfrey5, Berthold Koletzko6, Marie E. Latulippe7, Susan E. Ozanne8, Ricardo Rueda9,

Marieke H Schoemaker10, Eline van der Beek11, Stef van Buuren12 , Mary Fewtrell2

1. MRC Epidemiology Unit, University of Cambridge, UK; 2. Institute of Child Health, UCL, London, UK; 3. Nestlé Research Center, Switzerland; 4. DSM-Martek Division, UK; 5. MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research

Centre, University of Southampton, UK; 6. University of Munich, Germany, 7. ILSI Europe, Brussels, Belgium; 8. Metabolic Research Laboratories, University of Cambridge, UK; 9. Abbott Nutrition, Granada, Spain; 10. Mead Johnson Pediatric Nutrition Institute, Nijmegen, The Netherlands; 11. Nutricia Research, Danone Nutricia Early Life Nutrition, Singapore; 12. University of Utrecht, The Netherlands

Acta Paediatrica 2015 Oct; 104(10):974-86.

Methods

A systematic search (Medline, EMBASE and Google Scholar) published between 2003 and 2013 For studies reporting associations between growth of preterm infants participating in intervention trials (RCT) or cohorts (prospective or retrospective) and later cognitive or metabolic outcomes. Studies published before 2003 were extracted from a review by Baird et al. Baird J, Lucas P, Kleijnen J, Fisher D, Roberts H, Law C.

Defining optimal infant growth for lifetime health: a systematic review of lay and scientific literature.

http://www.mrc.soton.ac.uk/systematic-review/2005.

Postnatal weight gain and Neurodevelopment

• 6 RCTs which promoted weight gain

• One RCT (Biasini2012) found a (transient) benefit of faster growth from birth to 3 months of age.

• One RCT (Lucas1998) reported a benefit of faster growth in boys but not girls.

• Four RCTs found no benefit of rapid growth on neurodevelopment.


RCT Exposure Timing N Age at outcome

Summary result Effect on growth

Biasini 2012

Human milk fortifier

Enteral feeding-discharge 61

3 & 12m (Griffith)

++ (3m only)

Increased HC, WT & HT gains

Cooke 2001

Enriched formula

Discharge-6m 113

18m (Bayley) 0

Increased HC, WT & HT gains in boys

Aimone 2009


Discharge-12wk 39

18m (Bayley) 0

Increased WT & HT (not HC)

Lucas 2001

Enriched formula

Discharge-9m 229

18m (Bayley) 0

Increased WT & HT (not HC)

Lucas 1994

Enriched formula

Birth-discharge 215

18m (Bayley) 0 Increased WT & HC

Lucas 1998

Enriched formula

Birth-discharge 360 7-8y (IQ)

++ (Boys only) Increased WT & HC


• 19 observational studies relating weight to a neurodevelopmental outcome.

• 15/19 observational studies reported that rapid weight gain was associated with some improvement in neurodevelopment.

Figures: ‘Gain-outcome graphs’. Each row indicates a study result. A red bar indicates a significant positive association. A grey bar indicates a non-significant positive association.

Postnatal head growth and Neurodevelopment

• 4 RCTs and 16 observational studies

• One RCT (Biasini2012) found a (transient) benefit of early head growth on cognition.

• One RCT (Lucas1998) reported a benefit of faster growth only in boys.

• Most observational studies reported a consistent positive association between head growth and neurodevelopmental outcomes at ages 12 months to adulthood.

Postnatal weight gain and Adiposity

• 3 RCTs • 4 observational studies


RCT Exposure Timing N Age at

outcome Summary

result Comments

Koo 2006

Enriched formula 41d-12m 89 12m ++

Intervention group surprisingly grew slower and had lower %BF

Aimone 2009


Discharge-3m 39 12m 0

Intervention increased WT and length gains, but not %BF

Cooke 1999

Enriched formula

Discharge-6m 129 12m +

Intervention increased WT gain and both fat and lean mass; non-significant increase in %BF


• 3 RCTs • 4 observational studies • 3 observational studies reported positive associations

with percentage body fat • The two larger studies reported positive associations

with percentage body fat in young adults • And stronger effects of weight gain during earlier

(between birth to three months corrected age) versus later infancy (between 3–12 months).

Postnatal weight gain and Insulin resistance

• 1 RCT & 4 observational studies

• In the one RCT (Singhal2003), the nutrient enriched diet increased both postnatal weight gain and fasting 32-33 split proinsulin levels at 15 years

Postnatal weight gain and Insulin resistance

• 1 RCT & 4 observational studies

• In the one RCT (Singhal2003), the nutrient enriched diet increased both postnatal weight gain and fasting 32-33 split proinsulin levels at 15 years

• 3/4 observational studies reported positive associations between weight gain and insulin resistance at ages 10 to 22 years. The timing of the window of the weight gain was variable

Postnatal weight gain and other CVD risk factors

• 8 observational studies reported associations between weight gain and: blood pressure, total cholesterol, flow mediated dilatation and carotid intima-media thickness.

• These tended to be bigger (n>160) and have longer follow-up periods (>6 years) than the studies of cognitive outcomes.

Summary

• RCTs – Sparse evidence. Early (pre-discharge) interventions appeared more promising for Neurocognition

• Observational studies – Consistent positive associations with Neurocognition (15/19 studies), Adiposity (3/4 studies), & Insulin Resistance (3/4 studies)

• Observational studies – Inconsistent associations with Blood Pressure (2/5 studies), Cholesterol (1/3 studies), CIMT (1/1 study), & FMD (1/1 study)

Comments

• Discordance between RCT & Observational studies might be explained by possible confounding factors in the observational studies (e.g. neonatal morbidities).

Serial MR Imaging of Brain Growth in a Normal Female Preterm Infant

Changes in brain volume and maturation with

increasing gestational age

In an infant born at 25 weeks gestational age,

weighing 710 g.

Kapellou et al. PLoS Med 2006

Comments


• Few observational studies included non-preterm controls.

Persisting effects of early postnatal rapid (“catch-up”) weight gain

129269 129269 129269 129269 129269N =

Change in Weight SDS 0-3y

Catch-upNo catch-up

UK

199

0 W

eigh

t SD

S

1.5

1.0

.5

0.0

-.5

-1.0 Birth 2yr 5yr 7yr 8yr Birth 2yr 5yr 7yr 8yr Ong et al. BMJ 2000

plus updated ALSPAC data

at age 8y

34-36 weeks – Outcomes at 2 years

Underweight OR=3.36

Stunting OR=2.30

Wasted OR=1.87

UK Millennium Cohort Study

Boyle et al. BMJ 2012

Comments


• Few observational studies included non-preterm controls.

Suggestions for future research:

• RCTs of nutritional interventions in preterm and term infants should report effects on weight gain and growth, as well as later body composition and neurocognitive outcomes.

Pro’s & Con’s of promoting postnatal growth

Neurocognition Adult height

Obesity Blood pressure

Type 2 diabetes?

Genome-wide associations for birth weight and correlations with adult disease. Nature, Sept 2016 Momoko Horikoshi*, Robin Beaumont*, Felix Day*, Nicole Warrington*, Marjolein Kooijman*, Juan Fernandez-Tajes*, ………….on behalf of the Early Growth Genetics (EGG) Consortium

60 loci associated with BW (P<5x10-8)

Genetic correlations with BW +ve with BMI, Waist circ. -ve with CVD, BP, T2DM

Weight to length growth trajectory in term SGA infants classified by latent class model. The US Collaborative Perinatal Project 1959-1976

The Optimal Postnatal Growth Trajectory for Term Small for Gestational Age Babies: A Prospective Cohort Study

Lei X, et al. J Peds, 166 (1) 2015

Optimal outcomes

Kathy Kennedy2, Eurídice Castañeda Gutiérrez3, Stewart Forsyth4, Keith Godfrey5, Berthold Koletzko6, Marie E. Latulippe7, Susan E. Ozanne8, Ricardo Rueda9,

Marieke H Schoemaker10, Eline van der Beek11, Stef van Buuren12 , Mary Fewtrell2 2. Institute of Child Health, UCL, London, UK; 3. Nestlé Research Center, Switzerland; 4. DSM-Martek Division, UK; 5. MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical

Research Centre, University of Southampton, UK; 6. University of Munich, Germany, 7. ILSI Europe, Brussels, Belgium; 8. Metabolic Research Laboratories, University of Cambridge, UK; 9. Abbott Nutrition, Granada, Spain; 10. Mead Johnson Pediatric Nutrition Institute, Nijmegen, The Netherlands; 11. Nutricia Research, Danone Nutricia Early Life Nutrition, Singapore; 12. University of Utrecht, The Netherlands

Acta Paediatrica 2015 Oct; 104(10): 974-86.

Acknowledgements

ILSI Europe fosters collaboration between the best scientists from industry, academic and public sectors to provide scientific consensus on nutrition and food safety that improves public health.

International Life Sciences Institute (ILSI Europe). Metabolic Imprinting Task Force. Scientific Project Managers: Dr Pratima Rao Jasti & Dr Jackie Whyte, Former member: Dr Florence Rochat

programming of ncds in preterm infants focus on …...programming of ncds in preterm infants focus...

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