Programming of NCDs in Preterm Infants Focus on Growth

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1 Note: for non-commercial purposes only Power of Programming 13 th Oct 2016 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

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3 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.

4 6.7% higher 2-hour glucose 6.7% higher fasting insulin 40.0% higher 2-hour insulin 18.9% higher HOMA-insulin-resistance index

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

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

7 Physiological adjustment to postnatal growth trajectories in healthy preterm infants Rochow et al. Ped Res 2016

8 Rapid Infancy Weight Gain and Subsequent Obesity Systematic Reviews: Monteiro & Victora (Obes Rev 2005): Baird et al. (BMJ 2005): Ong & Loos (Acta Paediatrica 2006): 13 studies 10 studies 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

9 Pro s & Con s of promoting postnatal growth Neurocognition Adult height Obesity Blood pressure Type 2 diabetes

10 Postnatal growth in preterm infants and later health outcomes: A systematic review Ken K. Ong 1, Kathy Kennedy 2, Eurídice Castañeda Gutiérrez 3, Stewart Forsyth 4, Keith Godfrey 5, Berthold Koletzko 6, Marie E. Latulippe 7, Susan E. Ozanne 8, Ricardo Rueda 9, Marieke H Schoemaker 10, Eline van der Beek 11, Stef van Buuren 12, Mary Fewtrell 2 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):

11 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.

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13 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.

14 Postnatal weight gain and Neurodevelopment Age at outcome Summary result RCT Exposure Timing N Effect on growth Enteral Biasini Human milk feedingdischarge 3 & 12m ++ Increased HC, WT & 2012 fortifier 61 (Griffith) (3m only) HT gains Cooke Enriched Discharge- 18m Increased HC, WT & 2001 formula 6m 113 (Bayley) 0 HT gains in boys Aimone Human milk Discharge- 18m Increased WT & HT 2009 fortifier 12wk 39 (Bayley) 0 (not HC) Lucas Enriched Discharge- 18m Increased WT & HT 2001 formula 9m 229 (Bayley) 0 (not HC) Lucas Enriched Birthdischarge 18m 1994 formula 215 (Bayley) 0 Increased WT & HC Lucas Enriched Birthdischarge formula y (IQ) (Boys only) Increased WT & HC

15 Postnatal weight gain and Neurodevelopment Age at outcome Summary result RCT Exposure Timing N Effect on growth Enteral Biasini Human milk feedingdischarge 3 & 12m ++ Increased HC, WT & 2012 fortifier 61 (Griffith) (3m only) HT gains Cooke Enriched Discharge- 18m Increased HC, WT & 2001 formula 6m 113 (Bayley) 0 HT gains in boys Aimone Human milk Discharge- 18m Increased WT & HT 2009 fortifier 12wk 39 (Bayley) 0 (not HC) Lucas Enriched Discharge- 18m Increased WT & HT 2001 formula 9m 229 (Bayley) 0 (not HC) Lucas Enriched Birthdischarge 18m 1994 formula 215 (Bayley) 0 Increased WT & HC Lucas Enriched Birthdischarge formula y (IQ) (Boys only) Increased WT & HC

16 Postnatal weight gain and Neurodevelopment 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.

17 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.

18 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.

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20 Postnatal weight gain and Adiposity 3 RCTs 4 observational studies

21 Postnatal weight gain and Adiposity RCT Exposure Timing N Koo 2006 Aimone 2009 Cooke 1999 Age at Summary outcome Enriched formula 41d-12m 89 12m ++ Human milk fortifier Enriched formula Discharge- 3m 39 12m 0 Discharge- 6m m + result Comments Intervention group surprisingly grew slower and had lower %BF Intervention increased WT and length gains, but not %BF Intervention increased WT gain and both fat and lean mass; non-significant increase in %BF

22 Postnatal weight gain and Adiposity 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).

23 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.

24 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 split proinsulin levels at 15 years

25 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 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

26 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.

27 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.

28 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.

29 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)

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

31 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

32 Comments Discordance between RCT & Observational studies might be explained by possible confounding factors in the observational studies (e.g. neonatal morbidities). Few observational studies included non-preterm controls.

33 Persisting effects of early postnatal rapid ( catch-up ) weight gain UK 1990 Weight SDS N = Birth 269 2yr 269 5yr 269 7yr 269 8yr Birth 2yr 5yr 7yr 8yr No catch-up Catch-up Change in Weight SDS 0-3y 129 Ong et al. BMJ 2000 plus updated ALSPAC data at age 8y

34 34-36 weeks Outcomes at 2 years Underweight Stunting Wasted OR=3.36 OR=2.30 OR=1.87

35 UK Millennium Cohort Study Boyle et al. BMJ 2012

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

37 Pro s & Con s of promoting postnatal growth Neurocognition Adult height Obesity Blood pressure Type 2 diabetes?

38 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

39 The Optimal Postnatal Growth Trajectory for Term Small for Gestational Age Babies: A Prospective Cohort Study Optimal outcomes Weight to length growth trajectory in term SGA infants classified by latent class model. The US Collaborative Perinatal Project Lei X, et al. J Peds, 166 (1) 2015

40 Acknowledgements Kathy Kennedy 2, Eurídice Castañeda Gutiérrez 3, Stewart Forsyth 4, Keith Godfrey 5, Berthold Koletzko 6, Marie E. Latulippe 7, Susan E. Ozanne 8, Ricardo Rueda 9, Marieke H Schoemaker 10, Eline van der Beek 11, Stef van Buuren 12, Mary Fewtrell 2 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): 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 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.