EARLY INFANT FEEDING AND LONG-TERM CONSEQUENCES (OBESITY)

Adequate protein intake 0 – 12 (24) months Exclusive breastfeeding until 6 months, continuation of breastfeeding until 2 years >6 months introduction of solids

The First 1,000 Days – Programming for Healthy Life 270 days of pregnancy 365 days of baby’s first year 365 days of baby’s second year The ‘programming’ that takes place during this period has a life-long impact on many aspects of future health Programming of healthy or non-healthy growth Metabolic programming (Obesity, cognitive deficits) Programming of Immune response (infections, allergy) Saavedra JM and Dattilo AM. Elsevier, Oxford 2017:xxxv.

Worldwide, the prevalence of overweight and obesity combined rose by 27.5% for adults and 47.1% for children between 1980 and 2013 Ng et al. Lancet 2014;388:766-781

Risk factors for later obesity: early nutrition and lifestyle Maternal overweight/obesity Rapid weight gain during infancy High protein intake during infancy and early childhood Weng SF et al. Arch Dis Child 2012;97:1019–1026; Salsberry PJ et al. Pediatrics. 2005;116(6):1329-38. Li L et al. J Dev Orig Health Dis 2014;5:435-447; Rolland-Cachera Mf et al. Int J Obes Relat Metab Disord. 1995;19(8):573-8 .

True protein concentration in breastmilk is rapidly decreasing between 0–12 months True Protein (g/100mL) 3 2 1 4 6 8 10 12 Time (months) 6 -24 months 1.3 – 1.5 g protein/100 kcal 1 -6 months 1.4 – 1.7 g protein/100 kcal Lonnerdal B et al. J Nutr Biochem 2017;41:1-11.

Protein concentrations (g/100ml) in old infant formulas, old follow-up formulas and cow’s milk are higher than in breast milk True Protein (g/100mL) 3 2 1 4 6 8 10 12 Time (months) Old infant formulas Old Follow-up formulas Cow´s milk Lonnerdal B et al. J Nutr Biochem 2017;41:1-11.

Protein intake (grams/day) Average protein intake, g/day, of non-breastfed infants and young children compared to the Recommended Dietary Allowance (FITS 2016) Protein intake (grams/day) RDA RDA RDA Cut? Average energy intake > EER at all time points. Possible that Mother’s overestimated portion sizes consumed – yet, extensive training with 4-pass methodology to accurately represent 24-hr food consumption with FITS methodology. In 2004: increase over EER was 10% at 4-6 mo, 23% at 7-12 mo and 31% at 12-24 mo. In 2008: increase over EER at 0-5 mo = 13.6%; 6-11 mo = 18.4% and 12-23 mo = 21.8% In 2008, infants participating in the FITS survey, age birth to 5months, consumed nearly 14% more calories (83 kcal/d) than estimated needs. Applying the first law of thermodynamics in its simplest form, after 6 weeks, an estimated 0.45 kg weight gain would be possible, and after 6 months, an additional 1.9 kg of weight could be predicted. Utilizing an average weight of 7.9 kg for a 6-month-old infant boy, the weight differential of 1.9 kg corresponds to the difference between a weight for age between the 50th percentile and the 98th percentile. Computed the mean EER for each age group based on the average weights/heights available on the subset of kids EER: 0 to 5 6 to 11 12 to 23 24 to 35 36- to 47 528 697 897 1096 1284 Actual intake: Age mo 0 to 5 6 to 11 12 to 23 24 to 35 36 to 47 Energy intake (kcal/d) 611 854 1141 1260 1355 Age in Months Bailey RL et al. J Nutr 2018;148:1557S-1566S; IOM, Washington (DC): National Academies Press; 2005.

Increased risk of Childhood Obesity Protein in early life influence health and metabolic programming, affecting growth and weight gain High Protein Intake Accelerated Growth Increased risk of Childhood Obesity Haschke F et al. NNI Workshop Series 2016;85:pp101-109

Breastfeeding is associated with lower prevalence of obesity at 5–6 years 12.6% 9.2% Prevalence (%) 4.5% 2.8% Key message: breastfed infants have a lower risk of overweight and obesity in later childhood, with a stronger effect for those who are breastfed longer A cross-sectional survey to assess the impact of breastfeeding on the risk of obesity and risk of being overweight in children at the time of entry to school Subjects were 9,357 children aged 5 and 6 whose height and weight data were collected at an obligatory health examination at the time of school entry; feeding, diet and lifestyle factors were assessed using responses to a questionnaire completed by their parents The prevalence of obesity in children who had never been breastfed was 4.5%, compared with 2.8% in breastfed children; prevalence of overweight was 12.6% and 9.2%, respectively A clear dose-­response effect was identified for the duration of breastfeeding on the prevalence of obesity: the prevalence was 3.8% for 2 months of exclusive breastfeeding, 2.3% for 3­5 months, 1.7% for 6­12 months, and 0.8% for more than 12 months In children who had been breastfed for ≥6 months or more, the risk of being overweight or obese was reduced (>30% and >40%, respectively) Reference von Kries R et al. BMJ 1999; 319:147–150. Overweight = BMI >90th percentile Obesity = BMI >97th percentile von Kries R et al. BMJ 1999; 319:147–150.

FORMULAS – HIGH PROTEIN BREASTMILK – LOW PROTEIN Weight/length z-score differences – breastfeeding vs high-protein formula (before 2000) -0.8 -0.6 0.6 0.8 Age (months) 3 6 9 12 15 18 21 0.4 0.2 -0.4 -0.2 …the problem seems to start at 3 months FORMULAS – HIGH PROTEIN BREASTMILK – LOW PROTEIN SDS weight-for-length Key message: high protein intake (formula) compared with low protein intake (breast milk) is associated with greater weight-for-length over 2 years Anthropometric indexes from 1–24 months were compared between matched cohorts of infants either breastfed (n=46) or formula-fed (n=41) until ≥12 months Neither group received solid foods before 4 months Weight-for-length was significantly greater among formula fed infants from 7–24 months Reference Dewey KG et al. Am J Clin Nutr 1993; 57:140–145. *Significant difference Dewey KG et al. Am J Clin Nutr 1993;57:140-145.

A Longitudinal Cohort Study in France Indicated Higher BMI until Adulthood, if Protein Intake at 0-24 Months was High

High protein intake during the first 2 years is associated with increased BMI later in life 14 16 24 Age (year) 2 6 8 10 12 18 20 22 BMI (kg/m2) 4 Early Rebound Late Rebound High protein intake Higher BMI High protein intake Earlier adiposity rebound Seen in subjects who become overweight Key message: high versus low protein intake in the first 2 years is associated with a higher BMI at 20 years Children with high (>16% of calories) or low (<16% of calories) protein intakes during the first 2 years were followed until the age of 20 years At the endpoint of the study (age 20 years), the group with the higher protein intake during the first 2 years had a BMI that was >2 kg/m2 higher Reference Rolland-Cachera MF et al. Int J Environ Res Public Health 2016; 13:E564. Rolland-Cachera MF et al. Int J Environ Res Public Health 2016;13:2-7.

RCTs to Proof Causality: With New Low Protein Children Grow Like Breastfed Infants Breastfed Infants (Reference) Low Protein Formula High Protein Formula

Protein – improvement in protein quality allow protein in formulas to be closer to breast milk True Protein (g/100mL) 3 2 1 4 6 8 10 12 Time (months) Breast Milk 0 – 12 Months High Protein Infant/follow up Formula Low Protein Infant/follow up Formula Lonnerdal B et al. J Nutr Biochem 2017;41:1-11; Haschke F et al. NNI Workshop Series 2016;85:pp101-109, 2016; Ziegler EE et al, JPGN 2015;6(5):596-603.

Lower protein infant and FU formula: lower weight gain 0–12 months versus higher protein formula Three randomised controlled trials comparing LOW PROTEIN and HIGH PROTEIN formula with BREASTFED reference groups (n=456) 10 15 30 Breastfed Lower protein (1.6-1.8 g / 100 kcal) Higher protein (2.15- 2.4 g / 100 kcal) 20 25 Weight gain 0–12 months (g/day) P < 0.05 Key message: lower protein infant formulas followed by lower protein formulas from 4–12 months lower weight gain than high protein formulas Three recent randomised controlled trials with similar experimental designs compared growth and metabolic outcome of infants who received formulas with higher (HP) and lower protein (LP) contents until 12 months of age, or breast milk Combined results indicate that low protein formulas slow rapid growth during the first year of life in infants of normal weight and overweight mothers while supporting normal growth1 Biomarkers of protein nutrition reflect the lower protein intake and levels are more like those of breastfed infants1 CHOP – Europe2 The Childhood Obesity Project (CHOP), a multicentre European trial compared outcomes of feeding formulas with 2.9 g and 4.4 g protein/100 kcal from 6 to 12 months of age Up to 6 months the infants received formula with 1.77 or 2.2 g/ 100 kcal BMI was significantly higher between 6 and 12 months in the group that received the HP formula US3 and Chilean4 trials Tested an experimental whey-based formula (3–12 months) with 1.61 g protein /100 kcal (< minimum protein limit in EU and USA), with a modified whey fraction with amino acid profile close to mature breast milk Under 3 months the infants received formula with 1.8 g protein/100 kcal In a multicentre US study, weight gain (g/day) from 3–6 months (1° outcome) was similar in the LP and HP groups3 Longitudinal analysis indicated lower weight from 4–12 months (p=0.031) and a lower % of infants with weight >85th percentile (p=0.015) in the group fed LP formula3 Serum biochemical parameters in the LP group reflected protein intake and were closer to biomarkers in breastfed infants than to those in the HP group3 The Chilean study tested whether a LP formula with slows weight gain in infants of overweight mothers4 Infants fed LP formula gained less weight (–1.77 g/day; p=0.028) from 3–6 months than infants fed HP formula4 The weight of infants fed the LP formula remained below that of infants fed the HP formula until 2 years of age (p=0.031), but was similar to the weight of breastfed infants4 Biomarkers of protein nutrition of infants fed the low protein formula were close to those of breastfed infants4 References Haschke F et al. NNI Workshop Series; Vol 85, 2016. Koletzko B et al. Am J Clin Nutr 2009;89:1836–45. Ziegler EE et al. J Pediatr Gastroenterol Nutr 2015;61(5):596–603. Inostroza J at el. JPGN 2014;59:70–77. Haschke F et al. NNI Workshop Series 2016(85):pp101-109, 2016; Ziegler EE et al, JPGN 2015;6(5):596-603.

BMI: breastfed infants, low-protein and high-protein formula: lower BMI at 6 years 17.5 Low Protein High Protein Breastfed 17.0 16.5 Adiposity rebound Mean BMI kg/m2 16.0 15.5 Key message: in follow-up outcomes to 6 years BMI was similar in children who were breastfed and those who were fed low protein formula, and was increased in infants fed high protein formula The Childhood Obesity Project (CHOP), a multicentre European trial compared outcomes of feeding high protein formulas, low protein formulas or breastfeeding2 The low protein formula group received formulas containing: 1.77 g protein/100 kcal (0–6 months) and 2.9 g/100 kcal (6–12 months)2 The high protein formula group received formulas with: 2.2 g / 100 kcal (0–6 months) and 4.4 g/100 kcal (6–12 months)2 Follow-up at 6 years: higher protein group (n=221), lower protein group (n=227), breastfed group (n=209)1 BMI at 6 years of age was significantly higher in the high protein than in the low protein group; the estimated difference in BMI was 0.51 (95% CI: 0.13–0.90; p=0.009)1 No significant difference was found between the low protein and breastfed children in mean BMI or obesity risk1 References Weber M et al. Am J Clin Nutr 2014; 99:1041–1051. Koletzko B et al. Am J Clin Nutr 2009; 89:1836–1845. [NOTE TO SPEAKER: PLEASE DELETE FIGURE FROM SLIDE BEFORE PRINTING, DUE TO COPYRIGHT RESTRICTIONS] 15.0 3 6 12 24 30 36 42 48 54 60 66 72 Age (months) Higher protein formulas – 2.2 g protein/100 kcal then 4.4 g protein/100 kcal Lower protein formulas – 1.77 g protein/100 kcal then 2.9 g protein/100 kcal Weber M et al. AJCN 2014;99:1041-1051

Breastfeeding and lower protein formula: lower obesity risk at 6 years Obesity prevalence (%) Key message: reduced protein formula (infant and follow-on formula) in the first year reduces weight gain and BMI compared with higher protein formula and produces outcomes closer to that of children who were breastfed The Childhood Obesity Project (CHOP), a multicentre European trial compared outcomes of feeding high protein formulas, low protein formulas or breastfeeding2 The low protein formula group received formulas containing: 1.77 g protein/100 kcal (0–6 months) and 2.9 g/100 kcal (6–12 months)2 The high protein formula group received formulas with: 2.2 g / 100 kcal (0–6 months) and 4.4 g/100 kcal (6–12 months)2 Follow-up at 6 years: higher protein group (n=221), lower protein group (n=227), breastfed group (n=209)1 Weight, length, weight-for-length and BMI were determined at inclusion and at 3, 6, 12 and 24 months of age, and thereafter every 6 months until 6 years of age At 6 years the prevalence of obesity was 5.6% (95% CI: 0.9–10.4) higher in the high protein than in the low protein group1 Odds ratio (adjusted for confounders)=2.87 (95% CI: 1.22–6.75; p=0.016) 1 No significant difference was found between the low protein formula and breastfed children in mean obesity risk1 References Weber M et al. Am J Clin Nutr 2014;99:1041–1051. Koletzko B et al. Am J Clin Nutr 2009; 89:1836–1845. Weber M et al. AJCN 2014;99:1041-1051

HIGH PROTEIN INTAKE: BIOMARKERS INDICATE ACCELERATED GROWTH Insulinogenic Aminoacids (Growth drivers) Insulin IGF-1 Koletzko et al. AJCN 2011;94:2036-43S

High protein intake in early life affect growth and weight gain SUMMARY: High protein intake in early life affect growth and weight gain Slower growth is not so bad Demand to be breastfed > 6mo Avoid high protein supply: If infant not (fully) breastfed: formula with reduced protein (high quality) No cow‘s milk as a drink in infancy        

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