Breastmilk and Infant Appetite Regulation DACLC 25 Februar 2014 Århus What is regulating macronutrient and energy intake in term infants being exclusively breastfed? Kim Fleischer Michaelsen Paediatric and International Nutrition Research group Department of Nutrition, Exercise and Sports, University of Copenhagen Mean Z-scores of healthy breastfed infants relative to the NCHS/WHO reference Exclusively Breastfed at 6 mo Weight 12 kg Source: An Evaluation of Infant Growth, WHO, 1994 Source: An Evaluation of Infant Growth, WHO, 1994 1978 6 1
The normally increasing fat content in breast-milk obviously cannot occur with cow s milk formula, which is of uniform composition. This may have an appetite-controlling (or fluidseeking) effect, the baby ceasing to take later hind-milk, possibly in response to changes in flavour or viscosity but restarting feeding when moved to the second breast 7 Also, it is possible that that stimuli from the nursing baby may affect the milk composition, by as yet unappreciated mechanisms, such as alteration in the details of suckling or even the weight of the bay. The suggestions are speculative and seem fanciful. However the ability of the female kangaroo to secrete two milks of quite different composition in addition to differing stimulation of the young of varying stages may be indicative 8 Better Sateity Regulation in Breastfeeding Breastmilk composition and taste changes during a feeding This provides satiety signals for the infant to stop suckling The BF infant plays an active role in the feeding process Many studies have shown that breastfed infants can self-regulate intake However, energy intake and growth differ considerably between infants What are the factors determining intake? 24 h breastmilk intake Test weigning 48 h Human milk intake Mean 781 ml Weigth 1 mo: 4.2 kg 170 ml/kg Weigth 6 mo: 7.3 kg 110 ml/kg Mean 855 ml Michaelsen et al AJCN 1994 11 2
Milk fat and satiety Robert G Jensen. Lipids 1999 Milk fat Increases in lipid content and numbers of globules during a nursing may help develop appetite and its control in the infant by approaching satiety and and by the tactile effects of the globules 14 Increasing fat content with increasing duration of breastfeeding Mandel et al. Pediatrics 2005 Predictors of breast milk macronutrients in Filipino mothers Quinn et al. Am J Hum Biology 2012 Creamatocrit (%) 102 mothers from the CEBU cohort Fat and energy density increased with duration of breastfeeding not protein No association with maternal adiposity Duration of breastfeeding (months) 15 16 Milk fat in donor milk and maternal BMI Michaelsen et al. JPGN 1990 Analysis of 2554 samples from 224 mothers Positive association between mothers BMI and milk fat content (+ 0.6 g/l per BMI unit) Two studies from Bangladesh and the Gambia showed pos association between skin fold thickness and milk fat content (Brown et al. Pediatrics 1986; Prentice et al. Br J Nutr 1981) Several other studies did not find an association between maternal BMI and fat content Milk Fat Content Term Infants n= 633 82 infants Michaelsen et al. AJCN 1994 18 3
Milk Fat Content Donor milk 2554 samples from 224 mothers Milk Fat Content Donor milk Months after delivery Michaelsen et al. JPGN 1990 Months after delivery Michaelsen et al. JPGN 1990 Fat content in human milk according to pregnancy weight gain Michaelsen er al AJCN 1994 > 16.8 kg Early nutrient intakes and increased body weight or body fat compiled by Rolland-Cachera Authors Reference Association Rolland-Cachera et al. Int J Obesity, 1995 Protein Dorosty et al. Pediatrics, 2000 None Scaglioni et al. Int J Obesity, 2000 Protein Gunnarsdottir & Int J Obes 2003 Protein Thorsdottir Hoppe et al. Am J Clin Nutr 2004 Protein (Wt, height, not BF) Skinner Int J Obesity, 2004 Protein and fat < 11.2 kg Günther et al. Int J Obesity, 2006 Protein Günther et al. Am J Clin Nutr 2007 Protein Öhlund et al. Eur J Clin Nutr 2010 Protein 21 Koletzko et al. Am J Clin Nutr 2009 Protein Role of fats in the first two years of life as related to later development of NCDs Review by Agostoni et al - Nutr Metab Cardiovasc Dis 2012 Proceedings - WHO meeting on complementary feeding and later NCD There is no evidence of any convincing association between fat intake during the 6-24-mo period and later indices of adiposity. Association between fat intake at 2 y and body composition at 20 y (n=68) Rolland Cachera et al, Int J Obes 13. nov 2012 Associations with fat intake Subscapular skin fold 2.3 ( 4.4 to 0.2) (% change) Body fat mass (kg) 0.31 ( 0.60 to 0.01) S Leptin (µg/l) 0.21 ( 0.38 to 0.03) No associations with protein intake. No associations between fat intake and BMI or triceps skin folds 4
Milk Protein 25 Early nutrient intakes and increased body weight or body fat compiled by Rolland-Cachera Authors Reference Association Rolland-Cachera et al. Int J Obesity, 1995 Protein Dorosty et al. Pediatrics, 2000 None Scaglioni et al. Int J Obesity, 2000 Protein Gunnarsdottir & Int J Obes 2003 Protein Thorsdottir Hoppe et al. Am J Clin Nutr 2004 Protein (Wt, height, not BF) Skinner Int J Obesity, 2004 Protein and fat Günther et al. Int J Obesity, 2006 Protein Günther et al. Am J Clin Nutr 2007 Protein Öhlund et al. Eur J Clin Nutr 2010 Protein Koletzko et al. Am J Clin Nutr 2009 Protein Milk Protein Content Term Infants Milk Protein Content Donor milk 2554 samples from 224 mothers n= 632 82 infant Michaelsen et al. AJCN 1994 27 Months after delivery Michaelsen et al. JPGN 1990 Breast milk macronutrient intake and infant feeding pattern Kahn et al. J Hum Lact 2013 15 mothers of healthy term infants collected pre and postfeed breast milk samples from each feed over 24 h No association between fat content and number of feeds or 24 h breast milk volume Protein, whey and casein intake is inversely related to number of breastfeeds per day, but not with volume, duration of or interval between feeds Behavioral factors 29 30 5
Behavioral factors Bartok and Ventura. Int J Ped Obesity 2009 Breastfeeding mothers are more likely to trust the infants ability to self regulate and be attentive to the infants expressions and cues indicating fullness and satiation Patterns of caregiver control over feeding established during infancy, mayextentlater into childhood infants s emerging ability to self regulate intake can be overridden by caregiver behavior 31 Infants fed from the breast have improved appetite control later in life compared to infants fed breastmilk from a bottle 3 6 year children (n=104): 68% less likely to have high satiety responsiveness if fed breastmilk from bottle compared to from the breast ( DiSantis et al. Int J Behave Nutrition Phys Activ 2011) Bottle fed infants (incl. Breastmilk) less likely to empty bottle or cup in late infancy compared to breast fed (Rouwei et al, Pediatrics 2010) 32 Is human milk given to boys different form human milk given to girls? Factors influencing breast milk intake in exlusively breastfed infants Michaelsen et al AJCN 1994 33 34 Breast milk to boys have higher energy density Powe et al. Am J Hum Biol 2009 Controllling for time since last feeding boys received milk with 25% higher energy density (p=0.049, n=25, one breast pumped) Increase in maternal bra cup size during pregnancy was positively associated with milk energy density (p=0.029) They speculate that fetal sex-based differences in hormones secreted by the placenta might have an effect Investing in boys or girls? Trivers-Willard Hypotesis Fulita et al. Am J Phys Anthopology 2012 Economically sufficient mothers can achieve higher reproductive succes through preferential investment in sons Mothers in poor conditions who can provide fewer resources attain higher reproductive success by investing more i daughters who can choose a mate of higher status 6
83 excl. BF mothers from Kenya Foremilk samples analysed by creamatocrit Fat: Interaction Sex SES: p= 0.014 Milk Protein Content Term Infants P=0.3 Boys: 281 samples Girls: 351 samples? Fulita et al. Am J Phys Anthopology 2012 38 Milk Fat Content Term Infants P=0.4 Boys: 281 samples Girls: 352 samples Appetite hormones Leptin Ghrelin Adiponectin 39 40 Breast milk leptin and infant weight gain Schuster et al. Ped Res 2011 r=0.298 P<0.001 Breast milk leptin and infant weight gain Schuster et al. Ped Res 2011 r= 0.68 P=0.007 41 42 7
Milk adiponectin associated with infant weight Woo et al. Breastfeeding Med 2009 Fasting Insulin at 9 Months and Number of Breastfeedings SKOT Cohort P=0.0015 n=115 n=88 n=46 n=3 Madsen AL, et al. Diabet Med. 2010;27:1350-1357. 44 IGF-I at 9 Months and Number of Breastfeedings SKOT Cohort P=0.0006 Free amino acids in human milk and appetite regulation n=115 n=88 n=46 n=3 Madsen AL, et al. Growth Hormone IGF Res. 2011;21:199-204. 45 Is free glutamate reducing appetite in infants? Ventura, Beauchamp and Mennella, AJCN 2012 Glutamate is a key signal for satiety in adults and animals Infants recieving hydrolysed protein formula, which has a high level of glutamate, eat less (Menella et al Pediatrics 2011) Glutamate is the most abundant FAA in breast milk 47 8
Growth CMF and ephf formula Menella et al. Pediatrics 2011 15 % reduction Free Glutamate mg 1.8 84.1 106.5 Meal Duration min 9.3 8.2 8.7 No effect on linear growth Ventura, Beauchamp and Mennella, AJCN 2012 Human milk intake Weigth 1 mo: 4.2 kg 170 ml/kg Weigth 6 mo: 7.3 kg 110 ml/kg 51 Large variation in milk content of free glutamine and glutamic acid Carretu et al. Food Chem 2003 Milk samples from 195 mothers of healthy term one month old infants µmol/l mean SD min max Glutamine 259 163 12 819 Glutamic acid 1171 386 200 2175 Formula (Agostoni 2000) min max Glutamine 0 38 Glutamic acid 20 129 53 Potential effects of glutamate and glutamate receptors Signal for satiety large umami litterature In preterm infants oral glutamate is extracted by the gut for metabolism and is not a significant contributor to gluconeogenesis Hays et al. Ped Res 2007 Energy substrate for intestinal cells (also glutamine) Neurotransmitter of the brain 9
Glutamate research questions Are glutamate levels in breastmilk regulating intake of breastmilk? Is there a continous increase in glutamate levels after the age of 3 months? What are determinants of glutamate levels in breastmilk? Are glutamate levels associated with infant growth patterns? Conclusions In well functioning breastfeeding the infant is selfregulating energy intake Breastfeeding protects against obesity, but the effect is not very strong Energy intake and growth of exclusively breastfed differs considerably, but limited knowledge of determining factors With increasing fat content infants down regulate energy intake, whichseemsnot to be the case with protein intake Some suggestions that milk composition differs according to off spring gender, but the evidence is not strong Conclusions Emerging evidence that appetite hormones in human milk are both related to maternal BMI/adiposity and infant growth, but the role in regulating infant intake and growth is not fully understood Glutamate added to infant formula reduce energy intake High content of free glutamate in human milk does it have a role in appetite regulation? Need for better understanding of appetite regulation in breastfed infants Studies examining BF and later obesity in the offspring It is a myth that breastfeeding protects against obesity??? 33.768 children from Czech Republic Followed until age of 6-14 y Controlled for maternal BMI and other confounders Duration of BF: Never < 1mo 1-3 mo 3-6 mo > 6 mo % Overweight : 12.4% 9.7% 9.1% 9.0% 9.0% Toschke et al, J Pediatr 2002 10
Meta-analysis: Breastfeeding and obesity Owen et al Pediatrics 2005 Better sateity regulation Breastmilk composition and taste changes during a feeding This provides satiety signals for the infant to stop suckling The BF infant plays a more active role in the feeding process 62 Possible mechanisms for protective effect of BF on childhood obesity Low protein intake in BF infants Bioactive factors in human milk Better sateity regulation in BF infants Parental interest/care/neglect Residual confounding 63 AJCN 2007 Telephone based support prolongs breastfeeding duration in obese women: A randomized trial E Malchau Carlsen, A Kyhnaeb, K Renault, D Cortes, KF Michaelsen, O Pryds Am J Clin Nutr 2013 192 obese mothers randomised to structured interview and at least nine supportive telephone calls or standard care Improved support increased: Excl BF from median of 40 d to 120 d, p=0.003 Any BF from 108 to 184 d, p=0.002 Exclusively Breastfed at 6 mo Weight 12 kg 65 11
!!!!! 23 02 2014 Kim F Michaelsen - kfm@kvl.dk - Obergurgl January 2005 68 Mean Z-scores of healthy breastfed infants relative to the NCHS/WHO reference Eligibility criteria of individuals Source: An Evaluation of Infant Growth, WHO, 1994 No health, environmental or economic constraints on growth Mother willing to follow feeding recommendations Full BF 4-6 mo and continued breastfeeding for at least 9-12 mo Term birth Single birth Lack of significant perinatal morbidity No smoking mothers (before and after delivery) Source: An Evaluation of Infant Growth, WHO, 1994 Adoption of WHO Child Growth Standards 1 (December 2010) Adoption Status Adopted Adoption being discussed Not adopted Status unknown More than 140 countries have adopted the standards 2 1. Zorlu G. Bull World Health Organ. 2011;89:250-251. 2. WHO. http://www,who.int/global_health_histories/seminars/presentation48b.pdf. Accessed November 11, 2011. 72 12
Comparison of WHO with Danish reference - boys Comparison of WHO with Danish BMI-for-age percentiles for boys Birth to 60 months Comparison of WHO with Danish reference - boys Weight (kg) 5 10 15 20 WHO Danish Comparison of WHO with Danish reference weight-for-age percentiles for boys 97th 90th 75th 50th 25th 10th 3rd BMI (kg/m²) 12 14 16 18 20 WHO Danish 97th 90th 75th 50th 25th 10th 3rd 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Age (months) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Age (months) SKOT Cohort 312 healthy term infants from Copenhagen 54 % breastfed at 9 months University of Copenhagen Anni Larnkjær Christian Mølgaard Rikke Laursen Thanks to Discussions and inspiration Carlo Agostoni Alison Ventura Julie Minella Danish Technical University Susanne Jacobsen University of Odense Steffen Husby Signe Bruun Always Protect, Promote and Support Breastfeeding Thank you 77 13