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Oken o&p2013

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Maternal obesity can negatively impact fetal growth and development and increase health risks for offspring. A study found that offspring of obese mothers are at increased risk for various birth defects as well as issues like stillbirth, needing treatment in the NICU, and poorer neonatal outcomes. Children of obese mothers also have an increased risk of becoming obese themselves and developing poorer metabolic health and higher blood pressure. While genes play a role, factors like shared behaviors, fetal growth patterns, gestational diabetes, breastfeeding, and early life diet also contribute to associations between maternal weight and child outcomes.

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Effects of maternal obesity on fetal growth and metabolic health of the offspring Emily Oken, MD, MPH Obesity Prevention Program Department of Population Medicine Harvard Medical School and Harvard Pilgrim Health Care Institute
0 5 10 15 PrevalenceofOverweight Year 24-71 months 0-11 months 12-23 months 1980 1985 1990 1995 2000 Obesity increasing not only in adults and children, also in infants Kim et al., Obesity 2006; ~500,000 well child visits in Mass.
Lancet. 2010 May 15; 375(9727): 1737–1748.
‘Fetal Origins’ hypothesis David Barker. Mothers, Babies, and health in later life.
‘Developmental Origins’ and obesity Hediger et al., Pediatrics, 1998; Sorensen et al., BMJ 1997; Innes et al. JAMA 2002 21 22 23 24 25 <2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 >4.5 AdultBMI(kg/sqm) Birthweight(kg)
Oken, Ob Gyn Clinics of N. America, 2009; NHANES data Maternal obesity 0 10 20 30 40 50 60 1960-1962 1971-1974 1976-1980 1988-1994 1999-2002 2005-2008 Percentage Overweight (BMI >= 25.0) Obese (BMI >= 30.0)
Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies. 2.36 1.31 1.00 0.52 3225 3281 3429 3334 0 0.5 1 1.5 2 2.5 3 Underweight Normal Overweight Obese Maternal BMI OddsRatio 3100 3200 3300 3400 3500 Meanbirthweight(g) Odds of high birth weight Mean birth weight Maternal weight predicts fetal growth
Birth defects – meta-analysis • Infants of obese mothers at increased risk for: – neural tube defects (OR 1.87; 95% CI, 1.62-2.15) – spina bifida (OR 2.24; 95% CI, 1.86-2.69) – cardiovascular anomalies (OR 1.30; 95% CI, 1.12-1.51) – septal anomalies (OR 1.20; 95% CI, 1.09-1.31) – cleft palate (OR 1.23; 95% CI, 1.03-1.47) – cleft lip and palate (OR 1.20; 95% CI, 1.03-1.40) – anorectal atresia (OR, 1.48; 95% CI, 1.12-1.97) – hydrocephaly (OR 1.68; 95% CI, 1.19-2.36) – limb reduction anomalies (OR 1.34; 95% CI, 1.03-1.73) • Lower risk for: – gastroschisis (OR 0.17; 95% CI, 0.10-0.30). Stothard KJ, et al. JAMA 2009;301(6):636-650
Stillbirth 2.07 (1.59, 2.74)
NICU treatment Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies. 1.35 (1.22, 1.49)
Neonatal outcomes Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies. 1.5 2.1 2.1 1.6 1.0 1.0 0.1 1 10 Low 1m Apgar Low 5m Apgar Fetal compromise Meconium Shoulder dystocia Jaundice OddsRatio(95%CI) n=3 n=4 n=4 n=5 n=9 n=4
Other neonatal outcomes Heslehurst, et al. Obesity Reviews 2008. Non meta-analysis results. No association: asphyxia, hyperbilirubinemia, hypoglycemia, cord pH<7.2 1.6 1.7 1.8 1.3 1.5 1.5 1 10 Incubator requirement Respiratory distress Resuscitation Fetal heart rate abnormalities Tube feeding required Birth trauma OddsRatio(95%CI)
Infant death Chen A, et al. Epidemiology 2009;20:74-81.
Outcomes in childhood and beyond
Oken, Ob Gyn Clinics of N. America, 2009 Jun;36(2):361-77. Odds of child obesity for obese vs. normal weight mothers 3.1 4.1 4.3 5.1 4.3 1 10 Whitaker 2004 (age 4) Li 2005 (ages 2-14) Reilly 2005 (age 7) Li 2007 (Ages 2-12, early onset) Salsberry 2007 (ages 12-13) Author, year, child age Oddsratioforchildobesity
Offspring of obese mothers have poorer cardio-metabolic status  At birth, higher body fat, reduced energy expenditure, and more atherogenic lipid profiles  In childhood, higher blood pressure, risk for metabolic syndrome - even after adjustment for attained BMI  In adulthood, increased risk of death from coronary heart disease Oken, Ob Gyn Clinics of N. America, 2009 Jun;36(2):361-77.
 Genes What accounts for associations of maternal weight with child weight?
Schultz et al. Diabetes Care 2006;29(8):1866-71 Environment matters, too 7% 38% 13% 70% 0% 10% 20% 30% 40% 50% 60% 70% 80% Type 2 Diabetes Obesity Mexico United States
The uterus is the environment of the fetus
 Genes  Shared behaviors  Parents and children tend to share diet, physical activity habits (Oliveria et al, AJCN, 1992) What accounts for associations of maternal weight with child weight?
 Genes  Shared behaviors  Mediators  Fetal growth  GDM  Breastfeeding  Infant diet quality and feeding interactions What accounts for associations of maternal weight with child weight?
0.29 -0.25 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 <10 10-14 15-19 20-24 25-29 30-34 35-39 40-44 >=45 Gestational weight gain (pounds) ChangeinchildBMIz-score Without adjustment for maternal BMI With adjustment for maternal BMI IOM 2009;Oken et al., AJOG 2008 Gestational weight gain Distribution of GWG relative to 1990 guid by prepregnancy BMI category (PRAMS, 2 Body mass index category (IOM criteri Under- Normal- Over- Obese Proportion(%)ofwomen 0 20 40 60 80 100 120 weight weight weight < IOM Within IOM > IOM 19.5 49.9 30.6 38.4 41.1 20.5 63 26.8 10.3 36.3 30.2 23.5 (25-35 lb) (15-25 lb) (12-20 lb) (28-40 lb)
 Genes  Shared behaviors  Mediators  Confounders  SES  Smoking What accounts for associations of maternal weight with child weight?
Maternal prenatal smoking and child overweight – meta-analysis Odds Ratio .5 1 5 Combined von Kries, 2002 Wideroe, 2003 Whitaker, 2004 Toschke, 2003 Toschke, 2002 Salsberry, 2005 Reilly, 2005 Power, 2002 M Power, 2002 F Oken, 2005 Dubois, 2006 Chen, 2006 M Chen, 2006 F Bergmann, 2003 Al Mamun, 2006 Adams, 2005 OR 1.50, 95% CI: 1.36, 1.65 Oken, et al. Int J Obes (Lond) 2008; 32(2):201-10
 Genes  Shared behaviors  Mediators  Confounders  Direct effect of “obese” intrauterine environment What accounts for associations of maternal weight with child weight?
Maternal diet 0.1 1 10 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 OddsRatio Maternal prenatal diet and child ow/obesity at age 5 % Saturated Fat % Sugar Murrin et al. EJCN 2013 Donahue et al. AJCN 2011
Obesity disproportionately affects racial/ethnic minority children • In 2010: 14% of white, 24.3% of Black, and 21.2% of Hispanic children 2-19 years were obese • Overall rates are stubbornly high; racial/ethnic disparities are starting early and appear to be widening Ogden et al. JAMA 2012. Weden et al. AJPH 2012. 0 5 10 15 20 25 Non-Hispanic White Non-Hispanic Black Hispanic 1.59 1.46 1.18 Odds of obesity for black vs. white children in the US Adjusted for sociodemographic characteristics Adjusted for prenatal & perinatal factors • Pre- and peri-natal factors explain most of the disparity in obesity
Weights of children born before (BMS, n=45) and after (AMS, n=172) maternal weight-loss surgery 0% 10% 20% 30% 40% 50% 60% Underweight Normal weight Overweight Obese BMS AMS Kral JG, et al. Pediatrics. 2006 Dec;118(6):e1644-9
Dabelea et al., Diabetes 2000. 19 Pima families/58 sibs
Animal studies suggested early energy intake can permanently program body size 75 days: Weights 86g, 230g 21 days: Weights 14g, 60g Widdowson and McCance, 1960
Weight(g) Age (weeks) Food restriction during weeks 0-3 results in sustained lower body weight (and food excess in higher weight) 21 day period of food restriction weaning
Timing is important weaning Weight(g) Later food restriction (weeks 9-12) - rats quickly regain and perhaps overshoot body weight Age (weeks) Widdowson and McCance, 1963 21 day period of food restriction
Offspring of overfed mother rats have higher body weight … Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 Male offspring Female offspring Offspring of obese dams Offspring of control dams Offspring of obese dams Offspring of control dams
…higher fat mass… Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 OC – Offspring of control dams OO – Offspring of obese dams
…higher energy intake… Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 Offspring of obese dams Offspring of control dams Offspring of obese dams Offspring of control dams
…and adverse cardio-metabolic profiles Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 OC – Offspring of control dams OO – Offspring of obese dams
Pathways linking maternal weight with child outcomes Maternal pre-pregnancy size Gestational weight gain Child adiposity Birth weight Disease outcomes Fetal growth Gestation length Shared genes and behaviors Gestational Diabetes Infant feeding & growth Oken, E. In “Influence of Pregnancy weight on maternal and child health.” IOM 2007.
The microbiome and obesity Huh et al. Arch Dis Child 2012. Dominguez-Bello et al. Proc Natl Acad Sci USA. 2010;107[26]:11973.)
„Agouti‟ mice - Genetic cause for obesity first identified >100 years ago These mice are identical twins! How do you get from here back to here?
Epigenetics Genes = hardware Epigenetic markers = software
The Placenta Al Wasel et al., Placenta 2010
Diet Extrauterine environment Mom’s own intrauterine and childhood experiences Mom’s prenatal health Fetal and placental metabolism Child growth and behaviors
Inter- and trans-generational influences Kaati et al. European Journal of Human Genetics (2007) 15, 784–790 Excess early nutrition in grandmother (pink line) results in shorter lifespan in grandchild Innes et al,. JAMA 2002 Longevity of grandchild
Air pollution and obesity Fleisch et al. Submitted. Fleisc h Et al 0.1 1 10 1 2 3 4 5 Black Carbon Traffic Density Quintile Overweightat6m
Built environment Air Pollution Social stressors Overnutrition Which comes first?
Taveras et al. Arch Ped Adol Med 2012. What can you do after birth? • Watch out for accelerated postnatal growth
What can you do after birth? • Watch out for accelerated postnatal growth • Promote postpartum weight loss Large for Gestational Age 0.1 1 10 <-1 -1 to <1 1 to <2 2 to <3 >= 3 Change in BMI OddsRatio BMI < 25 BMI >= 25 Gestational Diabetes 0.1 1 10 <-1 -1 to <1 1 to <2 2 to <3 >= 3 Change in BMI OddsRatio BMI < 25 BMI >= 25
Dabelea D, et al. Diabetes Care 2008;31(7):1422-6. 79 youth aged 10-22y with Type 2 DM and 190 nondiabetic controls % exposed to maternal diabetes % exposed to maternal obesity Cases Controls What is the impact? Overall, 47.2% (95% CI 30.9–63.5) of type 2 diabetes in youth could be attributed to intrauterine exposure to maternal diabetes and obesity.
Oken o&p2013

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Oken o&p2013

  • 1. Effects of maternal obesity on fetal growth and metabolic health of the offspring Emily Oken, MD, MPH Obesity Prevention Program Department of Population Medicine Harvard Medical School and Harvard Pilgrim Health Care Institute
  • 2. 0 5 10 15 PrevalenceofOverweight Year 24-71 months 0-11 months 12-23 months 1980 1985 1990 1995 2000 Obesity increasing not only in adults and children, also in infants Kim et al., Obesity 2006; ~500,000 well child visits in Mass.
  • 3. Lancet. 2010 May 15; 375(9727): 1737–1748.
  • 4. ‘Fetal Origins’ hypothesis David Barker. Mothers, Babies, and health in later life.
  • 5. ‘Developmental Origins’ and obesity Hediger et al., Pediatrics, 1998; Sorensen et al., BMJ 1997; Innes et al. JAMA 2002 21 22 23 24 25 <2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 >4.5 AdultBMI(kg/sqm) Birthweight(kg)
  • 6. Oken, Ob Gyn Clinics of N. America, 2009; NHANES data Maternal obesity 0 10 20 30 40 50 60 1960-1962 1971-1974 1976-1980 1988-1994 1999-2002 2005-2008 Percentage Overweight (BMI >= 25.0) Obese (BMI >= 30.0)
  • 7. Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies. 2.36 1.31 1.00 0.52 3225 3281 3429 3334 0 0.5 1 1.5 2 2.5 3 Underweight Normal Overweight Obese Maternal BMI OddsRatio 3100 3200 3300 3400 3500 Meanbirthweight(g) Odds of high birth weight Mean birth weight Maternal weight predicts fetal growth
  • 8. Birth defects – meta-analysis • Infants of obese mothers at increased risk for: – neural tube defects (OR 1.87; 95% CI, 1.62-2.15) – spina bifida (OR 2.24; 95% CI, 1.86-2.69) – cardiovascular anomalies (OR 1.30; 95% CI, 1.12-1.51) – septal anomalies (OR 1.20; 95% CI, 1.09-1.31) – cleft palate (OR 1.23; 95% CI, 1.03-1.47) – cleft lip and palate (OR 1.20; 95% CI, 1.03-1.40) – anorectal atresia (OR, 1.48; 95% CI, 1.12-1.97) – hydrocephaly (OR 1.68; 95% CI, 1.19-2.36) – limb reduction anomalies (OR 1.34; 95% CI, 1.03-1.73) • Lower risk for: – gastroschisis (OR 0.17; 95% CI, 0.10-0.30). Stothard KJ, et al. JAMA 2009;301(6):636-650
  • 10. NICU treatment Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies. 1.35 (1.22, 1.49)
  • 11. Neonatal outcomes Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies. 1.5 2.1 2.1 1.6 1.0 1.0 0.1 1 10 Low 1m Apgar Low 5m Apgar Fetal compromise Meconium Shoulder dystocia Jaundice OddsRatio(95%CI) n=3 n=4 n=4 n=5 n=9 n=4
  • 12. Other neonatal outcomes Heslehurst, et al. Obesity Reviews 2008. Non meta-analysis results. No association: asphyxia, hyperbilirubinemia, hypoglycemia, cord pH<7.2 1.6 1.7 1.8 1.3 1.5 1.5 1 10 Incubator requirement Respiratory distress Resuscitation Fetal heart rate abnormalities Tube feeding required Birth trauma OddsRatio(95%CI)
  • 13. Infant death Chen A, et al. Epidemiology 2009;20:74-81.
  • 14. Outcomes in childhood and beyond
  • 15. Oken, Ob Gyn Clinics of N. America, 2009 Jun;36(2):361-77. Odds of child obesity for obese vs. normal weight mothers 3.1 4.1 4.3 5.1 4.3 1 10 Whitaker 2004 (age 4) Li 2005 (ages 2-14) Reilly 2005 (age 7) Li 2007 (Ages 2-12, early onset) Salsberry 2007 (ages 12-13) Author, year, child age Oddsratioforchildobesity
  • 16. Offspring of obese mothers have poorer cardio-metabolic status  At birth, higher body fat, reduced energy expenditure, and more atherogenic lipid profiles  In childhood, higher blood pressure, risk for metabolic syndrome - even after adjustment for attained BMI  In adulthood, increased risk of death from coronary heart disease Oken, Ob Gyn Clinics of N. America, 2009 Jun;36(2):361-77.
  • 17.  Genes What accounts for associations of maternal weight with child weight?
  • 18. Schultz et al. Diabetes Care 2006;29(8):1866-71 Environment matters, too 7% 38% 13% 70% 0% 10% 20% 30% 40% 50% 60% 70% 80% Type 2 Diabetes Obesity Mexico United States
  • 19. The uterus is the environment of the fetus
  • 20.  Genes  Shared behaviors  Parents and children tend to share diet, physical activity habits (Oliveria et al, AJCN, 1992) What accounts for associations of maternal weight with child weight?
  • 21.  Genes  Shared behaviors  Mediators  Fetal growth  GDM  Breastfeeding  Infant diet quality and feeding interactions What accounts for associations of maternal weight with child weight?
  • 22. 0.29 -0.25 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 <10 10-14 15-19 20-24 25-29 30-34 35-39 40-44 >=45 Gestational weight gain (pounds) ChangeinchildBMIz-score Without adjustment for maternal BMI With adjustment for maternal BMI IOM 2009;Oken et al., AJOG 2008 Gestational weight gain Distribution of GWG relative to 1990 guid by prepregnancy BMI category (PRAMS, 2 Body mass index category (IOM criteri Under- Normal- Over- Obese Proportion(%)ofwomen 0 20 40 60 80 100 120 weight weight weight < IOM Within IOM > IOM 19.5 49.9 30.6 38.4 41.1 20.5 63 26.8 10.3 36.3 30.2 23.5 (25-35 lb) (15-25 lb) (12-20 lb) (28-40 lb)
  • 23.  Genes  Shared behaviors  Mediators  Confounders  SES  Smoking What accounts for associations of maternal weight with child weight?
  • 24. Maternal prenatal smoking and child overweight – meta-analysis Odds Ratio .5 1 5 Combined von Kries, 2002 Wideroe, 2003 Whitaker, 2004 Toschke, 2003 Toschke, 2002 Salsberry, 2005 Reilly, 2005 Power, 2002 M Power, 2002 F Oken, 2005 Dubois, 2006 Chen, 2006 M Chen, 2006 F Bergmann, 2003 Al Mamun, 2006 Adams, 2005 OR 1.50, 95% CI: 1.36, 1.65 Oken, et al. Int J Obes (Lond) 2008; 32(2):201-10
  • 25.  Genes  Shared behaviors  Mediators  Confounders  Direct effect of “obese” intrauterine environment What accounts for associations of maternal weight with child weight?
  • 26. Maternal diet 0.1 1 10 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 OddsRatio Maternal prenatal diet and child ow/obesity at age 5 % Saturated Fat % Sugar Murrin et al. EJCN 2013 Donahue et al. AJCN 2011
  • 27. Obesity disproportionately affects racial/ethnic minority children • In 2010: 14% of white, 24.3% of Black, and 21.2% of Hispanic children 2-19 years were obese • Overall rates are stubbornly high; racial/ethnic disparities are starting early and appear to be widening Ogden et al. JAMA 2012. Weden et al. AJPH 2012. 0 5 10 15 20 25 Non-Hispanic White Non-Hispanic Black Hispanic 1.59 1.46 1.18 Odds of obesity for black vs. white children in the US Adjusted for sociodemographic characteristics Adjusted for prenatal & perinatal factors • Pre- and peri-natal factors explain most of the disparity in obesity
  • 28. Weights of children born before (BMS, n=45) and after (AMS, n=172) maternal weight-loss surgery 0% 10% 20% 30% 40% 50% 60% Underweight Normal weight Overweight Obese BMS AMS Kral JG, et al. Pediatrics. 2006 Dec;118(6):e1644-9
  • 29. Dabelea et al., Diabetes 2000. 19 Pima families/58 sibs
  • 30. Animal studies suggested early energy intake can permanently program body size 75 days: Weights 86g, 230g 21 days: Weights 14g, 60g Widdowson and McCance, 1960
  • 31. Weight(g) Age (weeks) Food restriction during weeks 0-3 results in sustained lower body weight (and food excess in higher weight) 21 day period of food restriction weaning
  • 32. Timing is important weaning Weight(g) Later food restriction (weeks 9-12) - rats quickly regain and perhaps overshoot body weight Age (weeks) Widdowson and McCance, 1963 21 day period of food restriction
  • 33. Offspring of overfed mother rats have higher body weight … Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 Male offspring Female offspring Offspring of obese dams Offspring of control dams Offspring of obese dams Offspring of control dams
  • 34. …higher fat mass… Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 OC – Offspring of control dams OO – Offspring of obese dams
  • 35. …higher energy intake… Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 Offspring of obese dams Offspring of control dams Offspring of obese dams Offspring of control dams
  • 36. …and adverse cardio-metabolic profiles Samuelsson, A.-M. et al. Hypertension 2008;51:383-392 OC – Offspring of control dams OO – Offspring of obese dams
  • 37. Pathways linking maternal weight with child outcomes Maternal pre-pregnancy size Gestational weight gain Child adiposity Birth weight Disease outcomes Fetal growth Gestation length Shared genes and behaviors Gestational Diabetes Infant feeding & growth Oken, E. In “Influence of Pregnancy weight on maternal and child health.” IOM 2007.
  • 38. The microbiome and obesity Huh et al. Arch Dis Child 2012. Dominguez-Bello et al. Proc Natl Acad Sci USA. 2010;107[26]:11973.)
  • 39. „Agouti‟ mice - Genetic cause for obesity first identified >100 years ago These mice are identical twins! How do you get from here back to here?
  • 41. The Placenta Al Wasel et al., Placenta 2010
  • 43. Inter- and trans-generational influences Kaati et al. European Journal of Human Genetics (2007) 15, 784–790 Excess early nutrition in grandmother (pink line) results in shorter lifespan in grandchild Innes et al,. JAMA 2002 Longevity of grandchild
  • 44. Air pollution and obesity Fleisch et al. Submitted. Fleisc h Et al 0.1 1 10 1 2 3 4 5 Black Carbon Traffic Density Quintile Overweightat6m
  • 45. Built environment Air Pollution Social stressors Overnutrition Which comes first?
  • 46. Taveras et al. Arch Ped Adol Med 2012. What can you do after birth? • Watch out for accelerated postnatal growth
  • 47. What can you do after birth? • Watch out for accelerated postnatal growth • Promote postpartum weight loss Large for Gestational Age 0.1 1 10 <-1 -1 to <1 1 to <2 2 to <3 >= 3 Change in BMI OddsRatio BMI < 25 BMI >= 25 Gestational Diabetes 0.1 1 10 <-1 -1 to <1 1 to <2 2 to <3 >= 3 Change in BMI OddsRatio BMI < 25 BMI >= 25
  • 48. Dabelea D, et al. Diabetes Care 2008;31(7):1422-6. 79 youth aged 10-22y with Type 2 DM and 190 nondiabetic controls % exposed to maternal diabetes % exposed to maternal obesity Cases Controls What is the impact? Overall, 47.2% (95% CI 30.9–63.5) of type 2 diabetes in youth could be attributed to intrauterine exposure to maternal diabetes and obesity.

Editor's Notes

  1. Thanks so much to the organizers for inviting me to speak here today. It is a great pleasure to be here among such an impressive group of co-speakers, and all of you.Evidence has been accumulating for several decades that risk for chronic health conditions, including obesity has its origins in very early life. As this field if inquiry has begun to pervade the popular press, including books, magazines, and the internet, it is increasingly common for our patients to come to us with questions about the strength of this evidence, and what individuals can do to optimize the health of their children.
  2. In research, we generally measure not only height, weight, and BMI, which are indirect measures of adiposity, but also more direct measures of fat and lean mass such as a DEXA scan. This one was taken of a young girl with a BMI of 38 kg/m2. We care about excess adiposity in childhood not only because of its association with chronic disease risk in adulthood, but also because of accumulating evidence that obese kids are at higher risk of a panoply of adverse outcomes on organ systems ranging from the brain to the bones, even when they are still children.