Developmental Origins of Health and  Diseases: when we become what we are. <ul><li>Original findings  </li></ul><ul><li>Fu...
Perhaps the single  most important observation made in the twentieth century  related to the origins of complex adult onse...
“ Two decades ago, a British physician named  David Barker  noticed an odd correlation on a map:  the poorest regions of E...
Environmental Effects via Developmental Plasticity:  Types of Response to the Early Environment  Gluckman Science 2004;305...
ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart dise...
ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart dise...
ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart dise...
ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart dise...
The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life  DJ P Ba...
Fetal origins of non-insulin dependent diabetes D J P Barker BMJ 1995;311:171-4 *
Birthweight and the risk for type 2 diabetes mellitus in adult women.  Rich-Edwards JW, Ann Intern Med. 1999;130:278 <ul><...
may permanently affect ( fetal   programming )   the structure and physiology of a range of organs and tissues, including ...
fetal programming directed by  intrauterine signals that may  optimize structure and function  of organs in the in utero e...
Living with the past: evolution, development and patterns of disease.   Gluckman PD, Science 2004; 305:1733–1736 <ul><li>D...
DEVELOPMENTAL PLASTICITY AND LATER DISEASE <ul><li>Inadequate maternal nutrition, which can induce a range  of  phenotypes...
DEVELOPMENTAL PLASTICITY AND LATER DISEASE <ul><li>Inadequate maternal nutrition, which can induce a range  of  phenotypes...
DEVELOPMENTAL PLASTICITY AND LATER DISEASE <ul><li>Inadequate maternal nutrition, which can induce a range  of  phenotypes...
<ul><li>The  fetuses’ adaptations to  undernutrition  are associated  with  changes in the concentrations  of fetal and pl...
<ul><li>The  fetuses’ adaptations to  undernutrition  are associated  with  changes in the concentrations  of fetal and pl...
Hormonal responses to undernutrition <ul><li>Insulin  and the  insulin-like growth factors (IGFs), hormones  thought to ha...
Intrauterine growth restriction (IUGR) can affect tissue in two ways. <ul><li>First, intrauterine growth retardation  (IUG...
Intrauterine growth restriction (IUGR) can affect tissue in two ways. <ul><li>First, intrauterine growth retardation  (IUG...
Intrauterine growth restriction (IUGR) can affect tissue in two ways. <ul><li>First, intrauterine growth retardation  (IUG...
<ul><li>The associations with  cardiovascular risk factors  are  independent of known influences in adult lifestyle.  </li...
This inverse relationship between birth weight and coronary artery disease death rates has been reproduced in populations ...
Not only cardiovascular disease <ul><li>tend to develop the combination of: </li></ul><ul><li>hypertension ,  </li></ul><u...
Relation of birth weight to infant mortality and Complex Adult-Onset Disease  Dover GJ. Trans Am Clin Climatol Assoc. 2009...
Developmental Origins of Health and  Diseases: when we become what we are. <ul><li>Original findings   </li></ul><ul><li>F...
Morbidities associated with intrauterine growth restriction (IUGR) can be split into metabolic and nonmetabolic effects  J...
Metabolic Syndrome <ul><li>Elevated waist circumference (Central Obesity) : </li></ul><ul><ul><li>Men — Equal to or greate...
<ul><li>There are two different  relationships between birthweight and obesity : </li></ul><ul><li>a  direct  relationship...
Parental determinants of neonatal body composition.   Harvey NC,  J Clin Endocrinol Metab 2007;92:523. neonatal body compo...
Parental determinants of neonatal body composition.   Harvey NC,  J Clin Endocrinol Metab 2007;92:523. Maternal lifestyle ...
Gestational weight gain and child adiposity at age 3 years.  Oken E, Am J Obstet Gynecol. 2007;196:322.e1-8. <ul><li>1044 ...
Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18...
Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18...
Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18...
Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18...
<ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL-  at birth and 6 months  of age)  </l...
<ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL-  at birth and 6 months  of age)  </l...
<ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL-  at birth and 6 months  of age)  </l...
<ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL-  at birth and 6 months  of age)  </l...
Infant Obesity: Are We Ready to Make this Diagnosis?   McCormick, J Pediatr 2010;157:15-9 16% prevalence of infant obesity...
14% % children diagnosed as obese 6 mo 24 mo 23% 30 – 20 – 10 – 0 If obese at age Infant Obesity: Are We Ready to Make thi...
Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice. Isganaitis E...
Blood Pressure
Prenatal Factors for Childhood Blood Pressure Mediated by Intrauterine and/or Childhood Growth? Wen  Pediatrics 2011;127:e...
Promotion of faster weight gain in infants born small for gestational age: is there an adverse effect on later blood press...
Promotion of faster weight gain in infants born small for gestational age: is there an adverse effect on later blood press...
2 – 1 – 0 <ul><li>23-27 y follow-up (1997-1999) of the Barry Caerphilly Growth study cohort (1972-1974) </li></ul><ul><li>...
Size at birth, infant growth, and blood pressure at three years of age.  Belfort MB, J Pediatr. 2007;151:670-4 <ul><li>530...
Size at birth, infant growth, and blood pressure at three years of age.  Belfort MB, J Pediatr. 2007;151:670-4 <ul><li>530...
Type 2 diabetes
Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutritio...
Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutritio...
Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutritio...
Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutritio...
contributes to childhood  insulin resistance   in humans imbalance in maternal vitamin B12 (low) and  folate (high) status...
Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutritio...
Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutritio...
Vitamin B12 ,  vitamin B12  or  vitamin B-12 , also called  cobalamin , is a water soluble vitamin with a key role in the ...
<ul><li>Lung </li></ul>
Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund  Thorax 2010;65:146...
Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund  Thorax 2010;65:146...
Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei  Pediatrics 2010;125:8...
Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei  Pediatrics 2010;125:8...
Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei  Pediatrics 2010;125:8...
Spirometric Lung Function in School-Age Children: Effect of Intrauterine Growth Retardation and  Catch-up Growth.   Kotech...
Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years  Pike  Thorax  2010;65:1099...
Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years  Pike  Thorax  2010;65:1099...
<ul><li>CONCLUSIONS:   </li></ul><ul><li>A rapid growth trajectory during 11-19 weeks gestation followed by late gestation...
<ul><li>Immune </li></ul><ul><li>responses </li></ul>
Prenatal undernutrition, postnatal environments, and antibody response to vaccination in adolescence.   McDade TW, Am J Cl...
Prenatal undernutrition and postnatal growth are associated with adolescent thymic function.  McDade TW, J Nutr. 2001;131:...
Early immunological development and mortality from infectious disease in later life.   Moore SE, Proc Nutr Soc. 2006;65:31...
<ul><li>Aterosclerosis </li></ul>
Maternal diet during pregnancy and carotid intima-media thickness in children.   Gale CR, Arterioscler Thromb Vasc Biol 20...
Maternal diet during pregnancy and carotid intima-media thickness in children.   Gale CR, Arterioscler Thromb Vasc Biol 20...
Maternal diet during pregnancy and carotid intima-media thickness in children.   Gale CR, Arterioscler Thromb Vasc Biol 20...
Regulation of cholesterol synthesis Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, t...
<ul><li>Mental - Brain health </li></ul>
The Sources of Mental Ilnesses “ At the farthest edge of fetal-origins  research,  scientists are exploring the  possibili...
Early life origins of psychological development and mental health  Raikkonen, Scand J Psychol 2009;50:583–591 <ul><li>Slow...
Birth weight and the risk of depressive disorder in late life   Thompson C. Br J Psychiatry  2001;179:450-455 <ul><li>882 ...
Birth weight and the risk of depressive disorder in late life   Thompson C. Br J Psychiatry  2001;179:450-455 <ul><li>882 ...
Interpretation of the findings It has been known for many years that foetal growth is determined by the intra-uterine envi...
Candidate mechanisms There are several mechanisms by which undernutrition of the foetus might cause permanent changes that...
Candidate mechanisms Thyroid function  also may be set during foetal growth and infant feeding ( Philips  et al , 1993 ) a...
Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. St Clair D, JAMA. 2005;294:55...
Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. Malaspina D, BMC Psychiatry...
Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. Malaspina D, BMC Psychiatry...
Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. Malaspina D, BMC Psychiatry...
Fetal Growth Retardation and Risk of Febrile Seizures Visser  Pediatrics 2010;126:919-25 OR  for febrile seizures 3 -2 - 1...
Fetal Growth Retardation and Risk of Febrile Seizures Visser  Pediatrics 2010;126:919-25 OR  for febrile seizures 3 -2 - 1...
Fetal Growth Retardation and Risk of Febrile Seizures Visser  Pediatrics 2010;126:919-25 OR  for febrile seizures 3 -2 - 1...
Neonatal Jaundice, Autism, and Other Disorders of Psychological Development Maimburg  Pediatrics 2010;126:872-78 <ul><li>A...
<ul><li>A cohort of 9- to 10-month-old infants. </li></ul><ul><li>The infants were given oral iron for  3 months . </li></...
<ul><li>A cohort of 9- to 10-month-old infants. </li></ul><ul><li>The infants were given oral iron for  3 months . </li></...
Iron-Deficiency Anemia in Infancy and Social Emotional Development in Preschool-Aged Chinese Children Chang  Pediatrics 20...
Iron-Deficiency Anemia in Infancy and Social Emotional Development in Preschool-Aged Chinese Children Chang  Pediatrics 20...
Developmental Origins of Health and  Diseases: when we become what we are. <ul><li>Original findings   </li></ul><ul><li>F...
<ul><li>Mother’s anxiety and depression </li></ul>
Mothers’ anxiety during pregnancy is associated with asthma in their children  Cookson  JACI 2009; 123:847 <ul><li>Avon Lo...
CONTINUED EXPOSURE TO MATERNAL DISTRESS IN EARLY LIFE IS ASSOCIATED WITH AN INCREASED RISK OF CHILDHOOD ASTHMA.   Kozrskyj...
Maternal Prenatal Anxiety and Stress Predict Infant Illnesses and Health Complaints  Beijers  Pediatrics 2010;126;e401 <ul...
Maternal Prenatal Anxiety and Stress Predict Infant Illnesses and Health Complaints  Beijers  Pediatrics 2010;126;e401 <ul...
Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-City Cohort   Wright  AJRCCM  2...
High pregnancy anxiety during midgestation is associated with decreased gray matter density  in 6–9-year-old children.   B...
Stress-related maternal–placental–fetal endocrine and immune processes as potential mediators of fetal programming of heal...
ADHD deficits as measured in adolescent boys with a continuous performance task is related to antenatal maternal anxiety. ...
Maternal antenatal anxiety and behavioral/emotional problems in children: a test of a programming hypothesis. O’Connor TG,...
Maternal antenatal anxiety and behavioral/emotional problems in children: a test of a programming hypothesis. O’Connor TG,...
Longitudinal study of maternal depressive symptoms and child well being.   Luoma I, J Am Acad Child Adolesc Psychiatry. 20...
Longitudinal study of maternal depressive symptoms and child well being.   Luoma I, J Am Acad Child Adolesc Psychiatry. 20...
Type 2 diabetes
Effect of diabetes in pregnancy on offspring:  follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;...
Effect of diabetes in pregnancy on offspring:  follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;...
Effect of diabetes in pregnancy on offspring:  follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;...
Effect of diabetes in pregnancy on offspring:  follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;...
Gestational glucose tolerance and risk of type 2 diabetes in young Pima Indian offspring. Franks PW, Diabetes. 2006;55:460...
An understanding of the role of gestational factors in disease  can change  individual behavior , notes  Daniel Benyshek ,...
Associations of physical activity and inactivity before and during pregnancy with glucose tolerance. Oken E, Obstet Gyneco...
Associations of physical activity and inactivity before and during pregnancy with glucose tolerance. Oken E, Obstet Gyneco...
Associations of physical activity and inactivity before and during pregnancy with glucose tolerance. Oken E, Obstet Gyneco...
Diabetes risk begins in utero. Woo M, Patti ME. Cell Metab. 2008;8:5-7. Intrauterine stressors, including maternal undernu...
<ul><li>Asthma in pregnancy </li></ul>
Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth.   Bakhireva LN, Ann Allergy Ast...
Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control ...
Sleep-disorderd breathing or sleep deprivation  during pregnancy
Sleep-disordered breathing and pregnancy: potential mechanisms and evidence for maternal and fetal morbidity  Izci-Balsera...
Sleep-disordered breathing and pregnancy: potential mechanisms and evidence for maternal and fetal morbidity  Izci-Balsera...
Snoring, pregnancy-induced hypertension, and growth retardation of the fetus.   Franklin KA, Chest 2000; 117:137 <ul><li>5...
Outcomes of pregnancy in a national sample of resident physicians.   Klebanoff MA, N Engl J Med 1990; 323:1040–1045. <ul><...
Outcomes of pregnancy in a national sample of resident physicians.   Klebanoff MA, N Engl J Med 1990; 323:1040–1045. <ul><...
Developmental Origins of Health and  Diseases: when we become what we are. <ul><li>Original findings   </li></ul><ul><li>F...
 
Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the ra...
Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the ra...
“ Mia will be an incredible swimmer”  Uncle Grooming
The Rat Model of Nurturing In rats, an important component of maternal care consists of  licking   and  grooming , which v...
The Rat Model of Nurturing In rats, an important component of maternal care consists of  licking   and  grooming , which v...
This provides a biological basis for speculations about the  effects of poverty  on early experience, and how exposure to ...
<ul><li>primary insulin resistance and a lipid profile consistent with the metabolic syndrome,  Entringer S, Am J Obstet G...
<ul><li>Smoking in pregnancy </li></ul>
Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective ...
Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective ...
Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective ...
Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective ...
Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis.   Oken E, Int J Obes (Lond) 2...
First trimester maternal tobacco smoking habits and fetal growth   Prabhu  Thorax 2010;65:235–240 Mean differences in  fem...
Maternal smoking during pregnancy and neonatal behavior: a large-scale community study.   Stroud LR, Pediatrics 2009;123:e...
Maternal smoking during pregnancy and neonatal behavior: a large-scale community study.   Stroud LR, Pediatrics 2009;123:e...
Maternal smoking during pregnancy and neonatal behavior: a large-scale community study.   Stroud LR, Pediatrics 2009;123:e...
Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children.   Braun JM, Environ He...
Smoking during pregnancy and hyperactivity-inattention in the offspring—comparing results from three Nordic cohorts.   Obe...
Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment.   Herrmann M, Curr Opin Pediatr...
Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment.   Herrmann M, Curr Opin Pediatr...
CEREBELLUM (mL) 23.1 24.5 EXPOSED NON-EXPOSED P=0.03 150 – 100 – 50 – 0 25 – 20 – 15 – 10 – 5 – 0 FRONTAL LOBE (mL) 118 12...
CEREBELLUM (mL) 23.1 24.5 EXPOSED NON-EXPOSED P=0.03 150 – 100 – 50 – 0 25 – 20 – 15 – 10 – 5 – 0 FRONTAL LOBE (mL) 118 12...
Association of passive exposure of pregnant women to environmental tobacco smoke with asthma symptoms in children.  Xepapa...
Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke  Strulovici-Barel  Am J Resp...
Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke  Strulovici-Barel  Am J Resp...
<ul><li>121 individuals.   </li></ul><ul><li>Small airway epithelium by bronchoscopy. </li></ul><ul><li>Microarrays to ass...
<ul><li>121 individuals.   </li></ul><ul><li>Small airway epithelium by bronchoscopy. </li></ul><ul><li>Microarrays to ass...
Indoor Pollution  during  Pregancy and first years of  life
OR FOR 5 - 4 - 3 – 2 – 1 – 0 A prospective association between synthetic cocoon use in infancy and childhooh asthma.  Trev...
OR FOR 5 - 4 - 3 – 2 – 1 – 0 A prospective association between synthetic cocoon use in infancy and childhooh asthma.  Trev...
<ul><li>Bedding type at 1mo </li></ul><ul><li>Wheeze at 7 yrs </li></ul><ul><li>(n=6,378 ch) </li></ul>SYNTHETIC BEDDING A...
spray detergents and  atopy-asthma
FREQUENT USE OF CHEMICAL HOUSEHOLD PRODUCTS  IS ASSOCIATED WITH PERSISTENT WHEEZING IN  PRE-SCHOOL AGE CHILDREN.  Sherriff...
FREQUENT USE OF CHEMICAL HOUSEHOLD PRODUCTS  IS ASSOCIATED WITH PERSISTENT WHEEZING IN  PRE-SCHOOL AGE CHILDREN.  Sherriff...
<ul><li>European Community Respiratory Health Survey in 10 countries. </li></ul><ul><li>3.503 persons doing the cleaning i...
<ul><li>For young children, the most important indoor environment is the home. </li></ul><ul><li>On overage,  children  sp...
Outdoor Pollution  during  pregnancy
The Impact of Air The chance of a healthier life is what  Frederica Perera   is trying to give children in some of New Yor...
Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction.  Choi H, Envir...
Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction.  Choi H, Envir...
Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction.  Choi H, Envir...
Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction.  Choi H, Envir...
Predictors of personal polycyclic aromatic hydrocarbon exposures among pregnant minority women in New York City.  Tonne CC...
Relationship between ambient air pollution and DNA damage in Polish mothers and newborns. Whyatt RM, Environ Health Perspe...
Relationship between ambient air pollution and DNA damage in Polish mothers and newborns. Whyatt RM, Environ Health Perspe...
Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarb...
Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarb...
Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarb...
OR for methylation of the acyl-CoA synthetase long-chain family member 3 (ACSL3 5'-CGI) in UCWBC  Relation of DNA methylat...
OR for a parental report of asthma symptoms in children prior to age 5  Relation of DNA methylation of 59-CpG island of AC...
The Impact of Air &quot;We used to worry about elderly people and asthma patients,&quot;  Perera says.  &quot;Now we worry...
Diet of the mother diuring pregnancy
Modulation of the effect of prenatal PAH exposure on PAH-DNA adducts in cord blood by plasma antioxidants.  Kelvin EA, Can...
Modulation of the
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Developmental origins adult diseases

  1. 1. Developmental Origins of Health and Diseases: when we become what we are. <ul><li>Original findings </li></ul><ul><li>Further discoveries </li></ul><ul><li>Maternal diseases </li></ul><ul><li>Maternal life style-environment </li></ul><ul><li>Epigenetic </li></ul><ul><li>More than 1 generation </li></ul><ul><li>Prevention & Reversibility </li></ul><ul><li>Public Health Implications </li></ul><ul><li>Conclusions </li></ul>University of Verona, Italy Attilio L Boner
  2. 2. Perhaps the single most important observation made in the twentieth century related to the origins of complex adult onset disorders was made by Barker and his colleagues ORIGIN OF COMPLEX ADULT ONSET DISEASES Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease . Lancet 1989;2:577–80.
  3. 3. “ Two decades ago, a British physician named David Barker noticed an odd correlation on a map: the poorest regions of England and Wales were the ones with the highest rates of heart disease. Why would this be, he wondered, when heart disease was supposed to be a condition of affluence — of sedentary lifestyles and rich food? He decided to investigate, and after comparing the adult health of some 15,000 individuals with their birth weight, he discovered an unexpected link between small birth size (1921-25)— often an indication of poor prenatal nutrition — and heart disease in middle age (1968-78). Faced with an inadequate food supply, Barker conjectured, the fetus diverts nutrients to its most important organ, the brain, while skimping on other parts of its body — a debt that comes due decades later in the form of a weakened heart .” Barker Hypothesis *
  4. 4. Environmental Effects via Developmental Plasticity: Types of Response to the Early Environment Gluckman Science 2004;305:1733 <ul><li>the fetus has many homeostatic and homeorhetic * mechanisms that confer immediate survival advantage e.g ., alterations in regional blood flows and organ growth when nutrient or oxygen </li></ul><ul><li>supply is reduced — even if there may be subsequent </li></ul><ul><li>postnatal costs . </li></ul>Homeorhesis , derived from the Greek for &quot;similar flow&quot;, is a concept encompassing dynamical systems which return to a trajectory , as opposed to systems which return to a particular state , which is termed homeostasis . The word describes the tendency of developing or changing organisms to continue development or change towards a given state.
  5. 5. ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;1:1077 . </li></ul><ul><li>Barker DJ , Weight in infancy and death from ischaemic heart disease. Lancet 1989;2:577. </li></ul><ul><li>Barker DJ , Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938. </li></ul><ul><li>Barker DJ . The origins of the developmental origins theory. J Intern Med. 2007;261:412. </li></ul>a large positive geographic correlation (~0.7) for standardized rates for infant mortality from 1921 to 1925 and ischemic heart disease from 1968 to 1978 . *
  6. 6. ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;1:1077. </li></ul><ul><li>Barker DJ , Weight in infancy and death from ischaemic heart disease. Lancet 1989;2:577 . </li></ul><ul><li>Barker DJ , Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938. </li></ul><ul><li>Barker DJ . The origins of the developmental origins theory. J Intern Med. 2007;261:412. </li></ul>a possible relationship between birthweight and coronary heart disease in adulthood.
  7. 7. ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;1:1077. </li></ul><ul><li>Barker DJ , Weight in infancy and death from ischaemic heart disease. Lancet 1989;2:577. </li></ul><ul><li>Barker DJ , Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938 . </li></ul><ul><li>Barker DJ . The origins of the developmental origins theory. J Intern Med. 2007;261:412. </li></ul>undernutrition during gestation was an important contributor to low birthweight and an early origin of adult cardiac and metabolic disorders due to fetal programming in response to undernutrition that permanently shaped the body’s structure, function, and metabolism X
  8. 8. ORIGIN OF COMPLEX ADULT ONSET DISEASES <ul><li>Barker DJ , Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;1:1077. </li></ul><ul><li>Barker DJ , Weight in infancy and death from ischaemic heart disease. Lancet 1989;2:577. </li></ul><ul><li>Barker DJ , Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938. </li></ul><ul><li>Barker DJ . The origins of the developmental origins theory. J Intern Med. 2007;261:412 . </li></ul>“ thrifty phenotype” profound effects have been demonstrated if there is a “mismatch” between the early, developmental environment and the subsequent environment in childhood and adult life Before ≠ After
  9. 9. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life DJ P Barker, BMJ 1993;306:422-6 <ul><li>1586 men born in Sheffield, England during 1907-24 whose birth weights, head circumferences, </li></ul><ul><li>and other body measurements were recorded at birth </li></ul><ul><li>followed up to adulthood (59-70 years) </li></ul>120 - 110 - 100 – 0 90 – 0 80 – 0 70 – 0 60 – 0 50 – 0 40 – 0 30 – 0 20 – 0 10 – 0 P=0.02 mortality of men (n°) for cardiovascular disease Birth weight ≤2495 g 119 Birth weight ≥3856 g 74 *
  10. 10. Fetal origins of non-insulin dependent diabetes D J P Barker BMJ 1995;311:171-4 *
  11. 11. Birthweight and the risk for type 2 diabetes mellitus in adult women. Rich-Edwards JW, Ann Intern Med. 1999;130:278 <ul><li>The Nurses' Health Study, a cohort of 121,701 U.S. women born from 1921 to 1946 who have been followed since 1976. </li></ul><ul><li>Birthweight and type 2 diabetes </li></ul><ul><li>1lb = 453 g </li></ul>2 – 1 – 0 1.83 birthweight (lb) p<0.001 for trend OR for type 2 diabetes < 5 5.0-5.5 5.6-7.0 > 8.6 1.76 1.23 0.95 (3.9 kg) (2.3 Kg)
  12. 12. may permanently affect ( fetal programming ) the structure and physiology of a range of organs and tissues, including the endocrine pancreas, liver, and blood vessels. Numerous animal experiments have shown that poor nutrition , and other influences that impair growth during critical periods of early life Winick M, J Nutr 1966 ; 89:300. Hahn P, J Nutr 1984 ; 114:1231. Pregnancy Possible explanations Barker DJP Lancet 1993;341:938
  13. 13. fetal programming directed by intrauterine signals that may optimize structure and function of organs in the in utero environment in the short run but contribute to disease in childhood and adulthood in the long run if these adaptations are mismatched with later environments ; may permanently affect ( fetal programming ) the structure and physiology of a range of organs and tissues, including the endocrine pancreas, liver, and blood vessels. Possible explanations Barker DJP Lancet 1993;341:938
  14. 14. Living with the past: evolution, development and patterns of disease. Gluckman PD, Science 2004; 305:1733–1736 <ul><li>Developmental plasticity attempts to “tune” gene expression to produce a phenotype best suited to the predicted later environment . </li></ul><ul><li>When the resulting phenotype is matched to its environment, the organism will remain healthy. </li></ul><ul><li>When there is a mismatch, the individual’s ability to respond to environmental challenges may be inadequate and risk of disease increases. </li></ul><ul><li>Thus, the degree of the mismatch determines the individual’s susceptibility to chronic disease </li></ul>thrifty phenotypes maintained for generations
  15. 15. DEVELOPMENTAL PLASTICITY AND LATER DISEASE <ul><li>Inadequate maternal nutrition, which can induce a range of phenotypes that have been called “thrifty,” which means that the response of the developing fetus is a defense against an immediate challenge. </li></ul><ul><li>The defensive fetal response usually involves a reduction </li></ul><ul><li>in somatic growth, which may be specific to an organ or tissue, such as diminished skeletal muscle mass and restricted numbers of nephrons and neurons . </li></ul><ul><li>Once such a challenged fetus has been born, it has to cope with the consequences of altered body composition, often through tradeoffs affecting other functions such as ultimate adult size or the timing of reproductive function. </li></ul>
  16. 16. DEVELOPMENTAL PLASTICITY AND LATER DISEASE <ul><li>Inadequate maternal nutrition, which can induce a range of phenotypes that have been called “thrifty,” which means that the response of the developing fetus is a defense against an immediate challenge. </li></ul><ul><li>The defensive fetal response usually involves a reduction </li></ul><ul><li>in somatic growth, which may be specific to an organ or tissue, such as diminished skeletal muscle mass and restricted numbers of nephrons and neurons. </li></ul><ul><li>Once such a challenged fetus has been born, it has to cope with the consequences of altered body composition, often through tradeoffs affecting other functions such as ultimate adult size or the timing of reproductive function. </li></ul>One example is a poor intrauterine environment inducing the reduced development of skeletal muscle and increased visceral fat deposition , a pattern that favors survival in a poor postnatal environment.
  17. 17. DEVELOPMENTAL PLASTICITY AND LATER DISEASE <ul><li>Inadequate maternal nutrition, which can induce a range of phenotypes that have been called “thrifty,” which means that the response of the developing fetus is a defense against an immediate challenge. </li></ul><ul><li>The defensive fetal response usually involves a reduction </li></ul><ul><li>in somatic growth, which may be specific to an organ or tissue, such as diminished skeletal muscle mass and restricted numbers of nephrons and neurons. </li></ul><ul><li>Once such a challenged fetus has been born, it has to cope with the consequences of altered body composition, often through tradeoffs affecting other functions such as ultimate adult size or the timing of reproductive function. </li></ul>This pattern has been observed in some South Asian babies, such as those in India.
  18. 18. <ul><li>The fetuses’ adaptations to undernutrition are associated with changes in the concentrations of fetal and placental hormones . </li></ul><ul><li>Persisting changes in the levels of hormone secretion, and in the sensitivity of tissues to them , may link fetal undernutrition with abnormal structure, function, and disease in adult life. </li></ul>Possible explanations Barker DJP Lancet 1993;341:938
  19. 19. <ul><li>The fetuses’ adaptations to undernutrition are associated with changes in the concentrations of fetal and placental hormones . </li></ul><ul><li>Persisting changes in the levels of hormone secretion, and in the sensitivity of tissues to them , may link fetal undernutrition with abnormal structure, function, and disease in adult life. </li></ul>Possible explanations Barker DJP Lancet 1993;341:938 The associations are seen in babies who are born small for their gestational age rather than those born prematurely.
  20. 20. Hormonal responses to undernutrition <ul><li>Insulin and the insulin-like growth factors (IGFs), hormones thought to have a central role in the regulation of fetal growth , rapidly respond to changes in fetal nutrition. </li></ul>maternal starvation <ul><li>lowers fetal IGF-1 concentrations </li></ul><ul><li>impairs β -cell development </li></ul><ul><li>induce insulin resistance in tissues </li></ul><ul><li>increases plasma cortisol concentrations </li></ul><ul><li>which could initiate adult hypertension </li></ul>Possible explanations Barker DJP Lancet 1993;341:938
  21. 21. Intrauterine growth restriction (IUGR) can affect tissue in two ways. <ul><li>First, intrauterine growth retardation (IUGR) can produce structural changes in tissue . This reflects early interruptions in developmental processes , particularly those involving apoptosis . </li></ul><ul><li>Second, IUGR results in altered levels of homeostatic regulating factors and subsequent changes to intercellular and intracellular signaling . </li></ul>
  22. 22. Intrauterine growth restriction (IUGR) can affect tissue in two ways. <ul><li>First, intrauterine growth retardation (IUGR) can produce structural changes in tissue . This reflects early interruptions in developmental processes , particularly those involving apoptosis. </li></ul><ul><li>Second, IUGR results in altered levels of homeostatic regulating factors and subsequent changes to intercellular and intracellular signaling . </li></ul>Both these phenomena result from alterations in gene expression in developing cells , that occur in response to IUGR, and are maintained overtime .
  23. 23. Intrauterine growth restriction (IUGR) can affect tissue in two ways. <ul><li>First, intrauterine growth retardation (IUGR) can produce structural changes in tissue . This reflects early interruptions in developmental processes , particularly those involving apoptosis. </li></ul><ul><li>Second, IUGR results in altered levels of homeostatic regulating factors and subsequent changes to intercellular and intracellular signaling . </li></ul>……… and are maintained overtime. Ask how was the “granma” or the “grangranma” ! We are still paying !
  24. 24. <ul><li>The associations with cardiovascular risk factors are independent of known influences in adult lifestyle. </li></ul><ul><li>They occur in each social class and at each level of cigarette smoking, alcohol consumption, obesity , and in different populations , and prevalently in men . </li></ul><ul><li>Adult lifestyle influences , however, add to the effects of early life. For example, the risk of non-insulin-dependent diabetes was highest in people who had low weight at birth and during infancy but became obese as adults. </li></ul><ul><li>Hales CN, Barker DJP, BMJ 1991; 303: 1019-22. </li></ul>Possible explanations Barker DJP Lancet 1993;341:938
  25. 25. This inverse relationship between birth weight and coronary artery disease death rates has been reproduced in populations from all continents (except Africa) Dover GJ. The Barker hypothesis: how pediatricans will diagnose and prevent common adult-onset diseases. Trans Am Clin Climatol Assoc. 2009;120:199-207.
  26. 26. Not only cardiovascular disease <ul><li>tend to develop the combination of: </li></ul><ul><li>hypertension , </li></ul><ul><li>non-insulin-dependent diabetes , </li></ul><ul><li>lipid disorders known as syndrome X, </li></ul><ul><li>Osteoporosis later in life </li></ul><ul><li>Precocious puberty </li></ul><ul><li>Chronic bronchitis </li></ul><ul><li>Some form of cancer </li></ul>Those who are thin at birth , as measured by a low ponderal index (weight/length 3 ), Barker DJP Lancet 1993;341:938
  27. 27. Relation of birth weight to infant mortality and Complex Adult-Onset Disease Dover GJ. Trans Am Clin Climatol Assoc. 2009;120:199-207. 1 pound = 1lb = 453 g
  28. 28. Developmental Origins of Health and Diseases: when we become what we are. <ul><li>Original findings </li></ul><ul><li>Further discoveries </li></ul><ul><li>Maternal diseases </li></ul><ul><li>Maternal life style-environment </li></ul><ul><li>Epigenetic </li></ul><ul><li>More than 1 generation </li></ul><ul><li>Prevention & Reversibility </li></ul><ul><li>Public Health Implications </li></ul><ul><li>Conclusions </li></ul>University of Verona, Italy Attilio L Boner
  29. 29. Morbidities associated with intrauterine growth restriction (IUGR) can be split into metabolic and nonmetabolic effects Joss-Moore Curr Opin Pediatr. 2009; 21:230 + central adiposity = MS
  30. 30. Metabolic Syndrome <ul><li>Elevated waist circumference (Central Obesity) : </li></ul><ul><ul><li>Men — Equal to or greater than 40 inches (102 cm) </li></ul></ul><ul><ul><li>Women — Equal to or greater than 35 inches (88 cm) </li></ul></ul><ul><li>Elevated blood pressure : Equal to or greater than 130/85 mm </li></ul><ul><li>Hg or use of medication for hypertension </li></ul><ul><li>Elevated triglycerides : Equal to or greater than 150 mg/dL </li></ul><ul><li>(1.7 mmol/L) </li></ul><ul><li>Reduced HDL (“good”) cholesterol : </li></ul><ul><ul><li>Men — Less than 40 mg/dL (1.03 mmol/L) </li></ul></ul><ul><ul><li>Women — Less than 50 mg/dL (1.29 mmol/L) </li></ul></ul><ul><li>Elevated fasting glucose : Equal to or greater than 100 mg/dL </li></ul><ul><li>(5.6 mmol/L) or use of medication for hyperglycemia </li></ul>
  31. 31. <ul><li>There are two different relationships between birthweight and obesity : </li></ul><ul><li>a direct relationship held for birthweight with BMI in childhood and adulthood , but </li></ul><ul><li>an inverse relationship held for low birth-weight with central adiposity, insulin resistance, and the metabolic syndrome . </li></ul>Fetal origins of obesity. Oken E, Gillman MW. Obes Res 2003;11:496–506.
  32. 32. Parental determinants of neonatal body composition. Harvey NC, J Clin Endocrinol Metab 2007;92:523. neonatal body composition in 448 births evaluated with dual-energy x-ray absorptiometry scan assessment of fat and muscle mass components of body composition in the offspring within 2 weeks of birth total fat mass was related to maternal lifestyle factors (smoking and physical activity) as well as maternal height, parity, and triceps skinfold thickness
  33. 33. Parental determinants of neonatal body composition. Harvey NC, J Clin Endocrinol Metab 2007;92:523. Maternal lifestyle and anthropometric factors and neonatal body composition
  34. 34. Gestational weight gain and child adiposity at age 3 years. Oken E, Am J Obstet Gynecol. 2007;196:322.e1-8. <ul><li>1044 mother-child pairs in Project Viva. </li></ul><ul><li>associations of gestational weight gain with child adiposity </li></ul>OR for obesity in offspring at age 3 years, 5 - 4 - 3 – 2 – 1 – 0 4.35 Excessive (>16 Kg) weight gain during pregnancy
  35. 35. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Kral JG, Pediatrics. 2006;118:e1644-9. <ul><li>172 children born to 113 previous obese mothers (BMI: 31 ± 9 kg/m 2 ) with substantial weight loss after biliopancreatic bypass surgery </li></ul><ul><li>45 same-age siblings who were born before maternal surgery (mothers' BMI: 48 ± 8 kg/m 2 ) </li></ul>Biliopancreatic bypass with pylorus-preserving sleeve gastrectomy (“duodenal switch”) partial gastric resection and shunting of bile and pancreatic secretions to distal small bowel fecal losses of lipids
  36. 36. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Kral JG, Pediatrics. 2006;118:e1644-9. 0 – -10 – -20 – -30 – -40 – -50 – -60 – After maternal surgery % decrease in the offspring of -52% Obesity Severe Obesity -45% <ul><li>172 children born to 113 previous obese mothers (BMI: 31 ± 9 kg/m 2 ) with substantial weight loss after biliopancreatic bypass surgery </li></ul><ul><li>45 same-age siblings who were born before maternal surgery (mothers' BMI: 48 ± 8 kg/m 2 ) </li></ul>
  37. 37. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Kral JG, Pediatrics. 2006;118:e1644-9. <ul><li>172 children born to 113 obese mothers (BMI: 31 +/- 9 kg/m2) with substantial weight loss after biliopancreatic bypass surgery </li></ul><ul><li>45 same-age siblings who were born before maternal surgery (mothers' BMI: 48 +/- 8 kg/m2) </li></ul>0 – -10 – -20 – -30 – -40 – -50 – -60 – After maternal surgery % decrease in the offspring of -52% Obesity Severe Obesity -45% The prevalence of overweight and obesity in children of mothers with large voluntary postsurgical weight loss was similar to that in the general population, with no increase in SGA or prematurity.
  38. 38. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Kral JG, Pediatrics. 2006;118:e1644-9. <ul><li>172 children born to 113 obese mothers (BMI: 31 +/- 9 kg/m2) with substantial weight loss after biliopancreatic bypass surgery </li></ul><ul><li>45 same-age siblings who were born before maternal surgery (mothers' BMI: 48 +/- 8 kg/m2) </li></ul>0 – -10 – -20 – -30 – -40 – -50 – -60 – After maternal surgery % decrease in the offspring of -52% Obesity Severe Obesity -45% The results demonstrate the importance of potentially modifiable epigenetic factors in the cause of obesity.
  39. 39. <ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL- at birth and 6 months of age) </li></ul><ul><li>obesity (BMI >95th percentile) at 3 years of age. </li></ul>Weight status in the first 6 months of life and obesity at 3 years of age. Taveras EM Pediatrics 2009;123:1177. Predicted probability of obesity (BMI of > 95th percentile) at 3 years of age according to quartile of WFL z score at birth and at 6 months of age, The importance of the first months
  40. 40. <ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL- at birth and 6 months of age) </li></ul><ul><li>obesity (BMI >95th percentile) at 3 years of age. </li></ul>Weight status in the first 6 months of life and obesity at 3 years of age. Taveras EM Pediatrics 2009;123:1177. Predicted probability of obesity (BMI of > 95th percentile) at 3 years of age according to quartile of WFL z score at birth and at 6 months of age, The importance of the first months Weight early in life was directly associated with higher BMI at 3 years of age
  41. 41. <ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL- at birth and 6 months of age) </li></ul><ul><li>obesity (BMI >95th percentile) at 3 years of age. </li></ul>Weight status in the first 6 months of life and obesity at 3 years of age. Taveras EM Pediatrics 2009;123:1177. Predicted probability of obesity (BMI of > 95th percentile) at 3 years of age according to quartile of WFL z score at birth and at 6 months of age, The importance of the first months but the association was larger for standardized weight at 6 months of age than for birth-weight.
  42. 42. <ul><li>559 children </li></ul><ul><li>weight early in life ( weight-for-length –WFL- at birth and 6 months of age) </li></ul><ul><li>obesity (BMI >95th percentile) at 3 years of age. </li></ul>Weight status in the first 6 months of life and obesity at 3 years of age. Taveras EM Pediatrics 2009;123:1177. Predicted probability of obesity (BMI of > 95th percentile) at 3 years of age according to quartile of WFL z score at birth and at 6 months of age, The importance of the first months This suggest that increases in weight in the first 6 months of life may produce additional programming effects that increased risk for obesity in early childhood and thus may influence risk for later obesity more than birthweight alone
  43. 43. Infant Obesity: Are We Ready to Make this Diagnosis? McCormick, J Pediatr 2010;157:15-9 16% prevalence of infant obesity 20 – 10 – 0 <ul><li>Infant obesity (weight-for-length) ≥ 95th percentile for age and sex. </li></ul>
  44. 44. 14% % children diagnosed as obese 6 mo 24 mo 23% 30 – 20 – 10 – 0 If obese at age Infant Obesity: Are We Ready to Make this Diagnosis? McCormick, J Pedistr 2010;157:15-9 <ul><li>Infant obesity (weight-for-length) ≥ 95th percentile for age and sex. </li></ul>
  45. 45. Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice. Isganaitis E, Diabetes. 2009;58:1192-200. <ul><li>mice food restricted by 50% from gestational days 12.5-18.5, reducing offspring birth weight by 25% (LBW). </li></ul><ul><li>during the suckling period, dams were either fed ad libitum, permitting catch-up growth (CUG), in offspring, or food restricted, preventing CUG. </li></ul>Catch-up growth results in increased adipose tissue lipogenic gene expression and adipocyte diameter LBW mice with CUG LBW mice without CUG
  46. 46. Blood Pressure
  47. 47. Prenatal Factors for Childhood Blood Pressure Mediated by Intrauterine and/or Childhood Growth? Wen Pediatrics 2011;127:e713 <ul><li>30 461 mother-child pairs in the Collaborative Perinatal Project. </li></ul><ul><li>Prenatal data and children’s SBP measured at 7 years of age. </li></ul><ul><li>Maternal pregnancy weight gain. </li></ul><ul><li>+ </li></ul><ul><li>Child BMI. </li></ul>Significantly associated with higher offspring systolic BP at age 7 years were:
  48. 48. Promotion of faster weight gain in infants born small for gestational age: is there an adverse effect on later blood pressure? Singhal A, Circulation. 2007;115:213–220 <ul><li>Blood pressure measured at 6 to 8 years in 153 children born small for gestational age (birth weight 10th percentile) </li></ul><ul><li>randomly assigned at birth to receive either a standard or a nutrient-enriched formula. </li></ul>Diastolic blood pressure in children assigned to standard compared with nutrient-enriched formula 0 – - 1 – - 2 – - 3 – - 4 - - 3.5 mmHg p=0.01 at age 6-8 years
  49. 49. Promotion of faster weight gain in infants born small for gestational age: is there an adverse effect on later blood pressure? Singhal A, Circulation. 2007;115:213–220 <ul><li>Blood pressure measured at 6 to 8 years in 153 children born small for gestational age (birth weight 10th percentile) </li></ul><ul><li>randomly assigned at birth to receive either a standard or a nutrient-enriched formula. </li></ul>Diastolic blood pressure in children assigned to standard compared with nutrient-enriched formula 0 – - 1 – - 2 – - 3 – - 4 - - 3.5 mmHg p=0.01 In observational analyses, faster weight gain in infancy was associated with higher later blood pressure. at age 6-8 years
  50. 50. 2 – 1 – 0 <ul><li>23-27 y follow-up (1997-1999) of the Barry Caerphilly Growth study cohort (1972-1974) </li></ul><ul><li>mothers and their offspring had been randomly assigned to receive a milk supplement or usual care </li></ul><ul><li>systolic and diastolic blood pressure. </li></ul>Infant nutrition and blood pressure in early adulthood: the Barry Caerphilly Growth Study. Martin RM, Am J Clin Nutr 2003;77: 1489–97. For each increase in quartile of dried milk consumption (in oz) at 3 mo of age there was an increase at age 23-27 yrs blood pressure 0.63 mm Hg 1.28 mm Hg diastolic systolic
  51. 51. Size at birth, infant growth, and blood pressure at three years of age. Belfort MB, J Pediatr. 2007;151:670-4 <ul><li>530 children from the prospective cohort Project Viva, </li></ul><ul><li>birth length and 6-month weight and length </li></ul><ul><li>weight-for-length z-scores (WFL-z) </li></ul><ul><li>SBP at age 3 years </li></ul>Predicted difference in systolic blood pressure at age 3 years according to quartile of weight-for-length z-score at birth and age 6 months
  52. 52. Size at birth, infant growth, and blood pressure at three years of age. Belfort MB, J Pediatr. 2007;151:670-4 <ul><li>530 children from the prospective cohort Project Viva, </li></ul><ul><li>birth length and 6-month weight and length </li></ul><ul><li>weight-for-length z-scores (WFL-z) </li></ul><ul><li>SBP at age 3 years </li></ul>Predicted difference in systolic blood pressure at age 3 years according to quartile of weight-for-length z-score at birth and age 6 months More rapid increase in weight-for-length, a measure of adiposity, in the first 6 months of life is associated with higher early childhood SBP, particularly in children who are thin at birth.
  53. 53. Type 2 diabetes
  54. 54. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. <ul><li>India has the largest number of diabetic patients in the </li></ul><ul><li>world and this may be related to the fact that Indian </li></ul><ul><li>babies are amongst the smallest in the world. </li></ul><ul><li>We were the first to demonstrate that low birthweight of Indian </li></ul><ul><li>babies predicts insulin resistance and adiposity in childhood. </li></ul><ul><li>Subsequently we demonstrated that the apparently small Indian newborn babies are relatively adipose, hyperinsulinaemic and hyperleptinaemic compared with white babies. </li></ul><ul><li>These babies grow into shorter, thinner (low BMI) but more adipose (higher body fat per cent and higher central fat) adults compared with whites, and have a many times higher risk of type 2 diabetes. </li></ul>
  55. 55. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. Aims/hypothesis: Raised maternal plasma total homocysteine (tHcy) concentrations predict small size at birth, which is a risk factor for type 2 diabetes mellitus. We studied the association between maternal vitamin B12, folate and tHcy status during pregnancy, and offspring adiposity and insulin resistance at 6 years.
  56. 56. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. <ul><li>700 consecutive eligible pregnant women in India </li></ul><ul><li>maternal vitamin B12,folate and homocysteine (tHcy) status during pregnancy, at 18 and 28 weeks of gestation </li></ul><ul><li>offspring adiposity and insulin resistance at 6 years. </li></ul>Insulin resistance (HOMA-R) in the children at 6 years in relation to maternal vitamin B12 (18 weeks) and erythrocyte folate (28 weeks)
  57. 57. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. <ul><li>700 consecutive eligible pregnant women in India </li></ul><ul><li>maternal vitamin B12,folate and homocysteine (tHcy) status during pregnancy, at 18 and 28 weeks of gestation </li></ul><ul><li>offspring adiposity and insulin resistance at 6 years. </li></ul>Insulin resistance (HOMA-R) in the children at 6 years in relation to maternal vitamin B12 (18 weeks) and erythrocyte folate (28 weeks) Low maternal vitamin B12 (<150 pmol/l), and high folate (low folate = <283 nmol/l) status may contribute to the epidemic of adiposity and type 2 diabetes
  58. 58. contributes to childhood insulin resistance in humans imbalance in maternal vitamin B12 (low) and folate (high) status during pregnancy Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29.
  59. 59. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. Low vitamin B12 and erythrocyte folate concentrations were defined as <150 pmol/l and <283 nmol/l, respectively. Elevated total homocysteine (tHcy) and methylmalonic acid (MMA) concentrations were defined as >10 and >0.26 μmol/l
  60. 60. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. We can only speculate about the possible mechanisms for our findings. Vitamin B12 deficiency will trap folate as 5-methyltetrahydrofolate, prevent the generation of methionine from homocysteine and therefore reduce protein synthesis and lean tissue deposition . Elevated methylmalonyl-CoA could contribute to increased lipogenesis by inhibiting carnitine palmitoyltransferase and thereby inhibit β-oxidation. An analogous clinical situation is high-dose folic acid treatment of severely vitamin B12-deficient pernicious anaemia patients: anaemia improves but neurological damage worsens, possibly because of accumulation of odd-chain carbon fatty acids.
  61. 61. Vitamin B12 , vitamin B12 or vitamin B-12 , also called cobalamin , is a water soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins. It is normally involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. Vitamin B12 is found in foods that come from animals, including fish and shellfish, meat (especially liver), poultry, eggs, milk, and milk products. Eggs are often mentioned as a good B12 source, but they also contain a factor that blocks absorption. While lacto-ovo vegetarians usually get enough B12 through consuming dairy products, vegans will lack B12 unless they consume multivitamin supplements or B12-fortified foods. Examples of fortified foods include fortified breakfast cereals, fortified soy products, fortified energy bars, and fortified nutritional yeast.
  62. 62. <ul><li>Lung </li></ul>
  63. 63. Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146 <ul><li>Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 . </li></ul><ul><li>Information on asthma from parent-completed questionnaires at age 3-9 years. </li></ul>Prevalence of asthma according to birth weight in Danish twin pairs, 3-9 years of age.
  64. 64. Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis Kindlund Thorax 2010;65:146 <ul><li>Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 . </li></ul><ul><li>Information on asthma from parent-completed questionnaires at age 3-9 years. </li></ul>Prevalence of asthma according to birth weight in Danish twin pairs, 3-9 years of age. This finding lends support to the “fetal origins hypothesis” suggesting undisclosed prenatal determinants for the risk of asthma.
  65. 65. Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei Pediatrics 2010;125:899-905 <ul><li>A retrospective cohort study </li></ul><ul><li>A total of 627 men and women born between 1948 and 1954 </li></ul><ul><li>Lung function </li></ul><ul><li>Significant associations were observed between birth weight and FEV 1 , FVC, and PEF in adulthood (P <0.001). </li></ul><ul><li>FEV 1 , FVC, and PEF values increased with increasing birth weight. </li></ul>
  66. 66. Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei Pediatrics 2010;125:899-905
  67. 67. Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei Pediatrics 2010;125:899-905 Lung function may be affected by hypogenesis in utero.
  68. 68. Spirometric Lung Function in School-Age Children: Effect of Intrauterine Growth Retardation and Catch-up Growth. Kotecha AJRCCM 2010;181:969 <ul><li>Caucasian singleton births of 37 wks or longer gestation from the Avon Longitudinal Study of Parents and Children. </li></ul><ul><li>Spirometry at 8–9 years of age ( n = 5,770). </li></ul>In children with intrauterine growth retardation (IUGR) (i.e., birthweight <10th centile [ n =576]) mean Z scores at age 8-9 years in FEV 1 FVC FEV 25-75 0 -0.05 – -0.10 – -0.15 – -0.20 – -0.198 -0.131 -0.149
  69. 69. Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years Pike Thorax 2010;65:1099 % increase of risk of atopy at age 3 years 50 – 40 – 30 – 20 – 10 – 0 46% p=0.007 <ul><li>Birth weight and length </li></ul><ul><li>1548 children born at term </li></ul><ul><li>Fetal head and abdominal circumference growth velocities from antenatal ultrasound measurements . </li></ul><ul><li>Early childhood wheeze and to atopic status at age 3 years </li></ul>per SD increase in fetal abdominal circumference growth velocity from 11 to 19 weeks gestation 20% p=0.011 per SD decrease in fetal abdominal growth velocity from 19 to 34 weeks
  70. 70. Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years Pike Thorax 2010;65:1099 % increase of risk of non-atopy wheeze 10% <ul><li>Birth weight and length </li></ul><ul><li>1548 children born at term </li></ul><ul><li>Fetal head and abdominal circumference growth velocities from antenatal ultrasound measurements. </li></ul><ul><li>Early childhood wheeze and to atopic status at age 3 years </li></ul>per SD decrease in 11- 19-week head circumference growth 15 – 10 – 5 – 0
  71. 71. <ul><li>CONCLUSIONS: </li></ul><ul><li>A rapid growth trajectory during 11-19 weeks gestation followed by late gestation growth faltering is associated with atopy, suggesting that influences affecting fetal growth may also alter immune development </li></ul><ul><li>A lower early fetal growth trajectory is associated with non-atopic </li></ul><ul><li>wheeze, possibly reflecting an association with smaller airways. </li></ul><ul><li>An association between postnatal adiposity gain and wheeze may </li></ul><ul><li>partly reflect prenatal influences that cause fetal growth to </li></ul><ul><li>falter but are then followed by postnatal adiposity gain. </li></ul>Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years Pike Thorax 2010;65:1099
  72. 72. <ul><li>Immune </li></ul><ul><li>responses </li></ul>
  73. 73. Prenatal undernutrition, postnatal environments, and antibody response to vaccination in adolescence. McDade TW, Am J Clin Nutr. 2001;74:543–548. <ul><li>103 (14-15-y-olds) recruited from an ongoing longitudinal study </li></ul><ul><li>born small for gestational </li></ul><ul><li>age (SGA) or appropriate for gestational age (AGA) </li></ul><ul><li>Duration of breastfeeding (BF) </li></ul><ul><li>BMIs at age 14–15 y </li></ul><ul><li>typhoid vaccine was given, and anti-typhoid antibodies measured 2 wk and 3 mo later </li></ul>Predicted probabilities of mounting a positive antibody response 2 wk after vaccination
  74. 74. Prenatal undernutrition and postnatal growth are associated with adolescent thymic function. McDade TW, J Nutr. 2001;131:1225–1231. <ul><li>thymic hormone production in adolescents participating in an ongoing longitudinal study in the Philippines. </li></ul><ul><li>plasma thymopoietin concentration in 103 adolescents (14-15-y-old), </li></ul><ul><li>Duration of breastfeeding </li></ul>The interaction between birthweight-for-gestational age and duration of exclusive breast-feeding in predicting plasma thymopoietin concentration in 14- to 15-y olds p=0.006
  75. 75. Early immunological development and mortality from infectious disease in later life. Moore SE, Proc Nutr Soc. 2006;65:311–318. Kaplan-Meier survival plots by season of birth (the ‘harvest’ season is from January to June and the ‘hungry’ season is from July to December) <ul><li>3162 subjects (2059 alive and 1103 dead) resident in three villages in the rural West Kiang region of The Gambia. </li></ul>6912 left in Ghana
  76. 76. <ul><li>Aterosclerosis </li></ul>
  77. 77. Maternal diet during pregnancy and carotid intima-media thickness in children. Gale CR, Arterioscler Thromb Vasc Biol 2006;26:1877-82. <ul><li>IMT was greater </li></ul><ul><li>in boys, </li></ul><ul><li>in children who were heavier, </li></ul><ul><li>in those with higher systolic </li></ul><ul><li>blood pressure, </li></ul><ul><li>in those who took less exercise. </li></ul><ul><li>Increased IMT was associated with a lower maternal energy intake in early ( P= 0.029) or late ( P= 0.006) pregnancy , </li></ul><ul><li>carotid intima–media thickness (IMT) in 216 9-year-old children mothers’ nutrition during pregnancy. </li></ul>
  78. 78. Maternal diet during pregnancy and carotid intima-media thickness in children. Gale CR, Arterioscler Thromb Vasc Biol 2006;26:1877-82. Mean carotid IMT , according to thirds of the distribution of current weight and maternal energy intake in late pregnancy. <ul><li>carotid intima–media thickness (IMT) in 216 9-year-old children mothers’ nutrition during pregnancy. </li></ul>
  79. 79. Maternal diet during pregnancy and carotid intima-media thickness in children. Gale CR, Arterioscler Thromb Vasc Biol 2006;26:1877-82. Mean carotid IMT, according to thirds of the distribution of current weight and maternal energy intake in late pregnancy. <ul><li>One potential explanation is that maternal energy intake in pregnancy affects the lipid levels of the child. </li></ul><ul><li>Restricted energy intake in pregnant rats results in hypercholesterolemia </li></ul><ul><li>in the offspring . </li></ul><ul><li>Szitanyi P, Physiol Res. 2000;49:721–724. </li></ul>
  80. 80. Regulation of cholesterol synthesis Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect . Cholesterol is a waxy steroid of fat that is manufactured in the liver or intestines to produce hormones and cell membranes and transported in the blood plasma of all mammals . [2] It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity . In addition, cholesterol is an important component for the manufacture of bile acids , steroid hormones , and Vitamin D .
  81. 81. <ul><li>Mental - Brain health </li></ul>
  82. 82. The Sources of Mental Ilnesses “ At the farthest edge of fetal-origins research, scientists are exploring the possibility that intrauterine conditions influence not only our physical health but also our intelligence, temperament, even our psychological sanity ”. Annie M Paul Time October 4, 2010
  83. 83. Early life origins of psychological development and mental health Raikkonen, Scand J Psychol 2009;50:583–591 <ul><li>Slower postnatal growth </li></ul><ul><li>Gale, C. R., Brain., 2004;127:321–329. </li></ul><ul><li>Lundgren, E. M., Ped Res 2001;50:91–96. </li></ul><ul><li>Montgomery, S. M., Arch Dis Child 2006;91:61–62 </li></ul>low cognitive functioning later in life. <ul><li>smaller body size at birth </li></ul><ul><li>Sørensen, H. T., BMJ 1997;315:401 </li></ul>
  84. 84. Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455 <ul><li>882 singleton term births in the 1920s records of birth weight and weight at 1 year. </li></ul><ul><li>At 68 years Geriatric Depression Scale and Geriatric Mental State Examination. </li></ul>Odds ratios for depression according to birthweight and weight at 1 year 3.850 Kg 2.900 Kg
  85. 85. Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455 <ul><li>882 singleton term births in the 1920s records of birth weight and weight at 1 year. </li></ul><ul><li>At 68 years Geriatric Depression Scale and Geriatric Mental State Examination. </li></ul>Foetal undernutrition predisposes men but not women to depression in late adult life. Odds ratios for depression according to birthweight and weight at 1 year
  86. 86. Interpretation of the findings It has been known for many years that foetal growth is determined by the intra-uterine environment, specifically the ability of the mother to deliver nutrients. McCance, R. A. Proceedings of the Royal Society of London B, 1974;185:1-17 We postulate that male foetuses that are nutritionally stressed and grow slowly in utero are more likely to become depressed in adulthood. Female foetuses grow more slowly than males and therefore are less vulnerable at critical periods of development. Forsen, British Medical Journal, 1997;315: 837-840 Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455
  87. 87. Candidate mechanisms There are several mechanisms by which undernutrition of the foetus might cause permanent changes that increase later vulnerability to depression. Foremost among these is programming of the HPA axis . Small male babies have increased urinary adrenal androgen and glucocorticoid metabolite excretion at age 9 years ( Clark et al , 1996 ) and higher fasting cortisol concentrations as adults ( Philips et al , 1998 ). Raised plasma cortisol level is the most consistently demonstrated biological abnormality in primary depressive disorder ( Nemeroff et al , 1984 ; Murphy, 1991 ; Lopez et al , 1998 ). The growth hormone axis is another candidate. Median 24-h plasma growth hormone concentrations are related to weight at 1 year ( Fall et al , 1998 ), and in depression the control of growth hormone secretion is known to be disturbed. For example, growth hormone secretion in response to both clonidine ( Checkley et al , 1984 ) and slow wave sleep ( Sakkas et al , 1998 ) is reduced in patients with depression . Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455
  88. 88. Candidate mechanisms Thyroid function also may be set during foetal growth and infant feeding ( Philips et al , 1993 ) and reduced plasma thyrotropin levels coupled with impaired response to thyrotropin-releasing hormone ( Schule et al , 1997 ) are associated with depression ( Oomen et al , 1996 ). Although the brain is relatively protected during intra-uterine life, foetal undernutrition at critical periods can have neurodevelopmental effects — reducing cellular growth ( Winick et al , 1972 ), later IQ ( Davies & Stewart, 1975 ) and learning performance ( Katz, 1980 ). The effect on the serotonergic system has not been studied in any detail. Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455
  89. 89. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. St Clair D, JAMA. 2005;294:557-62. <ul><li>massive 1959-1961 famine in China as a cosequence of Mao Zedong's disastrous modernization campaign. </li></ul><ul><li>Rates of schizophrenia among those born before, during, and after the famine years. </li></ul>3 – 2 – 1 – 0 0.89% Born in 1959 1960 1961 % increase in the risk of future development of schizophrenia 2.15% 1.81%
  90. 90. Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. Malaspina D, BMC Psychiatry. 2008;8:71. <ul><li>consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli Six Day War of 1967. </li></ul><ul><li>a cohort of 88,829 born in Jerusalem in 1964-76. </li></ul>RR of incidence of schizophrenia for those who were in the 2°month of fetal life in June 1967 5 - 4 - 3 – 2 – 1 – 0 1.2 in male 4.3 in female
  91. 91. Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. Malaspina D, BMC Psychiatry. 2008;8:71. <ul><li>consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli Six Day War of 1967. </li></ul><ul><li>a cohort of 88,829 born in Jerusalem in 1964-76. </li></ul>RR of incidence of schizophrenia for those who were in the 3°month of fetal life in June 1967 5 - 4 - 3 – 2 – 1 – 0 1.8 in male 3.6 in female
  92. 92. Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. Malaspina D, BMC Psychiatry. 2008;8:71. <ul><li>consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli Six Day War of 1967. </li></ul><ul><li>a cohort of 88,829 born in Jerusalem in 1964-76. </li></ul>RR of incidence of schizophrenia for those who were in the 3°month of fetal life in June 1967 5 - 4 - 3 – 2 – 1 – 0 1.8 in male 3.6 in female Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters .
  93. 93. Fetal Growth Retardation and Risk of Febrile Seizures Visser Pediatrics 2010;126:919-25 OR for febrile seizures 3 -2 - 1 – 0 2.87 Lowest tertile vs highest tertile for transverse cerebellar diameter in the second trimester <ul><li>Cohort study from early fetal life onward for 3372 subjects. </li></ul><ul><li>Fetal growth characteristics (femur length, abdominal circumference, estimated fetal weight, head circumference, biparietal diameter, and transverse cerebellar diameter [TCD]) in the second and third trimesters of pregnancy. </li></ul><ul><li>Febrile seizures at the ages of 12 and 24 months . </li></ul>
  94. 94. Fetal Growth Retardation and Risk of Febrile Seizures Visser Pediatrics 2010;126:919-25 OR for febrile seizures 3 -2 - 1 – 0 2.57 <ul><li>Cohort study from early fetal life onward for 3372 subjects. </li></ul><ul><li>Fetal growth characteristics (femur length, abdominal circumference, estimated fetal weight, head circumference, biparietal diameter, and transverse cerebellar diameter [TCD]) in the second and third trimesters of pregnancy. </li></ul><ul><li>Febrile seizures at the ages of 12 and 24 months . </li></ul>Lowest tertile fetal weight vs highest tertile in the third trimester
  95. 95. Fetal Growth Retardation and Risk of Febrile Seizures Visser Pediatrics 2010;126:919-25 OR for febrile seizures 3 -2 - 1 – 0 2.57 <ul><li>Cohort study from early fetal life onward for 3372 subjects. </li></ul><ul><li>Fetal growth characteristics (femur length, abdominal circumference, estimated fetal weight, head circumference, biparietal diameter, and transverse cerebellar diameter [TCD]) in the second and third trimesters of pregnancy. </li></ul><ul><li>Febrile seizures at the ages of 12 and 24 months . </li></ul>Lowest tertile fetal weight vs highest tertile in the third trimester Adverse environmental and genetic factors during pregnancy may be important in the development of febrile seizures.
  96. 96. Neonatal Jaundice, Autism, and Other Disorders of Psychological Development Maimburg Pediatrics 2010;126:872-78 <ul><li>All children born alive in Denmark between 1994 and 2004 ( N=733 826) </li></ul><ul><li>Hazard ratios (HRs) </li></ul>Exposure to jaundice in neonates HR for 1.56 1.67 2 - 1 – 0 psychological development disorders infantile autism
  97. 97. <ul><li>A cohort of 9- to 10-month-old infants. </li></ul><ul><li>The infants were given oral iron for 3 months . </li></ul><ul><li>Behavioral coding from videotape at 12 months </li></ul>Dose-Response Relationships between Iron Deficiency with or without Anemia and Infant Social-Emotional Behavior Lozoff, J PED 2008; 152:696 <ul><li>There were significant ( P <0.05 ) linear effects of poorer iron status for: </li></ul><ul><li>increasing shyness, </li></ul><ul><li>decreasing orientation/engagement, </li></ul><ul><li>decreasing soothability, and, </li></ul><ul><li>when an examiner attempted to engage the infants in imitative play, decreasing positive affect and engagement. </li></ul>
  98. 98. <ul><li>A cohort of 9- to 10-month-old infants. </li></ul><ul><li>The infants were given oral iron for 3 months . </li></ul><ul><li>Behavioral coding from videotape at 12 months </li></ul><ul><li>There were significant ( P <0.05 ) linear effects of poorer iron status for: </li></ul><ul><li>increasing shyness, </li></ul><ul><li>decreasing orientation/engagement, </li></ul><ul><li>decreasing soothability, and, </li></ul><ul><li>when an examiner attempted to engage the infants in imitative play, decreasing positive affect and engagement. </li></ul>Infant social-emotional behavior appears to be adversely affected by ID with or without anemia. Dose-Response Relationships between Iron Deficiency with or without Anemia and Infant Social-Emotional Behavior Lozoff, J PED 2008; 152:696
  99. 99. Iron-Deficiency Anemia in Infancy and Social Emotional Development in Preschool-Aged Chinese Children Chang Pediatrics 2011;127:e927 <ul><li>Children with iron-deficiency anemia (IDA) in infancy whose anemia was not corrected before 24 months (chronic IDA) (n=27). </li></ul><ul><li>Children with IDA in infancy whose anemia was corrected before 24 months (corrected IDA) (n=70). </li></ul><ul><li>Children who were non-anemic in infancy and at 24 months (n =64). </li></ul>Children who had chronic IDA in infancy displayed: 1. less positive affect and frustration tolerance; 2. more passive behavior and physical self-soothing in the stranger approach; 3. delay of gratification.
  100. 100. Iron-Deficiency Anemia in Infancy and Social Emotional Development in Preschool-Aged Chinese Children Chang Pediatrics 2011;127:e927 <ul><li>Children with iron-deficiency anemia (IDA) in infancy whose anemia was not corrected before 24 months (chronic IDA) (n=27). </li></ul><ul><li>Children with IDA in infancy whose anemia was corrected before 24 months (corrected IDA) (n=70). </li></ul><ul><li>Children who were non-anemic in infancy and at 24 months (n =64). </li></ul>In contrast, the behavior and affect of children whose anemia was corrected before 24 mo of age were comparable to those of children who were non-anemic throughout infancy.
  101. 101. Developmental Origins of Health and Diseases: when we become what we are. <ul><li>Original findings </li></ul><ul><li>Further discoveries </li></ul><ul><li>Maternal diseases </li></ul><ul><li>Maternal life style-environment </li></ul><ul><li>Epigenetic </li></ul><ul><li>More than 1 generation </li></ul><ul><li>Prevention & Reversibility </li></ul><ul><li>Public Health Implications </li></ul><ul><li>Conclusions </li></ul>University of Verona, Italy Attilio L Boner
  102. 102. <ul><li>Mother’s anxiety and depression </li></ul>
  103. 103. Mothers’ anxiety during pregnancy is associated with asthma in their children Cookson JACI 2009; 123:847 <ul><li>Avon Longitudinal Study of Parents and Children (5810 children). </li></ul><ul><li>Anxiety assessed at 18 and 32 weeks of gestation. </li></ul><ul><li>Asthma was defined at age 7½ years. </li></ul>1 2.0 - 1.5 - 1.0 – 0.5 – 0 1.33 1.46 1.68 OR FOR CURRENT ASTHMA AT 7½ YRS. P<0.001 FOR TREND 1 st 2 nd 3 rd 4 th MATERNAL ANXIETY QUARTILE AT 32 WK
  104. 104. CONTINUED EXPOSURE TO MATERNAL DISTRESS IN EARLY LIFE IS ASSOCIATED WITH AN INCREASED RISK OF CHILDHOOD ASTHMA. Kozrskyj AJRCCM 2008; 177: 142 <ul><li>A birth cohort of 13,907 children. </li></ul><ul><li>Maternal distress on the basis of prescription medication for anxiety or depression. </li></ul>OR FOR CHILDHOOD ASTHMA 1.25 AMONG CHILDREN EXPOSED TO CONTINUED MATERNAL DISTRESS FROM BIRTH UNTIL AGE 7. 1.5 – 1.0 – 0.5 – 0
  105. 105. Maternal Prenatal Anxiety and Stress Predict Infant Illnesses and Health Complaints Beijers Pediatrics 2010;126;e401 <ul><li>174 mothers with normal pregnancies and term deliveries </li></ul><ul><li>Third-trimester questionnaires on general and pregnancy specific anxiety and stress </li></ul><ul><li>Saliva samples for circadian cortisol </li></ul>in mother with prenatal anxiety and stress % increase illness in infants 9.3% DISEASE 12 - 10 – 8 – 6 – 4 – 2 – 0 10.7% 8.9% RESPIRATORY GENERAL SKIN
  106. 106. Maternal Prenatal Anxiety and Stress Predict Infant Illnesses and Health Complaints Beijers Pediatrics 2010;126;e401 <ul><li>174 mothers with normal pregnancies and term deliveries </li></ul><ul><li>Third-trimester questionnaires on general and pregnancy specific anxiety and stress </li></ul><ul><li>Saliva samples for circadian cortisol </li></ul>9.3% DISEASE 12 - 10 – 8 – 6 – 4 – 2 – 0 10.7% 8.9% RESPIRATORY GENERAL SKIN And 7.6% for antibiotic use in mother with prenatal anxiety and stress % increase illness in infants
  107. 107. Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-City Cohort Wright AJRCCM 2010;182:25 <ul><li>Urban Environment and Childhood Asthma Study (n = 557 families). </li></ul><ul><li>Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. </li></ul><ul><li>CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. </li></ul><ul><li>Mothers with the highest cumulative stress were more likely to have asthma . </li></ul><ul><li>Higher prenatal stress was related to increased IL-8 and increased tumor necrosis factor- α to microbial stimuli. </li></ul><ul><li>Higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN- γ . </li></ul>
  108. 108. High pregnancy anxiety during midgestation is associated with decreased gray matter density in 6–9-year-old children. Buss C, Psychoneuroendocrinology 2010; 35:141–153. <ul><li>35 women </li></ul><ul><li>pregnancy anxiety at 19, 25 and 31 weeks gestation. </li></ul><ul><li>offspring evaluated between 6 and 9 years of age, </li></ul><ul><li>neurodevelopmental stage was assessed by a structural MRI scan. </li></ul>maternal pregnancy-specific anxiety in mid-gestation was associated with gray matter volume reductions in several child brain regions , including the prefrontal cortex
  109. 109. Stress-related maternal–placental–fetal endocrine and immune processes as potential mediators of fetal programming of health and disease Entringer S Curr Op Endocrinol, Diabetes & Obesity 2010, 17:507 <ul><li>cellular growth , </li></ul><ul><li>replication and differentiation </li></ul><ul><li>in the brain and peripheral tissues </li></ul>maternal–placental–fetal hormones and cytokines essential and obligatory role in orchestrating key events underlying <ul><li>Merrill JE. Dev Neurosci 1992; 14:1–10. </li></ul><ul><li>Matthews SG. Pediatr Res 2000; 47:291–300. </li></ul><ul><li>Zhao B, J Neurosci Res 1998; 52:7–16. </li></ul><ul><li>Trejo JL, J Neurosci Res 2000; 62:644–667. </li></ul><ul><li>Garbrecht MR, Biol Neonate 2006; 89:109–119. </li></ul><ul><li>Cole TJ, Genes Dev 1995; 9:1608–1621. </li></ul>
  110. 110. ADHD deficits as measured in adolescent boys with a continuous performance task is related to antenatal maternal anxiety. van den Berg BEH, Pediatr Res. 2006;59:78–82. <ul><li>64 adolescents </li></ul><ul><li>examined with a computerized continuous performance task (CPT) measuring sustained attention. </li></ul><ul><li>Antenatal maternal anxiety: </li></ul><ul><li>Black triangles: children of mothers with high levels of anxiety during the 12th to 22nd week of pregnancy; open diamonds: children of mothers with low-to average </li></ul><ul><li>levels of anxiety. </li></ul>time-on-task interaction for reaction time p=0.02
  111. 111. Maternal antenatal anxiety and behavioral/emotional problems in children: a test of a programming hypothesis. O’Connor TG, J Child Psychol Psychiatry. 2003;44:1025–1036. <ul><li>Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective, community-based study that has followed a cohort of women from pregnancy. </li></ul><ul><li>Self-report measures of maternal anxiety and depression were assessed at repeated intervals in pregnancy and the postnatal period. </li></ul><ul><li>Children's behavioural/emotional problems were assessed by parent report at age 47 and 81 months. </li></ul>3 – 2 – 1 – 0 1.91 for girls OR for behavioural/emotional problems at 81 months of age high levels of anxiety in late pregnancy 2.16 for boys
  112. 112. Maternal antenatal anxiety and behavioral/emotional problems in children: a test of a programming hypothesis. O’Connor TG, J Child Psychol Psychiatry. 2003;44:1025–1036. <ul><li>Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective, community-based study that has followed a cohort of women from pregnancy. </li></ul><ul><li>Self-report measures of maternal anxiety and depression were assessed at repeated intervals in pregnancy and the postnatal period. </li></ul><ul><li>Children's behavioural/emotional problems were assessed by parent report at age 47 and 81 months. </li></ul>3 – 2 – 1 – 0 1.91 for girls OR for behavioural/emotional problems at 81 months of age high levels of anxiety in late pregnancy 2.16 for boys antenatal stress/anxiety has a programming effect on the fetus which lasts at least until middle childhood.
  113. 113. Longitudinal study of maternal depressive symptoms and child well being. Luoma I, J Am Acad Child Adolesc Psychiatry. 2001;40:1367–1374. <ul><li>349 mothers </li></ul><ul><li>Edinburgh Postnatal Depression Scale prenatally, postnatally, and when the children were 8 to 9 years old . </li></ul><ul><li>children's psychosocial functioning and problems reported on the Child Behavior Checklist and Teacher's Report Form </li></ul>9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 3.1 In case of prenatal depressive symptoms OR for high externalizing total problem 8.5
  114. 114. Longitudinal study of maternal depressive symptoms and child well being. Luoma I, J Am Acad Child Adolesc Psychiatry. 2001;40:1367–1374. <ul><li>349 mothers </li></ul><ul><li>Edinburgh Postnatal Depression Scale prenatally, postnatally, and when the children were 8 to 9 years old . </li></ul><ul><li>children's psychosocial functioning and problems reported on the Child Behavior Checklist and Teacher's Report Form </li></ul>9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 3.1 In case of prenatal depressive symptoms OR for high externalizing total problem 8.5 Externalizing disorders include problems of control, such as conduct disorder , and problems of inattention and impulsivity , such as attention deficit/hyperactivity disorder (ADHD). Internalizing disorders include depression and various types of anxiety, such as separation anxiety disorder and generalized anxiety disorder.
  115. 115. Type 2 diabetes
  116. 116. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;9:83-8. OBJECTIVE: To review data on the long-term effects of prenatal exposure to the diabetic intrauterine environment in the Pima Indians of Arizona. This population has high rates of Type 2 diabetes mellitus that has a strong genetic component and develops at young ages. Quelli che vivono in Messico hanno un’incidenza del diabete pari circa all’8%, mentre quelli che sono emigrati negli Stati Uniti, dove lo stile di vita è più sedentario e l’accesso al cibo energetico (grasso) è più semplice, hanno un’incidenza di diabete che raggiunge il 50%.
  117. 117. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;9:83-8. <ul><li>Since 1965, biennial examinations </li></ul><ul><li>measurements of obesity and glucose tolerance and of glucose tolerance testing during pregnancy. </li></ul><ul><li>Development of type 2 diabetes </li></ul>80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 40% % subjects exposed to type 2 diabetes during pregnancy who developed Type 2 diabetes Age 5-19 yrs 25-34 yrs 70%
  118. 118. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;9:83-8. <ul><li>Since 1965, biennial examinations </li></ul><ul><li>measurements of obesity and glucose tolerance and of glucose tolerance testing during pregnancy. </li></ul><ul><li>Development of type 2 diabetes </li></ul>80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 40% % subjects exposed to type 2 diabetes during pregnancy who developed Type 2 diabetes Age 5-19 yrs 25-34 yrs 70% During pregnancy, a diabetic woman's high blood sugar appears to disrupt the developing metabolism of the fetus, predisposing it to diabetes and obesity.
  119. 119. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;9:83-8. <ul><li>Since 1965, biennial examinations </li></ul><ul><li>measurements of obesity and glucose tolerance and of glucose tolerance testing during pregnancy. </li></ul><ul><li>Development of type 2 diabetes </li></ul>80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 40% % subjects exposed to type 2 diabetes during pregnancy who developed Type 2 diabetes Age 5-19 yrs 25-34 yrs 70% &quot;If we could intensively control diabetic women's blood sugar during pregnancy,&quot; Dabelea says, &quot;we could really bring down the number of children who go on to develop diabetes.“ Time September 22, 2010
  120. 120. Gestational glucose tolerance and risk of type 2 diabetes in young Pima Indian offspring. Franks PW, Diabetes. 2006;55:460-5. <ul><li>911 nondiabetic Pima Indian mothers and 1,436 of their children. </li></ul><ul><li>maternal third trimester glucose tolerance and indexes of body composition and glycemic control in their children </li></ul>Cumulative incidence of type 2 diabetes in offspring stratified by category of maternal third trimester 2-h glucose.
  121. 121. An understanding of the role of gestational factors in disease can change individual behavior , notes Daniel Benyshek , a medical anthropologist at the University of Nevada at Las Vegas , who has interviewed members of Arizona's Native American tribes. He finds that those who believe diabetes is their genetic destiny tend to hold fatalistic attitudes about the illness. When Benyshek shared findings about the fetal origins of diabetes with tribe members, however, he noticed a different reaction. &quot;The idea that some simple changes made during pregnancy could reduce the offspring's risk for diabetes fosters a much more hopeful and engaged response,&quot; he says. &quot;Young women in particular are enthusiastic about the idea of intervening in pregnancy to break the cycle of diabetes. They say, 'I tried dieting , I tried exercising , and I couldn't keep it up. But I could do it for nine months if it meant that my baby would have a better chance at a healthy life.'&quot; Annie M Paul Time October 4, 2010
  122. 122. Associations of physical activity and inactivity before and during pregnancy with glucose tolerance. Oken E, Obstet Gynecol. 2006;108:1200-7. 100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 % women 83% glucose tolerance Normal Abnormal 17% <ul><li>1,805 women enrolled in Project Viva </li></ul><ul><li>duration and intensity of physical activity and time spent viewing television both before and during pregnancy </li></ul><ul><li>gestational diabetes mellitus (GDM) and abnormal glucose tolerance (AGT) </li></ul>Including 5% with GDM below 95 mg/dL at baseline and and below 140 mg/dL after challenge
  123. 123. Associations of physical activity and inactivity before and during pregnancy with glucose tolerance. Oken E, Obstet Gynecol. 2006;108:1200-7. <ul><li>1,805 women enrolled in Project Viva </li></ul><ul><li>duration and intensity of physical activity and time spent viewing television both before and during pregnancy </li></ul><ul><li>gestational diabetes mellitus ( GDM ) and abnormal glucose tolerance ( AGT ) </li></ul>In women with vigorous activity before pregnancy and light-to-moderate or vigorous activity during pregnancy OR for 1.0 – 0.5 – 0 0.49 GDM AGT 0.70
  124. 124. Associations of physical activity and inactivity before and during pregnancy with glucose tolerance. Oken E, Obstet Gynecol. 2006;108:1200-7. <ul><li>1,805 women enrolled in Project Viva </li></ul><ul><li>duration and intensity of physical activity and time spent viewing television both before and during pregnancy </li></ul><ul><li>gestational diabetes mellitus (GDM) and abnormal glucose tolerance (AGT) </li></ul>In women with vigorous activity before pregnancy and light-to-moderate or vigorous activity during pregnancy OR for 1.0 – 0.5 – 0 0.49 GDM AGT 0.70 Physical activity, before pregnancy and at least light-to-moderate activity during pregnancy, may reduce risk for abnormal glucose tolerance and GDM. -51% -30%
  125. 125. Diabetes risk begins in utero. Woo M, Patti ME. Cell Metab. 2008;8:5-7. Intrauterine stressors, including maternal undernutrition or placental dysfunction (leading to impaired blood flow, nutrient transport, or hypoxia) can initiate abnormal patterns of development and histone modification. Additional postnatal environmental factors, including accelerated postnatal growth, obesity, inactivity, and aging can further contribute to DM risk, potentially via further histone modifications and DNA methylation in critical tissues. Epigenetic events
  126. 126. <ul><li>Asthma in pregnancy </li></ul>
  127. 127. Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth. Bakhireva LN, Ann Allergy Asthma Immunol 2008; 101:137–143. <ul><li>Pregnant women with physician-diagnosed asthma (n = 719) </li></ul><ul><li>Asthma control during pregnancy </li></ul>20 – 10 – 0 11.4% asthma control p=0.02 incidence of preterm delivery inadequate adequate 6.3%
  128. 128. Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case–control study Martel ERJ 2009:34:579 <ul><li>8,226 children of asthmatic mothers. </li></ul><ul><li>30,318 age-matched controls. </li></ul>In children whose mothers had moderate-to-severe uncontrolled asthma during pregnancy versus mild controlled asthma. 1.27 OR for ASTHMA 1.5 – 1.0 – 0.5 – 0
  129. 129. Sleep-disorderd breathing or sleep deprivation during pregnancy
  130. 130. Sleep-disordered breathing and pregnancy: potential mechanisms and evidence for maternal and fetal morbidity Izci-Balseraka Current Op Pulmonary Med 2010,16:574 <ul><li>The term SDB refers to the spectrum of breathing disorders during sleep, ranging from uncomplicated snoring to the most severe forms of SDB, obstructive sleep apnea (OSA) and the </li></ul><ul><li>obesity–hypoventilation syndrome . </li></ul><ul><li>During the third trimester, when gestational SDB is most likely to occur, the prevalence of habitual snoring has been estimated to be 10–27% of pregnant women . </li></ul><ul><li>SDB is associated with adverse pregnancy outcomes, especially pregnancy-induced hypertension and gestational diabetes. </li></ul>
  131. 131. Sleep-disordered breathing and pregnancy: potential mechanisms and evidence for maternal and fetal morbidity Izci-Balseraka Current Op Pulmonary Med 2010,16:574 <ul><li>Fetal complications </li></ul><ul><li>Pregnant women with SDB can develop hypoxemia during sleep owing to decreased cardiorespiratory reserve. </li></ul><ul><li>Even small declines in maternal oxygenation can endanger oxygen delivery to the fetus . </li></ul><ul><li>Furthermore, any cause of maternal hypercapnia leads quickly to fetal respiratory acidosis . </li></ul><ul><li>Fetal heart decelerations and accompanying acidosis have been recorded during maternal apneic episodes with oxygen desaturation. Sahin FK, Int J Gynaecol Obstet 2008; 100:141–146. </li></ul>
  132. 132. Snoring, pregnancy-induced hypertension, and growth retardation of the fetus. Franklin KA, Chest 2000; 117:137 <ul><li>502 women with singleton pregnancies </li></ul><ul><li>questionnaire about snoring, witnessed sleep apneas, and daytime fatigue. </li></ul>4 – 3 – 2 – 1 – 0- 2.03 p<0.05 3.45 p<0.01 OR in snoring women for Developing hypertension Delivering a SGA infant
  133. 133. Outcomes of pregnancy in a national sample of resident physicians. Klebanoff MA, N Engl J Med 1990; 323:1040–1045. <ul><li>4412 women who graduated from medical school in 1985 ( sleep deprivation ) </li></ul><ul><li>wives of 4236 of their male classmates, who served as controls and who sleeped more </li></ul>10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 - % women who developed preeclampsia 3.5% Controls Residents 8.8%
  134. 134. Outcomes of pregnancy in a national sample of resident physicians. Klebanoff MA, N Engl J Med 1990; 323:1040–1045. <ul><li>4412 women who graduated from medical school in 1985 ( sleep deprivation ) </li></ul><ul><li>wives of 4236 of their male classmates, who served as controls and who sleeped more </li></ul>10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 - % women who developed preeclampsia 3.5% Controls Residents 8.8% Sleep-Disordered Breathing has been associated with: 1) increased risks of premature delivery, 2) intrauterine growth restriction, 3) lower infant Apgar scores, 4) infant mortality
  135. 135. Developmental Origins of Health and Diseases: when we become what we are. <ul><li>Original findings </li></ul><ul><li>Further discoveries </li></ul><ul><li>Maternal diseases </li></ul><ul><li>Maternal life style-environment </li></ul><ul><li>Epigenetic </li></ul><ul><li>More than 1 generation </li></ul><ul><li>Prevention & Reversibility </li></ul><ul><li>Public Health Implications </li></ul><ul><li>Conclusions </li></ul>University of Verona, Italy Attilio L Boner
  136. 137. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Caldji C, Proc Natl Acad Sci USA 1998; 95:5335–5340. Mean±SEM time spent in exploration of the inner area of an open field in the adult offspring of high versus low LG-ABN mothers. correlation between maternal arched-back nursing and exploration. correlation between maternal licking/grooming and exploration. licking/grooming and arched-back nursing P<0.001
  137. 138. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Caldji C, Proc Natl Acad Sci USA 1998; 95:5335–5340. HIGH licking grooming Adult rats 90 days old
  138. 139. “ Mia will be an incredible swimmer” Uncle Grooming
  139. 140. The Rat Model of Nurturing In rats, an important component of maternal care consists of licking and grooming , which varies widely across individuals. Maternal care as a model for experience-dependent chromatin plasticity? Meaney MJ, Trends Neurosci 2005;28:456. <ul><li>Increased hippocampal expression of the glucocorticoid receptor (GR) mRNA and protein , </li></ul><ul><li>Decreased hypothalamic corticotrophin-release factor, and </li></ul><ul><li>Reduced hypothalamic-pituitary-adrenal response to stress . </li></ul>increased licking and grooming
  140. 141. The Rat Model of Nurturing In rats, an important component of maternal care consists of licking and grooming , which varies widely across individuals. Maternal care as a model for experience-dependent chromatin plasticity? Meaney MJ, Trends Neurosci 2005;28:456. <ul><li>Increased hippocampal expression of the glucocorticoid receptor (GR) mRNA and protein , </li></ul><ul><li>Decreased hypothalamic corticotrophin-release factor, and </li></ul><ul><li>Reduced hypothalamic-pituitary-adrenal response to stress . </li></ul>increased licking and grooming This work showed a direct relationship between maternal behavior and DNA methylation in the rat hippocampal GR gene
  141. 142. This provides a biological basis for speculations about the effects of poverty on early experience, and how exposure to abuse , family strife , emotional neglect , and harsh discipline may have epigenetic effects that produce individual differences in neural and endocrine response to stress and may increase the susceptibility to common adult disorders such as depression and anxiety, drug abuse , and diabetes , heart disease , and obesity . From the Rat Model of Nurturing to the Child
  142. 143. <ul><li>primary insulin resistance and a lipid profile consistent with the metabolic syndrome, Entringer S, Am J Obstet Gynecol 2008;498:e1–7. </li></ul><ul><li>altered immune function, Entringer S, Dev Psychobiol 2008;50:579–587. </li></ul><ul><li>altered endocrine function, Entringer S, Horm Behav 2009;55:292–298. </li></ul><ul><li>compromised cognitive function. Entringer S, Behav Neurosci 2009;123:886–893 . </li></ul>Behavioral Perinatology Research Program Compared with healthy young individuals without this history, prenatal stress-exposed individuals exhibited
  143. 144. <ul><li>Smoking in pregnancy </li></ul>
  144. 145. Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study. McCowan LM, BMJ 2009;338:b1081. <ul><li>2504 nulliparous women (SCOPE study) grouped by maternal smoking status at 15 (+/-1) week's gestation . </li></ul><ul><li>preterm birth and small for gestational age infants (birth weight <10th centile) </li></ul>100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 % women 80% Non smoking Stopped smoking Continued smoking 10 % 10 %
  145. 146. Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study. McCowan LM, BMJ 2009;338:b1081. <ul><li>2504 nulliparous women (SCOPE study) grouped by maternal smoking status at 15 (+/-1) week's gestation . </li></ul><ul><li>preterm birth and small for gestational age infants (birth weight <10th centile) </li></ul>100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 % women 80% Non smoking Stopped smoking Continued smoking 10 % 10 % % spontaneous preterm birth 4% 4% 10% p=0.006
  146. 147. Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study. McCowan LM, BMJ 2009;338:b1081. <ul><li>2504 nulliparous women (SCOPE study) grouped by maternal smoking status at 15 (+/-1) week's gestation . </li></ul><ul><li>preterm birth and small for gestational age infants (birth weight <10th centile) </li></ul>100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 % women 80% Non smoking Stopped smoking Continued smoking 10 % 10 % % small for gestational age infants 10% 10% 17% p=0.03
  147. 148. Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study. McCowan LM, BMJ 2009;338:b1081. <ul><li>2504 nulliparous women (SCOPE study) grouped by maternal smoking status at 15 (+/-1) week's gestation . </li></ul><ul><li>preterm birth and small for gestational age infants (birth weight <10th centile) </li></ul>100 – 90 – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 % women 80% Non smoking Stopped smoking Continued smoking 10 % 10 % % small for gestational age infants 10% 10% 17% p=0.03 In women who stopped smoking before 15 weeks' gestation , rates of spontaneous preterm birth and small for gestational age infants did not differ from those in non-smokers, indicating that these severe adverse effects of smoking may be reversible if smoking is stopped early in pregnancy.
  148. 149. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. Oken E, Int J Obes (Lond) 2008;32(2):201–210. <ul><li>84 563 children </li></ul><ul><li>14 observational studies </li></ul>At age 2 yrs children whose mothers smoked during pregnancy were at elevated risk for overweight OR=1.5
  149. 150. First trimester maternal tobacco smoking habits and fetal growth Prabhu Thorax 2010;65:235–240 Mean differences in femur length (cm) and 95% CI between 20-week-old fetuses grouped by tertile of maternal daily cigarette consumption <ul><li>1924 pregnant women </li></ul><ul><li>Fetal ultrasound measurements at 11 weeks (crownerump length, CRL) and at 20 weeks gestation (femur length, FL, and biparietal diameter, BPD) </li></ul>P=0.03 -0.91 cm
  150. 151. Maternal smoking during pregnancy and neonatal behavior: a large-scale community study. Stroud LR, Pediatrics 2009;123:e842–e848. <ul><li>962 mothers and infants from the Providence Cohort of the National Collaborative Perinatal Project enrolled between 1960 and 1966. </li></ul><ul><li>Neonatal behavior assessed using the Graham-Rosenblith Behavioral Examination of the Neonate. </li></ul>Significant pair-wise differnces between Maternal Smoking Groups on Infant Irritability
  151. 152. Maternal smoking during pregnancy and neonatal behavior: a large-scale community study. Stroud LR, Pediatrics 2009;123:e842–e848. <ul><li>962 mothers and infants from the Providence Cohort of the National Collaborative Perinatal Project enrolled between 1960 and 1966. </li></ul><ul><li>Neonatal behavior assessed using the Graham-Rosenblith Behavioral Examination of the Neonate. </li></ul>Significant pair-wise differences between Maternal Smoking Groups on Infant Muscle Tone
  152. 153. Maternal smoking during pregnancy and neonatal behavior: a large-scale community study. Stroud LR, Pediatrics 2009;123:e842–e848. <ul><li>962 mothers and infants from the Providence Cohort of the National Collaborative Perinatal Project enrolled between 1960 and 1966. </li></ul><ul><li>Neonatal behavior assessed using the Graham-Rosenblith Behavioral Examination of the Neonate. </li></ul>Significant pair-wise differences between Maternal Smoking Groups on Infant Muscle Tone exposure to maternal smoking was associated with increased irritability and hypertonicity in neonates.
  153. 154. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Braun JM, Environ Health Perspect 2006;114:1904–1909. <ul><li>Prenatal and postnatal tobacco exposure </li></ul><ul><li>4,704 children 4-15 years of age </li></ul><ul><li>4.2% were reported to have ADHD </li></ul>3 – 2 – 1 – 0 2.5 prenatal tobacco exposure OR for attention deficit hyperactivity disorder (ADHD).
  154. 155. Smoking during pregnancy and hyperactivity-inattention in the offspring—comparing results from three Nordic cohorts. Obel C, Int J Epidemiol 2009;38:698–705. <ul><li>20 936 women with singleton pregnancies </li></ul><ul><li>self-reported data on their pre-pregnancy and pregnancy smoking habits </li></ul><ul><li>children follow-up to school age </li></ul><ul><li>teachers and parents rated hyperactivity and inattention symptoms. </li></ul>2 – 1 – 0 1.2 Quitters before pregnancy OR for ADHD compared to non-smoking mothers 1-9 cigarettes per day during pregnancy >10 cigarettes per day during pregnancy 1.6 2.0
  155. 156. Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Herrmann M, Curr Opin Pediatr 2008;20:184–190. effects of on child neurodevelopment. prenatal tobacco smoke exposure Low birth weight and decreased in-utero brain growth
  156. 157. Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Herrmann M, Curr Opin Pediatr 2008;20:184–190. effects of on child neurodevelopment. prenatal tobacco smoke exposure Low birth weight and decreased in-utero brain growth increased rates of: 1) irritability, 2) oppositional defiant behavior, 3) conduct disorders 4) attention deficit hyperactivity disorder.
  157. 158. CEREBELLUM (mL) 23.1 24.5 EXPOSED NON-EXPOSED P=0.03 150 – 100 – 50 – 0 25 – 20 – 15 – 10 – 5 – 0 FRONTAL LOBE (mL) 118 127 EXPOSED NON-EXPOSED P=0.01 Maternal Smoking during Pregnancy and Regional Brain Volumes in Preterm Infants Ekblad J Pediatr 2010;156:185 Magnetic Resonance
  158. 159. CEREBELLUM (mL) 23.1 24.5 EXPOSED NON-EXPOSED P=0.03 150 – 100 – 50 – 0 25 – 20 – 15 – 10 – 5 – 0 FRONTAL LOBE (mL) 118 127 EXPOSED NON-EXPOSED P=0.01 Maternal Smoking during Pregnancy and Regional Brain Volumes in Preterm Infants Ekblad J Pediatr 2010;156:185 Magnetic Resonance This is consistent with reports showing an association between prenatal smoking exposure and impairments in frontal lobe and cerebellar functions such as emotion, impulse control , and attention.
  159. 160. Association of passive exposure of pregnant women to environmental tobacco smoke with asthma symptoms in children. Xepapadaki Pediatr Allergy Immunol 2009:20:423 <ul><li>Passive exposure of pregnant women to ETS . </li></ul><ul><li>Questionnaires from 2374 Preschool children. </li></ul>In Children Born from Mother Passively Exposed to Tobacco Smoke During the 3° Trimester of Pregnancy OR for 1.42 CURRENT WHEEZE 1.5 – 1.0 – 0.5 – 0 PRURITIC RASH EVER 1.45
  160. 161. Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke Strulovici-Barel Am J Respir Crit Care Med 2011;182:1524 Rationale: Epidemiologic data demonstrate that individuals exposed to low levels of tobacco smoke have decrements in lung function and higher risk for lung disease compared with unexposed individuals. Although this risk is small, low-level tobacco smoke exposure is so widespread, it is a significant public health concern.
  161. 162. Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke Strulovici-Barel Am J Respir Crit Care Med 2011;182:1524 <ul><li>121 individuals. </li></ul><ul><li>Small airway epithelium by bronchoscopy. </li></ul><ul><li>Microarrays to assess genome-wide gene expression; </li></ul><ul><li>Urine nicotine used to categorize subjects as ‘‘nonsmokers,’’ ‘‘active smokers,’’ and ‘‘low exposure.’’ </li></ul>Genes in the small airway epithelium up- and down-regulated by smoking. (A, B)
  162. 163. <ul><li>121 individuals. </li></ul><ul><li>Small airway epithelium by bronchoscopy. </li></ul><ul><li>Microarrays to assess genome-wide gene expression; </li></ul><ul><li>Urine nicotine used to categorize subjects as ‘‘nonsmokers,’’ ‘‘active smokers,’’ and ‘‘low exposure.’’ </li></ul>Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke Strulovici-Barel Am J Respir Crit Care Med 2011;182:1524 Genes in the small airway epithelium up- and down-regulated by smoking. (A, B) There was no threshold of urine nicotine without a small airway epithelial response.
  163. 164. <ul><li>121 individuals. </li></ul><ul><li>Small airway epithelium by bronchoscopy. </li></ul><ul><li>Microarrays to assess genome-wide gene expression; </li></ul><ul><li>Urine nicotine used to categorize subjects as ‘‘nonsmokers,’’ ‘‘active smokers,’’ and ‘‘low exposure.’’ </li></ul>Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke Strulovici-Barel Am J Respir Crit Care Med 2011;182:1524 Genes in the small airway epithelium up- and down-regulated by smoking. (A, B) The small airway epithelium detects and responds to low levels of tobacco smoke with transcriptome modifications.
  164. 165. Indoor Pollution during Pregancy and first years of life
  165. 166. OR FOR 5 - 4 - 3 – 2 – 1 – 0 A prospective association between synthetic cocoon use in infancy and childhooh asthma. Trevillian Paed Perin Epidem 2004:18:281 <ul><li>Sleeping environment of 863 infants evaluated at 1 month of life </li></ul><ul><li>Follow-up: 7 years </li></ul>4.33 IN CH. SLEEPING IN A SYNTHETIC COCOON AT 1 MONTH OF AGE RECENT WHEEZE AT AGE 7 YEARS 3.35 NIGHT WHEEZE AT AGE 7 YEARS
  166. 167. OR FOR 5 - 4 - 3 – 2 – 1 – 0 A prospective association between synthetic cocoon use in infancy and childhooh asthma. Trevillian Paed Perin Epidem 2004:18:281 <ul><li>Sleeping environment of 863 infants evaluated at 1 month of life </li></ul><ul><li>Follow-up: 7 years </li></ul>4.33 IN CH. SLEEPING IN A SYNTHETIC COCOON AT 1 MONTH OF AGE RECENT WHEEZE AT AGE 7 YEARS 3.35 NIGHT WHEEZE AT AGE 7 YEARS In view of the increasing prevalence of asthma, the identification of potentially modifiable environmental factors which might operate in infancy is of importance
  167. 168. <ul><li>Bedding type at 1mo </li></ul><ul><li>Wheeze at 7 yrs </li></ul><ul><li>(n=6,378 ch) </li></ul>SYNTHETIC BEDDING AND WHEEZE IN CHILDHOOD. Ponsonby Epidemilogy 2003;14:37 7 – 6 – 5 – 4 – 3 – 2 – 1 – 0 OR for wheezing at 7 yrs 2.5 5.2 synthetic pillow +synthetic quilt +
  168. 169. spray detergents and atopy-asthma
  169. 170. FREQUENT USE OF CHEMICAL HOUSEHOLD PRODUCTS IS ASSOCIATED WITH PERSISTENT WHEEZING IN PRE-SCHOOL AGE CHILDREN. Sherriff Thorax 2005; 60: 45 <ul><li>Population based Avon Longitudinal Study of Parents and Children. </li></ul><ul><li>Frequency of use of 11 chemical based domestic products determined from questionnaires completed by women during pregnancy. </li></ul><ul><li>A total chemical burden ( TCB ) score was derived. </li></ul>2.3 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0.0 OR FOR PERSISTENT WHEEZE In children whose mothers had high TCB scores (>90th centile) than children whose mothers had a low TCB score (<10th centile). P =0.012
  170. 171. FREQUENT USE OF CHEMICAL HOUSEHOLD PRODUCTS IS ASSOCIATED WITH PERSISTENT WHEEZING IN PRE-SCHOOL AGE CHILDREN. Sherriff Thorax 2005; 60: 45 <ul><li>Population based Avon Longitudinal Study of Parents and Children. </li></ul><ul><li>Frequency of use of 11 chemical based domestic products determined from questionnaires completed by women during pregnancy. </li></ul><ul><li>A total chemical burden ( TCB ) score was derived. </li></ul>2.3 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0.0 OR FOR PERSISTENT WHEEZE In children whose mothers had high TCB scores (>90th centile) than children whose mothers had a low TCB score (<10th centile). P =0.012 A dose-dependent relationship was observed between frequency of use of common household chemical products in the prenatal period and persistent wheeze in the resulting offspring.
  171. 172. <ul><li>European Community Respiratory Health Survey in 10 countries. </li></ul><ul><li>3.503 persons doing the cleaning in their homes and who were free of asthma at baseline. </li></ul>Asthma symptoms and medication 2 – 1 – 0 1.49 RR in person using cleaning spray at least weekly THE USE OF HOUSEHOLD CLEANING SPRAYS AND ADULT ASTHMA Zock AJRCCM 2007;176:735
  172. 173. <ul><li>For young children, the most important indoor environment is the home. </li></ul><ul><li>On overage, children spend ˜ 15 h a day indoors at home. </li></ul><ul><li>Infants average nearly 20 h per day indoors. </li></ul><ul><li>In recent times, there have been concerns about domestic exposure to volatile organic compounds (VOCs) emitted from a broad range of sources, including cleaning agents, furnishings, paints, cosmetics. </li></ul>HOUSEHOLD CHEMICALS: GOOD HOUSEKEEPING OR OCCUPATIONAL HAZARD? Franklin Eur Respir J 2008; 31: 489
  173. 174. Outdoor Pollution during pregnancy
  174. 175. The Impact of Air The chance of a healthier life is what Frederica Perera is trying to give children in some of New York City's struggling neighborhoods. Perera, the director of the Center for Children's Environmental Health at Columbia University , became interested in the effects of pollution on fetuses more than 30 years ago , when she was conducting research on environmental exposures and cancer in adults. &quot;I was looking for control subjects to compare to the adults in my study, individuals who would be completely untouched by pollution,&quot; she says. She hit on the idea of using babies just out of the womb as her controls , but when she received the results from samples of umbilical-cord blood and placental tissue she'd sent to a laboratory to be analyzed, she was sure there had been a mistake. &quot;I was shocked,&quot; she says. &quot;These samples I thought would be pristine already had evidence of contamination.“ Annie M Paul Time October 4, 2010
  175. 176. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction. Choi H, Environ Health Perspect. 2008;116:658-65. <ul><li>nonsmoking, healthy African-American (n = 224) and Dominican (n = 392) mother-newborn pairs residing in New York City </li></ul><ul><li>prenatal PAH exposures estimated by personal air monitoring. </li></ul>5 - 4 - 3 – 2 – 1 – 0 2.0 SGA In African Americans per 1 log-unit increase in prenatal PAH exposure OR for PRETERM 5.0
  176. 177. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction. Choi H, Environ Health Perspect. 2008;116:658-65. <ul><li>nonsmoking, healthy African-American (n = 224) and Dominican (n = 392) mother-newborn pairs residing in New York City </li></ul><ul><li>prenatal PAH exposures estimated by personal air monitoring. </li></ul>5 - 4 - 3 – 2 – 1 – 0 2.0 SGA In African Americans per 1 log-unit increase in prenatal PAH exposure OR for PRETERM 5.0 These effects were not observed in Dominicans.
  177. 178. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction. Choi H, Environ Health Perspect. 2008;116:658-65. <ul><li>nonsmoking, healthy African-American (n = 224) and Dominican (n = 392) mother-newborn pairs residing in New York City </li></ul><ul><li>prenatal PAH exposures estimated by personal air monitoring. </li></ul>5 - 4 - 3 – 2 – 1 – 0 2.0 SGA In African Americans per 1 log-unit increase in prenatal PAH exposure OR for PRETERM 5.0 The lack of an association in Dominicans might reflect modification of the risk by healthful cultural practices among recent Dominican immigrants.
  178. 179. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction. Choi H, Environ Health Perspect. 2008;116:658-65. <ul><li>nonsmoking, healthy African-American (n = 224) and Dominican (n = 392) mother-newborn pairs residing in New York City </li></ul><ul><li>prenatal PAH exposures estimated by personal air monitoring. </li></ul>5 - 4 - 3 – 2 – 1 – 0 2.0 SGA In African Americans per 1 log-unit increase in prenatal PAH exposure OR for PRETERM 5.0 … including diets with higher nutritional quality, and greater social support .
  179. 180. Predictors of personal polycyclic aromatic hydrocarbon exposures among pregnant minority women in New York City. Tonne CC, Environ Health Perspect. 2004;112:754-9. <ul><li>personal exposures to polycyclic aromatic hydrocarbons (PAHs) among 348 pregnant women in northern Manhattan and the South Bronx, New York. </li></ul><ul><li>100% of the women were exposed to PAHs during their pregnancies. </li></ul><ul><li>analyses of cord blood from the infants showed that 40% had subtle DNA damage from PAHs — damage that has been linked to increased cancer risk . </li></ul><ul><li>those exposed prenatally to high levels of PAHs were more than twice as likely to be cognitively delayed at age 3 , scoring lower on an assessment that predicts performance in school; at age 5 , these children scored lower on IQ tests than children who received less exposure to PAHs in the womb. </li></ul>
  180. 181. Relationship between ambient air pollution and DNA damage in Polish mothers and newborns. Whyatt RM, Environ Health Perspect. 1998;106 Suppl 3:821-6. White blood cell PAH-DNA adducts by level of air pollution * p≤0.05 <ul><li>polycyclic aromatic hydrocarbons (PAHs) from coal burning for industry and home heating </li></ul><ul><li>amount of PAHs bound to DNA (PAH-DNA adducts) in maternal and umbilical white blood cells. </li></ul><ul><li>genotypes previously linked to risk of lung cancer, specifically glutathione S-transferase MI (GSTM1) and cytochrome P4501A1 (CYP1A1) Msp restriction fragment length polymorphism (RFLP), </li></ul>= mothers
  181. 182. Relationship between ambient air pollution and DNA damage in Polish mothers and newborns. Whyatt RM, Environ Health Perspect. 1998;106 Suppl 3:821-6. * p≤0.05 White blood cell PAH-DNA adducts by level of air pollution = newborn
  182. 183. Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. Perera F, PLoS One 2009; 4: e4488. <ul><li>a longitudinal cohort of approximately 700 children in New York City </li></ul><ul><li>transplacental exposure to traffic-related polycyclic aromatic hydrocarbons (PAHs) </li></ul><ul><li>methylation sensitive restriction fingerprinting was used to analyze umbilical cord white blood cell (UCWBC) DNA </li></ul>Incidence of Asthma 30 – 20 – 10 – 0 >25% among the highest asthma prevalence in the US
  183. 184. Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. Perera F, PLoS One 2009; 4: e4488. Over 30 DNA sequences were identified whose methylation status was dependent on the level of maternal PAH exposure. <ul><li>a longitudinal cohort of approximately 700 children in New York City </li></ul><ul><li>transplacental exposure to traffic-related polycyclic aromatic hydrocarbons (PAHs) </li></ul><ul><li>methylation sensitive restriction fingerprinting was used to analyze umbilical cord white blood cell (UCWBC) DNA </li></ul>
  184. 185. Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. Perera F, PLoS One 2009; 4: e4488. Methylation of the ACSL3 5'-CGI was found to be significantly associated with maternal airborne PAH exposure exceeding 2.41 ng/m 3 (OR = 13.8; p<0.001) and with a parental report of asthma symptoms in children prior to age 5 (OR = 3.9; p<0.05). <ul><li>a longitudinal cohort of approximately 700 children in New York City </li></ul><ul><li>transplacental exposure to traffic-related polycyclic aromatic hydrocarbons (PAHs) </li></ul><ul><li>methylation sensitive restriction fingerprinting was used to analyze umbilical cord white blood cell (UCWBC) DNA </li></ul>
  185. 186. OR for methylation of the acyl-CoA synthetase long-chain family member 3 (ACSL3 5'-CGI) in UCWBC Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. Perera F, PLoS One 2009; 4: e4488. maternal airborne PAH exposure exceeding 2.41 ng/m 3 20 – 10 – 0 13.8 P<0.001 <ul><li>a longitudinal cohort of approximately 700 children in New York City </li></ul><ul><li>transplacental exposure to traffic-related polycyclic aromatic hydrocarbons (PAHs) </li></ul><ul><li>methylation sensitive restriction fingerprinting was used to analyze umbilical cord white blood cell (UCWBC) DNA </li></ul>
  186. 187. OR for a parental report of asthma symptoms in children prior to age 5 Relation of DNA methylation of 59-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. Perera F, PLoS One 2009; 4: e4488. 4 – 2 – 0 3.9 P<0.05 methylation of the ACSL3 5'-CGI in UCWBC <ul><li>a longitudinal cohort of approximately 700 children in New York City </li></ul><ul><li>transplacental exposure to traffic-related polycyclic aromatic hydrocarbons (PAHs) </li></ul><ul><li>methylation sensitive restriction fingerprinting was used to analyze umbilical cord white blood cell (UCWBC) DNA </li></ul>
  187. 188. The Impact of Air &quot;We used to worry about elderly people and asthma patients,&quot; Perera says. &quot;Now we worry about fetuses.&quot; And efforts to reduce environmental toxins can make a measurable difference, she says. &quot;Over the years that we've been tracking exposures, New York City buses have switched to cleaner technology , and restrictions have been placed on the idling of diesel buses and trucks,&quot; Perera notes. &quot; As a result , we've seen the levels of pollutants in pregnant women's blood coming down , which means their fetuses are encountering fewer of these substances too.&quot; Annie M Paul Time October 4, 2010
  188. 189. Diet of the mother diuring pregnancy
  189. 190. Modulation of the effect of prenatal PAH exposure on PAH-DNA adducts in cord blood by plasma antioxidants. Kelvin EA, Cancer Epidemiol Biomarkers Prev. 2009;18:2262-8. <ul><li>The fetus is more susceptible than the adult to the effects of certain carcinogens, such as polycyclic aromatic hydrocarbons (PAH). </li></ul><ul><li>Nutritional factors, including antioxidants, have been shown to have a protective effect on carcinogen-DNA adducts and cancer risk in adults. </li></ul>
  190. 191. Modulation of the

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