1. Prenatal and Postnatal Growth and Endocrine Diseases Francesco Chiarelli

3. 1. Definition and causes of IUGR 2. Growth and growth factors 3. Insulin-resistance 4. Adrenals 5. Gonads

5. Pathological decrease of fetal growth IUGR: definition Birth weight < 2.5 Kg for gestational age of  37 weeks Birth weight < 2SD below the mean value for gestational age Birth weight < 10th (or 5th) percentile for gestational age

6. Definition of Small for Gestational Age (SGA) Birth weight and/or length of 2 or more standard deviations (SD) below the mean for gestational age and sex

7. IUGR and SGA newborns : Definition of clinical conditions at birth secondary to birth length (height) or birth weight according to gestational age Birth Length Below –2 SD Normal Greater than +2SD (IUGR or SGA) Chatelain P, Endocrine Regulation 2000 Birth weight overweight overweight macrosomic greater than +2SD IUGR 1 “proportionate” (or SGA 2 ) or “symmetrical” Birth weight IUGR 1 normal eutrophic normal (or SGA 2 ) or proportionate Birth weight proportionate SGA 1 hypotrophic below -2 SD (“symmetrical”) or hypotrophic tall newborn (SGA 2 ) SGA 2 1 IUGR is defined by birth length 2 SGA is defined by both birth length or birth weight

8. Boy, 5.2 years old. He is 95.3 cm tall and weighs 11.9 kg, which is –4.2 SD score below the mean. His birth weight was 2,160 grams, which is –2.59 SD scores below the mean. His physical appearance is typical of SGA children showing a triangular-shaped face with a relatively large head and high forehead, a very lean body mass which is especially evident in his thinner than usual arms and legs. Courtesy of Dr. Anita Hoekken-Koelega

9. What are the causes of SGA? Maternal Vascular disease Environmental factors Infection Nutrition Placental Insufficiency Abruption Infarction Vascular abnormalities Fetal Genetic abnormalities Congenital malformations Metabolic problems Multiple gestations Demographic Maternal age and height Father’s size Obstetric history Race

10. IUGR: phenotypes Symmetrical IUGR (20-30%) Proportionate reduction of all fetal mesurements Aetiology: intrinsic alteration in growth potential or severe nutritional deprivation overwhelming protective brain-sparing mechanism occuring prior to 26 weeks nd persisting until delivery Asymmetrical IUGR (70-80%) Disproportionate reduction of fetal mesurements due to uteroplacental insufficiency with preferential shunting of blood to fetal brain High HC/AC FL/AC

11. IUGR: short-term consequences Increased perinatal morbidity and mortality 6-8 fold increase for intrapartum and neonatal death Respiratory distress Necrotizing enterocolitis Meconium aspiration Electrolyte imbalance Polycythemia Intraventricular hemorrhage

12. IUGR: long-term consequences Short stature Cardiovascular disease Hypertension Metabolic disease (T2DM) Obesity Osteoporosis

13. 1. Definition and causes of IUGR 2. Growth and growth factors 3. Insulin-resistance 4. Adrenals 5. Gonads

14. 0 20 - 40 - 60 - 80 - 100 - 361224 Hokken-Koelega A, Pediatr Res 1995 Percentage (%) Age (months) PretermFullterm Catch-up growth in IUGR

15. Postnatal growth in children born SGA Karlberg J, Albertsson-Wikland K. Pediatr Res 1995;38:733–9.

16. The Concept of “CRITICAL WINDOW” Trait Critical window Time Fetal lifeInfancy Adulthood Welles J.C.K. J.Ther.Biol. 2003

17. PRENATALLY insulin IGF system switched-off Poor maternal nutrition Poor placental function Low maternal fat stores Nutrient demand > placental supply = Fetal Undernutrition Hormonal and metabolic adaptations in utero GH IGF-1 Amino acid oxidation Lactate oxidation Glucose oxidation cortisol Survival and development of vital organs (i.e brain) Fetal programming IUGR

18. IGF-II The regulation of fetal growth Early gestation IGF-I Late gestation Insulin IGFBP-1 IGFBP-3 GH Glucose and amino acid availability

19. GH-IGF axis HypothalamusGHRH Ghrelin Somatostatin IGF-1 Liver Pituitary Stomach GH receptor - - GH + - GHBP IGF-1 IGFBP and ALS + + IGF receptor Target tissues Endocrine Autocrine Paracrine + + + Trends Endocrinol Metab, 2002

20. Normal glucose and amino acid availability GH IGF-I Insulin IGFBP-1 The regulation of fetal growth IGFBP-3 GROWTH Normal glucose transport in muscle and brain

21. Reduced glucose and amino acid availability GH GH IGF-I IGF-I InsulinInsulin IGFBP-1 IGFBP-3 IUGR Fetal salvage hypothesis Reduced glucose transport in muscle and normal in brain

22. Simmons R, Pediatr Res 1992IUGR Control Brain tissue Glial cells Lung tissue FibroblastsType II Glucose transport % Fetal salvage hypothesis

23. Maternal glucose concentration Glucose sensing by fetal pancreas Insulin secretion by fetal pancreas Insulin-mediated growth of fetus Birthweight Fetal genetics Fetal insulin resistance Fetal insulin hypothesis

24. Glucose challenge in fetuses Time (min) Glucose (mmol/L) Insulin mU/L) Nicolini U, Horm Metab Res 1990 IUGR Control

25. Hormone levels in fetuses IGF-I (mcg/L)IGFBP-3 (mcg/L) IGFBP-1 (mcg/L) Insulin (mcU/ml) IUGRControl Langford KS, J Clin Endocrinol Metab 1994

26. Reprogramming of the GH-IGF axis in IUGR Hypothalamus GHRH Ghrelin Somatostatin IGF-1 Liver Pituitary Stomach GH receptor - - GH + - GHBP IGF-1 IGFBP-1 + + IGF receptor Target tissues + - - + Enhanced negative feedback Hepatic GH resistance Alterated target tissue GH resistance IGF resistance Insulin - + + Trends Endocrinol Metab, 2002

27. POSTNATALLY Adequate Nutrient Supply insulin production IGF system switched-on Catch-up Growth Insulin Resistance GH Resistance A. Mohn, F. Chiarelli, mod., 2002 Insulin like action + IGFBP-3 fragment

28. Kalhan SC, Pediatr Res 1995 Control IUGR Glucose infusion (2.6-4.6 mg/kg/min) Glucose mg/dl Insulin mU/L Glucose challenge in newborn Time (min)

29. Hormone levels in newborns IGF-I (mcg/L) IGFBP-3 (mcg/L) IGFBP-1 (mcg/L)GH (mcg/L) IUGR de Zegher F, Acta Paediatr 1997 Insulin (mU/L) Control

30. Hormone levels in IUGR from birth to 24 mo of age 1 12 24 6 46  4432  21 1.2  0.9 85  36 1.5  0.4 Leger J, Pediatr Res 2001 0 Time (months) GH IGF-1IGFBP-3 19  9 IUGR Control IUGR Control 12  8 10  8 79  33 90  35 1.8  0.5 1.7  0.7 6.1  3.581  37 2.3  0.7 IUGR Control 3.4  2.4102  362.1  0.6 Control 2.7  2.273  352.1  0.4 3.8  4.289  34 2.6  0.8 IUGR 2.6  2.598  44 2.7  0.6 IUGR Control 2.2  1.680  292.6  0.6 Values are mean  SD

31. Hormone levels in IUGR with and without catch-up growth 1 12 24 6 63  9028  18 1.2  1.6 31  21 1.1  0.9 Leger J, Pediatr Res 2001 0 Time (months) GH IGF-1IGFBP-3 48  43 < - 2 SDS > - 2 SDS 15  7 15  11 80  26 74  34 1.4  0.2 1.8  0.5 424275  411.9  0.5 < - 2 SDS > - 2 SDS 7  1081  36 2.3  0.7 > - 2 SDS 444489  35 2.7  0.8 434374  26 2.3  0.3 < - 2 SDS 3333 50  18 2.2  0.5 < - 2 SDS > - 2 SDS 3333101  43 2.8  0.6 Values are mean  SD < - 2 SDS > - 2 SDS

32. Hormone levels in infants IGF-I (mcg/L)IGFBP-3 (mcg/L)IGFBP-1 (mcg/L) IUGRControl Woods KA, Pediatr Res 2002 Insulin (mU/L) Insulin sensitivity Beta cell function

33. Maternal glucose concentration Glucose sensing by fetal pancreas Insulin secretion by fetal pancreas Insulin-mediated growth of fetus Birthweight Fetal genetics (IGF-1,GK,insulin, etc.) Fetal genetics (IGF-1,GK,insulin, etc.) Fetal insulin resistance Fetal insulin hypothesis

34. Overnight GH secretion in infancy GH (mUI/l) IUGR group (n=13) Control group (n= 15) p value (t test) Maximum Minimum No. of pulses Pulse amplitude Mean Area under curve 55.9 (30.4-80.5) 13.1 (7.2 –19.1) 39.6 (15.6-75.9)0.1 8.9 (3.7-18.5)0.004 1.2 (<0.4-2.1)0.6 (0.5-1.3)0.004 5.4 (3-7)4.3 (3-8) 0.02 115.8 (62-171.1)84.1 (28.7-165.8)0.02 25.2 (17.4-36.7)20.6 (9.1-40.8) 0.12 Values are mean and range Woods KA, Mohn A, Pediatr Res 2002