Prenatal and Postnatal Growth and Endocrine Diseases

1
Prenatal and Postnatal Growth and Endocrine
Diseases
Department of Pediatrics
University of Chieti, Italy

• Francesco Chiarelli

2
Francesco Chiarelli is Professor of
Pediatrics and Pediatric Endocrinology
at the Department of Pediatrics,
University of Chieti, Italy His field of
research is diabetes mellitus in
children, with reference to early
detection and prevention of vascular
complications Professor Chiarelli published
numerous papers on ranked international journals
and has been invited as speaker at many meetings
around the world He has recently been appointed
as both Chairman of ISPAD Scientific Committee
(International Society for Pediatric and
Adolescent Diabetes)(2002-2004) and Secretary
General of ESPE (European Society for Paediatric
Endocrinology)(2004-2007)
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1. Definition and causes of IUGR2. Growth and
growth factors3. Insulin-resistance4.
Adrenals5. Gonads
4
1. Definition and causes of IUGR2. Growth and
growth factors3. Insulin-resistance4.
Adrenals5. Gonads
5
IUGR definition
Pathological decrease of fetal growth
Birth weight lt 10th (or 5th) percentile for
gestational age
Birth weight lt 2.5 Kg for gestational age of ?
37 weeks
Birth weight lt 2SD below the mean value for
gestational age
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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

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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)
Birth weight overweight
overweight
macrosomic greater than 2SD IUGR1


proportionate
(or SGA2)
or symmetrical
Birth weight IUGR1
normal eutrophic

normal (or
SGA2) or proportionate
Birth weight proportionate
SGA1
hypotrophic below -2 SD
(symmetrical) or
hypotrophic tall newborn
(SGA2)

SGA2
Chatelain P, Endocrine Regulation 2000
1 IUGR is defined by birth length
2 SGA is defined by both birth length or birth
weight
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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
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What are the causes of SGA?

• Maternal
• Vascular disease
• Environmental
• factors
• Infection
• Nutrition

• Fetal
• Genetic abnormalities
• Congenital malformations
• Metabolic problems
• Multiple gestations

• Placental
• Insufficiency
• Abruption
• Infarction
• Vascular abnormalities

• Demographic
• Maternal age and height
• Fathers size
• Obstetric history
• Race

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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

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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

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IUGR long-term consequences

• Short stature
• Cardiovascular disease
• Hypertension
• Metabolic disease (T2DM)
• Obesity
• Osteoporosis

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1. Definition and causes of IUGR2. Growth and
growth factors3. Insulin-resistance4.
Adrenals5. Gonads
14
Catch-up growth in IUGR
Preterm
Fullterm
100 -
80 -
Percentage ()
60 -
40 -
20 -
0
3
6
12
24
Age (months)
Hokken-Koelega A, Pediatr Res 1995
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Postnatal growth in children born SGA
Karlberg J, Albertsson-Wikland K. Pediatr Res
1995387339.
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The Concept of CRITICAL WINDOW
Critical window
Trait
Fetal life
Infancy
Adulthood
Time
Welles J.C.K. J.Ther.Biol. 2003
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PRENATALLY
Poor maternal nutrition
Poor placental function
Low maternal fat stores
Nutrient demand gt placental supply
Fetal Undernutrition
Hormonal and metabolic adaptations in utero
GH
IGF system switched-off
Amino acid oxidation
IGF-1
insulin
Lactate oxidation
Glucose oxidation
cortisol
Fetal programming
Survival and development of vital organs (i.e
brain)
IUGR
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The regulation of fetal growth
IGF-II
Early gestation
GH
IGFBP-1
IGF-I
IGFBP-3
Late gestation
Insulin
Glucose and amino acid availability
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GH-IGF axis
-
Hypothalamus
GHRH
Somatostatin
Ghrelin

Stomach
Pituitary
-

-
GH receptor
GHBP
GH


IGF-1
Autocrine
Paracrine
IGF-1

Target tissues
Endocrine

Liver
IGFBP and ALS
IGF receptor
Trends Endocrinol Metab, 2002
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The regulation of fetal growth
Normal glucose and amino acid availability
IGFBP-1
IGFBP-3
GH
IGF-I
Insulin
GROWTH
Normal glucose transport in muscle and brain
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Fetal salvage hypothesis
Reduced glucose and amino acid availability
IGFBP-1
IGFBP-3
GH
Insulin
IGF-I
IUGR
Reduced glucose transport in muscle and normal in
brain
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Fetal salvage hypothesis
Glucose transport
Brain tissue
Lung tissue
Glial cells
Fibroblasts
Type II
Control
Simmons R, Pediatr Res 1992
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Fetal insulin hypothesis
Maternal glucose concentration
Glucose sensing by fetal pancreas
Fetal genetics
Insulin secretion by fetal pancreas
Fetal insulin resistance
Insulin-mediated growth of fetus
Birthweight
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Glucose challenge in fetuses
Glucose (mmol/L)
IUGR

Control

Insulin mU/L)
Time (min)
Nicolini U, Horm Metab Res 1990
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Hormone levels in fetuses
IGF-I (mcg/L)
IGFBP-3 (mcg/L)
Insulin (mcU/ml)
IGFBP-1 (mcg/L)
IUGR
Control
Langford KS, J Clin Endocrinol Metab 1994
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Reprogramming of the GH-IGF axis in IUGR
Hypothalamus
GHRH
Somatostatin
-
-
Ghrelin
Enhanced negative feedback

Stomach
Pituitary
-
Alterated target tissue GH resistance


-
-
GH receptor
Hepatic GH resistance
Liver
Target tissues
GHBP
GH


IGF-1

Insulin
IGF-1

-
IGF resistance
IGFBP-1
IGF receptor
Trends Endocrinol Metab, 2002
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POSTNATALLY
Adequate Nutrient Supply
Catch-up Growth
IGF system switched-on
insulin production
Insulin like action
Insulin Resistance

IGFBP-3 fragment
GH Resistance
A. Mohn, F. Chiarelli, mod., 2002
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Glucose challenge in newborn
Glucose infusion (2.6-4.6 mg/kg/min)
Glucose mg/dl
Control
IUGR
Insulin mU/L
Time (min)
Kalhan SC, Pediatr Res 1995
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Hormone levels in newborns
IGF-I (mcg/L)
Insulin (mU/L)
IGFBP-3 (mcg/L)
IGFBP-1 (mcg/L)
GH (mcg/L)
Control
IUGR
de Zegher F, Acta Paediatr 1997
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Hormone levels in IUGR from birth to 24 mo of age
GH
Time (months)
IGF-1
IGFBP-3
1.2 ?0.9
46?44
32 ?21
IUGR
0
85 ?36
1.5 ?0.4
Control
19 ?9
IUGR
12?8
1
79?33
1.8?0.5
Control
10?8
90?35
1.7?0.7
2.3 ?0.7
6.1?3.5
81 ?37
IUGR
6
Control
3.4?2.4
102?36
2.1?0.6
IUGR
2.6 ?0.8
3.8?4.2
89 ?34
12
Control
2.7?2.2
73?35
2.1?0.4
2.7 ?0.6
2.6?2.5
98 ?44
IUGR
24
Control
2.2?1.6
80?29
2.6?0.6
Values are mean ? SD
Leger J, Pediatr Res 2001
31
Hormone levels in IUGR with and without catch-up
growth
Time (months)
GH
IGF-1
IGFBP-3
1.2 ?1.6
63?90
28 ?18
lt - 2 SDS
0
31 ?21
1.1 ?0.9
48?43
gt - 2 SDS
lt - 2 SDS
1
15?7
80?26
1.4?0.2
74?34
1.8?0.5
15?11
gt - 2 SDS
4?2
75 ?41
1.9 ?0.5
lt - 2 SDS
6
2.3?0.7
7?10
81 ? 36
gt - 2 SDS
2.3 ?0.3
4?3
74 ?26
lt - 2 SDS
12
2.7?0.8
4?4
89?35
gt - 2 SDS
50 ?18
3?3
2.2 ?0.5
lt - 2 SDS
24
gt - 2 SDS
3?3
101?43
2.8?0.6
Leger J, Pediatr Res 2001
Values are mean ? SD
32
Hormone levels in infants
IGF-I (mcg/L)
IGFBP-3 (mcg/L)
IGFBP-1 (mcg/L)
Beta cell function
Insulin (mU/L)
Insulin sensitivity
IUGR
Control
Woods KA, Pediatr Res 2002
33
Fetal insulin hypothesis
Maternal glucose concentration
Glucose sensing by fetal pancreas
Fetal genetics (IGF-1,GK,insulin, etc.)
Insulin secretion by fetal pancreas
Fetal insulin resistance
Insulin-mediated growth of fetus
Birthweight
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Overnight GH secretion in infancy
IUGR group (n13)
Control group (n 15)
p value (t test)
GH (mUI/l)
Maximum
55.9 (30.4-80.5)
39.6 (15.6-75.9)
0.1
Mean
13.1 (7.2 19.1)
8.9 (3.7-18.5)
0.004
Minimum
1.2 (lt0.4-2.1)
0.6 (0.5-1.3)
0.004
No. of pulses
5.4 (3-7)
4.3 (3-8)
0.02
Area under curve
115.8 (62-171.1)
84.1 (28.7-165.8)
0.02
0.12
Pulse amplitude
25.2 (17.4-36.7)
20.6 (9.1-40.8)
Values are mean and range
Woods KA, Mohn A, Pediatr Res 2002