Lecture 13; Fetal Growth part Two

Question 1

What is post natal growth determined by?

Answer 1

Growth is determined by genetic potential

Question 2

What is post natal growth regulated by?

Answer 2

Provided that minimal nutritional requirements are
met, growth is regulated by endocrine status (GH
is important)

Question 3

What is pre natal growth restrained by?

Answer 3

Constrained by maternal environment

Question 4

What regulates pre natal growth?

Answer 4

• Provided minimal endocrine requirements are

met, growth is regulated by substrate supply

Question 5

What hormone is not important in pre natal growth?

Answer 5

GH not important

Question 6

How does age affect pre natal growth?

Answer 6

Maternal and paternal age appear to have
significant but poorly defined effects

– In humans, U-shaped relationship between
mother’s age and birth outcomes: optimal ~
20 to 28 years

Question 7

What did sheep studies show about maternal age?

Answer 7

In sheep pregnancy during adolescence is

associated with fetal growth retardation

Question 8

What are other maternal factors that may affect growth?

Answer 8

Smoking: >9 cigarettes per day associated
with 200g decreased birth weight

• Starvation/undernutrition
  • Severe exercise in late gestation
  • Maternal health

Question 9

What can poor maternal health lead to?

Answer 9

e.g. Chronic infection can lead to maternal
catabolism and thus, to nutrient competition
between mother and placenta

Question 10

How does maternal size influence birth weight?

Answer 10

Most of the variation (60%) in birthweight
in humans is attributed to environmental
factors

The maternal environment has a major influence on fetal growth

i.e Temp, body fat, glucose, oxygen

Mother modifies fetal growth

Question 11

How does the mum constrain fetal nutrition?

Answer 11

• Delivery of nutrients to the fetus is
actively constrained by mother;
– placental transport capacity
– diffusion area

• Hormones facilitate nutrition

Question 12

What is the major regulator of fetal growth?

Answer 12

• The supply of nutrients to the fetus is the

major regulator of fetal growth

Question 13

What does fetal growth late in gestation reflect?

Answer 13

Fetal growth in late gestation reflects

compartmentalisation of nutrients

Question 14

What is IUGR?

Answer 14

Inter Uterine Growth Restriction

Question 15

How can IUGR occur?

Answer 15

– Frank maternal malnutrition, starvation
– Placental dysfunction: e.g. infarction,
– impaired blood flow to the uterus: preeclampsia
– Smoking

Because mum is the supply of nutrients to the fetus

Question 16

Whats the incidence of IUGR in nz?

Answer 16

• In NZ -50,000 births/year

* 5000 SGA (=<10th percentile), of which 2000 IUGR infants/year

Question 17

What is IUGR associated with?

Answer 17

• Stillbirth rate is doubled
• Perinatal mortality and asphyxia increased 6-fold
• ~30% of neonatal unit admissions
• 21% of short children
• On average 8 IQ points lower by adolescence – problems with behaviour

Question 18

What is the barker hypothesis?

Answer 18

IUGR has a Strong association with later insulin

resistance and diseases such as coronary artery disease

Question 19

What is critical in fetal growth?

Answer 19

The effects of an insult are determined by the duration of that insult

Question 20

What does the impact of nutritional deprivation depend on?

Answer 20

The impact of nutritional deprivation
depends on the gestational age when this
occurs and the severity of the insult

Question 21

What is embryonic growth influenced by?

Answer 21

• Embryonic growth is influenced by nutrient

concentration

Question 22

What does maternal under nutrition result in mid pregnancy?

Answer 22

Maternal undernutrition after
conception and throughout the
1st and 2nd trimester of
gestation results in“symmetrical”
SGA by the 2nd trimester of
gestation; 

• Baby’s head and body are proportionately small
• Weight, length + head circumference are all =<10th%tile
• Ponderal index is normal.

Question 23

What is symmetrical IUGR?

Answer 23

• baby grew slowly through out pregnancy

* head circumference is proportionate to body

Question 24

What does maternal undernutrition result in during late gestation?

Answer 24

• Nutritional deprivation later in pregnancy generally
results in asymmetric IUGR (head size is bigger
than body size)

• The effects of undernutrition in late gestation
depend on its duration

Ponderal index is low

Question 25

Describe asymetrical or head sparing IUGR?

Answer 25

``` • Head and brain are normal in size but the abdomen is smaller • Suggests last trimester • Redistribution of cardiac output → ↑ flow to brain, adrenal and heart at expense of splanchic circulation • Liver size diminished ``` No fat

Question 26

What happens to the fetus during malnutrition?

Answer 26

• The fetus becomes less reliant on maternally supplied glucose during fasting and must consume other substrates Starts to use AA (doubles in rate) but No change in umbilical uptake of a.a. from placenta or other potential substrates such as lactate

Question 27

What was found across species in terms of oxygen consumption?

Answer 27

Very similar rate across species for the fetus

Question 28

What is the equation for the fetal substrate/oxygen quotient?

Answer 28

Substrate/O2 quotient = ((v-a)substrate X n) / ((v-a) O2) n = number of moles O2 required for complete oxidation of a substrate.

Question 29

What does the fetal substrate/oxygen quotient mean?

Answer 29

• The demonstration of a substrate – oxygen quotient near or equal to 1.0 suggests that if the particular substrate measured were completely oxidised it could provide 100% of the carbon for the measured fetal O2 consumption.

Question 30

What is the extent of glucose oxidation responsible for oxygen consumption?

Answer 30

Non-ruminants have a greater dependence on glucose metabolism than ruminants • Under physiological conditions, not all glucose is oxidised • Therefore, glucose carbon only accounts for 25- 30% of the total rate of fetal O2 consumption

Question 31

Describe the major AA metabolism during fetal under nutrition;

Answer 31

Fasting → glucose fell by 40% Glucose O2 quotient fell from 1.20 → 0.621. (using other substrates) Fasting saw significant changes in net balance of several amino acids

Question 32

What particular AA are metabolised during fasting?

Answer 32

Both alanine & glutamine, which demonstrated a +ve uptake by fetus when fed, showed an efflux during fasting • observations consistent with fetus adapting to a diminished supply of glucose from the mother by enhanced amino acid catabolism and, possibly, proteolysis with subsequent release of gluconeogenic precursors in the form of alanine and glutamine

Question 33

Describe the rate of fetal growth;

Answer 33

Fetal growth is exponential

Question 34

Describe the rate of placental growth;

Answer 34

Placental weight increases at a much slower rate and | does not parallel the steep rise in fetal weight

Question 35

Why do post term babies stop growing?

Answer 35

Placenta determines the rate of nutrient supply thus at post term it cannot provide enough nutrients to sustain growth Thus post term babies stop growing

Question 36

What is the slow growth of the placenta in the second trimester compensated by?

Answer 36

increased exchange area in the placenta to sustain nutrient delivery: - Increased total villous surface area of the placenta  - Decreased proliferation and dilation of the fetal capillaries - Decreased resistance of the feto-placental vasculature

Question 37

What placental factors are released that aid fetus growth?

Answer 37

* Placental lactogen (hPL) * Growth Hormone (GH) * Insulin-like growth factors (IGFs) * Insulin-like binding proteins (IGFBPs)

Question 38

What is the dominant source of alternative GH in the second trimester and what is the effect of this?

Answer 38

By end of first trimester of human pregnancy, the placenta is the dominant source for an alternate form of GH (placental GH or GH-2 ie GH-variant) which suppresses pituitary GH (GH-1)

Question 39

Where is GH2 in circulation?

Answer 39

GH-2 only secreted into maternal circulation

Question 40

What creates a state of relative insulin resistance?

Answer 40

Both hPL and GH-2 are believed to create a state of relative maternal insulin resistance = Increased glucose for the baby

Question 41

What is the other function of GH2?

Answer 41

• GH-2 may also directly affect placental function or development

Question 42

What is the role of IGF in the placenta?

Answer 42

• IGF-I and IGF-II are produced in the placenta as well as the fetus • Across a group of normal and diabetic pregnancies, placental IGF-II mRNA was positively correlated with placental weight

Question 43

In what instance is IGF1 increased?

Answer 43

• Placental expression of IGF-I is increased in | some cases of IUGR

Question 44

What is a key enzyme in the placental barrier?

Answer 44

11βHSD2

Question 45

What does 11βHSD2 do?

Answer 45

Converts cortisol (active) into cortisone (inactive) maternal cortisol would cause differentiation and maturation of tissues prematurely

Question 46

What happens if the fetus is exposed to high levels of glucocorticoids?

Answer 46

Exposure of the fetus to high | levels of glucocorticoids negatively impacts on growth

Question 47

What are the key fetal factors in fetal growth?

Answer 47

 Growth hormone  IGFs  Insulin  Thyroid hormones

Question 48

When do GHs act?

Answer 48

Post birth

Question 49

Describe the levels of GH prior to birth;

Answer 49

GH levels are much higher before birth... and yet have relatively little effect on fetal growth.... Lack of GH receptors in liver?

Question 50

What happens to those with congenital GH deficiency?

Answer 50

Children with congenital GH deficiency can also be average length at birth and don't begin to experience growth problems until about six months of age

Question 51

Does insulin cross the placenta?

Answer 51

No

Question 52

Is insulin an important fetal growth factor?

Answer 52

Insulin is a key mediator/facilitator of fetal growth & metabolism • Fetal islet tissue mass is correlated with body weight in newborn human infants

Question 53

What does a pancreatectomy in sheep show?

Answer 53

That growth is halted, unless analogous insulin is given in which case growth recovers

Question 54

What secretes IGF in the fetus and what are its effects?

Answer 54

IGF-I and IGF-II, are peptides primarily secreted by the fetal liver, that circulate in the blood - have a sequence similar to insulin and can bind insulin receptor

Question 55

What does IGF1 promote?

Answer 55

IGF-I + amino acids promote growth and differentiation of cells and tissues – Combination of insulin+IGF-1 is highly anabolic

Question 56

Which IGF is the primary growth factor?

Answer 56

IGF-2 is the primary growth factor involved in embryonic growth, whereas the dominant fetal growth regulator in late gestation is IGF-1 as well as postnatally Ironically, fetal growth is more closely related to IGF1 levels rather than IGF2

Question 57

What is the role of fetal produced GH?

Answer 57

GH has a limited role in the regulation of fetal growth, because of receptor immaturity, but begin to exert a limited influence after 36 weeks’ gestation

Question 58

What regulates these growth factors?

Answer 58

Fetal IGF-1 levels are regulated not by GH but by fetal insulin

Question 59

What is the role of thyroxine post natally and to the fetus?

Answer 59

* Postnatally, most of the effects of thyroxine are secondary to stimulation of O2 consumption * Thyroxine is anabolic in the fetus – Critical for brain development

Question 60

How does cortisol and catecholamines affect fetal metabolism?

Answer 60

In late gestation, normally cortisol and adrenaline are maturational rather than nutritional signals, but still have metabolic effects Promote increased fetal [glucose] during adverse nutritional conditions

Question 61

How much do maternal genes contribute to fetal growth?

Answer 61

25%

Question 62

How much does paternal genes influence fetal growth?

Answer 62

– 1-2% – at least in part: imprinting – IGF2 gene is paternally expressed in the fetus and placenta → crucial for placental development and fetal growth Note: imprinting is the epigenetic phenomenon by which genes are expressed in a parent-of-origin- specific manner

Question 63

What is IUGR?

Answer 63

a condition in which a fetus is unable to achieve its genetically determined potential size

Question 64

Write some notes on IUGR;

Answer 64

• SGA ≠ IUGR – Not all small fetuses are • ~40%insufficientnutrition= IUGR • ~40%healthy&normal • ~20%intrinsicallysmalle.g. • trisomy 21 • cytomegalovirus infection • fetal alcohol syndrome

Question 65

What is the Russell Silver syndrome?

Answer 65

pre- and post-natal asymmetrical growth restriction and relative macrocephaly

Question 66

Describe the genetic mutations in Russell silver syndrome;

Answer 66

– 30%-50% chromosome 11p15.5-related – Loss of methylation at paternal IC1 (imprinting control 1 region)biallelic expression of H19 and biallelic silencing of IGF-2 – abnormalities of spontaneous growth hormone (GH) secretion and subnormal responses to GH stimulation

Question 67

Define large for gestational age and some causes;

Answer 67

LGA: just >90th percentile for gestational age, i.e.> 4kg at term – Macrosomia: a subset of LGA – All organs, including head are large; + fat • e.g. poorly controlled diabetes in mother

Question 68

What results in maternal diabtetes?

Answer 68

Pregnancy is ‘catabolic’: – favours reduced use of glucose & a.a. by mother • Placental GH-2 and hPL (human placental lactogen)- normally raises maternal glucose & makes her body less sensitive to insulin – 30% increase in insulin requirements

Question 69

What does maternal diabetes before 20 weeks result in?

Answer 69

– fetal islet cells cannot respond | – fetus is exposed to unregulated hyperglycemia – typically decreased fetal growth

Question 70

What happens in maternal diabetes to the fetus in the 2nd trimester

Answer 70

• the fetus can respond to hyperglycemia: – pancreatic beta-cell hyperplasia – increased fetal insulin levels – Increased fetal amino acid transfer

Question 71

What does high levels of insulin for the fetus result in, during the second trimester?

Answer 71

Insulin favours glycogen + fat deposition: |  hepatosplenomegaly (enlarged liver and spleen) and cardiomegaly (enlarged heart)

Question 72

Describe what can happen after birth if the mother has had late gestation diabetes

Answer 72

Insulin is mitogenic as well. • Insulin+IGF-1 powerful • stimulants of increased cell proliferation • At birth baby still has islet cell hyperplasia What happens? – Hypoglycemia! - Increase  basal metabolism  Fetal hypoxia, -  Increased Hematocrit (Hct) ie “Polycythemia