Lecture 13; Fetal Growth part Two Flashcards
What is post natal growth determined by?
Growth is determined by genetic potential
What is post natal growth regulated by?
Provided that minimal nutritional requirements are
met, growth is regulated by endocrine status (GH
is important)
What is pre natal growth restrained by?
Constrained by maternal environment
What regulates pre natal growth?
• Provided minimal endocrine requirements are
met, growth is regulated by substrate supply
What hormone is not important in pre natal growth?
GH not important
How does age affect pre natal growth?
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
What did sheep studies show about maternal age?
In sheep pregnancy during adolescence is
associated with fetal growth retardation
What are other maternal factors that may affect growth?
Smoking: >9 cigarettes per day associated
with 200g decreased birth weight
- Starvation/undernutrition
• Severe exercise in late gestation
• Maternal health
What can poor maternal health lead to?
e.g. Chronic infection can lead to maternal
catabolism and thus, to nutrient competition
between mother and placenta
How does maternal size influence birth weight?
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
How does the mum constrain fetal nutrition?
• Delivery of nutrients to the fetus is
actively constrained by mother;
– placental transport capacity
– diffusion area
• Hormones facilitate nutrition
What is the major regulator of fetal growth?
• The supply of nutrients to the fetus is the
major regulator of fetal growth
What does fetal growth late in gestation reflect?
Fetal growth in late gestation reflects
compartmentalisation of nutrients
What is IUGR?
Inter Uterine Growth Restriction
How can IUGR occur?
– 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
Whats the incidence of IUGR in nz?
- In NZ -50,000 births/year
* 5000 SGA (=<10th percentile), of which 2000 IUGR infants/year
What is IUGR associated with?
- 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
What is the barker hypothesis?
IUGR has a Strong association with later insulin
resistance and diseases such as coronary artery disease
What is critical in fetal growth?
The effects of an insult are determined by the duration of that insult
What does the impact of nutritional deprivation depend on?
The impact of nutritional deprivation
depends on the gestational age when this
occurs and the severity of the insult
What is embryonic growth influenced by?
• Embryonic growth is influenced by nutrient
concentration
What does maternal under nutrition result in mid pregnancy?
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.
What is symmetrical IUGR?
- baby grew slowly through out pregnancy
* head circumference is proportionate to body
What does maternal undernutrition result in during late gestation?
• 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
Describe asymetrical or head sparing IUGR?
• 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
What happens to the fetus during malnutrition?
• 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
What was found across species in terms of oxygen consumption?
Very similar rate across species for the fetus
What is the equation for the fetal substrate/oxygen quotient?
Substrate/O2 quotient = ((v-a)substrate X n) / ((v-a) O2)
n = number of moles O2 required for complete oxidation of a substrate.
What does the fetal substrate/oxygen quotient mean?
• 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.
What is the extent of glucose oxidation responsible for oxygen consumption?
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
Describe the major AA metabolism during fetal under nutrition;
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
What particular AA are metabolised during fasting?
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
Describe the rate of fetal growth;
Fetal growth is exponential
Describe the rate of placental growth;
Placental weight increases at a much slower rate and
does not parallel the steep rise in fetal weight
Why do post term babies stop growing?
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
What is the slow growth of the placenta in the second trimester compensated by?
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
What placental factors are released that aid fetus growth?
- Placental lactogen (hPL)
- Growth Hormone (GH)
- Insulin-like growth factors (IGFs)
- Insulin-like binding proteins (IGFBPs)
What is the dominant source of alternative GH in the second trimester and what is the effect of this?
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)
Where is GH2 in circulation?
GH-2 only secreted into maternal circulation
What creates a state of relative insulin resistance?
Both hPL and GH-2 are believed to create a state of relative maternal insulin resistance
= Increased glucose for the baby
What is the other function of GH2?
• GH-2 may also directly affect placental function or development
What is the role of IGF in the placenta?
• 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
In what instance is IGF1 increased?
• Placental expression of IGF-I is increased in
some cases of IUGR
What is a key enzyme in the placental barrier?
11βHSD2
What does 11βHSD2 do?
Converts cortisol (active) into cortisone (inactive)
maternal cortisol would cause differentiation and maturation of tissues prematurely
What happens if the fetus is exposed to high levels of glucocorticoids?
Exposure of the fetus to high
levels of glucocorticoids negatively impacts on growth
What are the key fetal factors in fetal growth?
Growth hormone
IGFs
Insulin
Thyroid hormones
When do GHs act?
Post birth
Describe the levels of GH prior to birth;
GH levels are much higher before birth… and yet have relatively little effect on fetal growth….
Lack of GH receptors in liver?
What happens to those with congenital GH deficiency?
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
Does insulin cross the placenta?
No
Is insulin an important fetal growth factor?
Insulin is a key mediator/facilitator of fetal growth & metabolism
• Fetal islet tissue mass is correlated with body weight in newborn human infants
What does a pancreatectomy in sheep show?
That growth is halted, unless analogous insulin is given in which case growth recovers
What secretes IGF in the fetus and what are its effects?
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
What does IGF1 promote?
IGF-I + amino acids promote growth and differentiation of cells and tissues
– Combination of insulin+IGF-1 is highly anabolic
Which IGF is the primary growth factor?
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
What is the role of fetal produced GH?
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
What regulates these growth factors?
Fetal IGF-1 levels are regulated not by GH but by fetal insulin
What is the role of thyroxine post natally and to the fetus?
- Postnatally, most of the effects of thyroxine are secondary to stimulation of O2 consumption
- Thyroxine is anabolic in the fetus – Critical for brain development
How does cortisol and catecholamines affect fetal metabolism?
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
How much do maternal genes contribute to fetal growth?
25%
How much does paternal genes influence fetal growth?
– 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
What is IUGR?
a condition in which a fetus is unable to achieve its genetically determined potential size
Write some notes on IUGR;
• SGA ≠ IUGR
– Not all small fetuses are
• ~40%insufficientnutrition= IUGR
• ~40%healthy&normal
• ~20%intrinsicallysmalle.g. • trisomy 21
• cytomegalovirus infection • fetal alcohol syndrome
What is the Russell Silver syndrome?
pre- and post-natal asymmetrical growth restriction and relative macrocephaly
Describe the genetic mutations in Russell silver syndrome;
– 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
Define large for gestational age and some causes;
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
What results in maternal diabtetes?
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
What does maternal diabetes before 20 weeks result in?
– fetal islet cells cannot respond
– fetus is exposed to unregulated hyperglycemia – typically decreased fetal growth
What happens in maternal diabetes to the fetus in the 2nd trimester
• the fetus can respond to hyperglycemia: – pancreatic beta-cell hyperplasia
– increased fetal insulin levels
– Increased fetal amino acid transfer
What does high levels of insulin for the fetus result in, during the second trimester?
Insulin favours glycogen + fat deposition:
hepatosplenomegaly (enlarged liver and spleen) and cardiomegaly (enlarged heart)
Describe what can happen after birth if the mother has had late gestation diabetes
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
