Prenatal Development
Kari Kveim Lie
Nasjonalt folkehelseinstitutt,
Divisjon for epidemiologi
Changing Ideas Over Time
• Old idea: The human body is
already created in the sperm.
The female genital tract is
needed as an incubator for
the fetus to develop
Leonardo Da Vinci ca 1510
Prenatal development 2008
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Genes
Regulatory genes important
Gene-gene interaction
Gene-environmental interaction (naturenurture)
Phylogenetic Continuity
• The idea that because of our common
evolutionary history, humans share
physiologic characteristics with
other animals.
Humans
and apes
share 98%
of the genes
Prenatal development
Conseption
Cell division
Cell migration is the movement of cells from
their point of origin to somewhere else in the
embryo
Cell differentiation (from stem cells)
Selective death of certain cells, or apoptosis,
important in organ development
Conseption
• Conseption results from the union of two
gametes, the egg and the sperm.
Gametes are produced through a
specialized cell division, meiosis, which
results in each gamete’s having only half
the genetic material of all other normal
cells in the body. The fertilized egg,
zygote, has a full set of genetic material
Conception
Twins
• Identical twins originate from the
splitting in half of the inner cell
mass, resulting in the development
of genetically identical individuals
• Fraternal twins result when two
eggs are released into the fallopian
tube at the same time and are
fertilized by different sperm
By the 4th day after conception, the zygote
arranges itself into a hollow sphere of cells with a
bulge of cells, the inner cell mass, on one side
The Embryo
– Placenta: Permits the exchange of materials
between the bloodstream of the fetus and that
of the mother
– Umbilical cord:
The tube that
contains the
blood vessels
that travel
from the placenta
to the developing
organism and back again
Embryo at 4 Weeks
Face Development
from 5½ to 8 Weeks
Fetus at 9 Weeks
Fetus at 11 Weeks
Fetus at 16 Weeks
Fetus at 18 Weeks
Fetus at 20 Weeks
Fetus at 28 Weeks
Fetal development
Formation of genital organs
4-7 weeks:
• So called gonadal ridges are formed similar in both sexes – later to develop into
ovaries or testicles
• Both sexes have two sets of internal ducts
– later to develop into ducts connecting
the gonads with external genitalia
• External genitalia appear female
Gonadal differentiation
• In males gonadal ridges develop into
testicles as result of so called SRY (after
Sex Determining Region of the Y
chromosome)
• In females, due to absence of SRY,
expression of other genes trigger the
gonadal ridges to develop into ovaries
Gonadal differentiation
• XY fetus: SRYproduction:
Development of testicles
• XX fetus: no Y chromosome, no SRY:
Development of ovaries
Gonadal differentiation - males
• The developing testicles produce male
hormones that promote growth of the male
tubes. These are developing into the
structures connecting the testicles with
penis.
• The testicles also produce a hormone
causing the female tubes to disappear
• Both sexes are exposed to maternal
female hormones
Gonadal differentiation - females
• Anti-female-tube hormone is not produced: Female
tubes develop into fallopian tubes, uterus and upper part
of vagina.
• Male tube growth factor not produced:
• Male tubes disappears
• Fetal ovaries produce female hormones, promoting local
development in the ovary, but of little importance in
development of genital organ structure
• Both sexes are exposed to maternal female hormones
Development of internal genitalia
External genitalia
• In males, fetal male hormones masculinize
external genitalia.
• In females, no or lower level of male
hormones, hence, the external genitals
remain female.
External genitalia
Secondary sex characteristics
• Sex hormone levels are similar in
prepubertal girls and boys
• Further maturation of the gonads during
puberty, and the resultant hormone
production results in the secondary sex
characteristics.
Differentiation of genital organs – in
brief
• Female development – default path
• Male development – defeminization and
masculinization
Fetal development– sex differences
in brain development
• In most animals different exposure of fetal
and infant brain to sex hormones produce
irreversible differences that correlates with
reproductive behaviour
• Humans fetuses: Both androgen and
oestrogen receptors are found in the brain
• Sex-specific genes are expressed
differently in male and female brains
Sex differences in adult human
brain
• Structural sex differences are detectible in
like size and shape of corpus callosum
and certain hypothalamic nuclei.
• Differences in brain weight
• Different hormonal feedback response in
the hypothalamic-pituitary system
Psychological sex differentiation –
nature and nurture
• Gender versus sex ?
• John Money and John-Joan
• Diamond M. Sigmundson HK. Sex reassignment
at birth. Long-term review and clinical
implications. Archives of Pediatrics & Adolescent
Medicine. 151(3):298-304, 1997 Mar.
Psychological sex differentiation –
nature and nurture
• Reiner WG, Kropp BP. A 7-year experience of genetic males
with severe phallic inadequacy assigned female. The Journal of
Urology
Volume 172, Issue 6, Part 1, December 2004, Pages 2395-2398
• All patients demonstrated marked male typical
behaviours and interest.10 live as males, and 6
as females
• Those reared male and those reared female and
converted to male: functional psychosocial
development
• Those not converting to male: less succsessful
psychosocial development
Sex differentiation – what could og
wrong?
• Genes – environment
• Structure - function
Sex differentiation what could og
wrong
• Defect ormation of gonadal ridges, genital
tubes and early outer genitalia
• Hormon receptor defect – lack of hormon
effect
• Hormon metabolism or production
irregularity – to much hormone
Fetal development
The Embryo
• The neural tube is a
U-shaped groove formed
from the top layer of
differentiated cells in the
embryo
– It eventually becomes the
brain and the spinal cord
Brain development
• Migration of cells
• Formation of nerval
tracts in the brain
• Formation of
synapses –
continues after birth
Brain development
• Cell division
• Cell migration
• Development of synapses, receptors and
transmittor activity
• Involution of nerve tissue and nerve
connections
The Fetus: An active contributor to
its own development
• By 12 weeks after gestation, most of
the movements that will be present
at birth have appeared
– Swallowing amniotic fluid promotes the
normal development of the palate and
aids in the maturation of the digestive
system
– Movement of the chest wall and pulling
in and expelling small amounts of
amniotic fluid help the respiratory
Fetal Rest-Activity Cycles
• Become stable during the
second half of pregnancy
• Circadian rhythms are also
apparent
• Near the end of pregnancy, the
fetus’s sleep and wake states
are similar to those of the
newborn
Sensation
• The sensory structures are present
relatively early in prenatal
development and play a vital role in
fetal development and learning
– The fetus experiences tactile stimulation
as a result of its own activity, and tastes
and smells the amniotic fluid
– It responds to sounds from at least the
6th month of gestation
– Prenatal visual experience, however, is
negligible
The Fetus is protected, but-• The placental membrane is a barrier
against some, but not all toxins and
infectious agents
• The amniotic sac, a membrane filled with
fluid in which the
fetus floats,
provides a
protective
buffer for
the fetus
What can go wrong?
Miscarriage
• By far the most common
misfortune in prenatal
development is spontaneous
abortion (miscarriage)
• Around 45% or more of
conceptions result in very early
miscarriages
• The majority of embryos that
miscarry very early have severe
defects
What can go wrong in the
central nervous system?
• Genetic defect
• Environmental damage
What can go wrong?
• Malformation
• Other structural and
or functional
abnormality
• Metabolic process
Spina bifida
Closing of the neural tube occurs day 24-26 after conception
I Norway around 60 children are born every year with spina bifida
Neural tube defects Norway 19672002
Neurodevelopmental disorders
Genetic factors
• Chromosomal disorder
• Single gene disorder
• Gene-gene interaction
• Gene-environment interaction
Neurodevelopmental disorders
Environmental factors
• Reduced blood
circulation/placenta function
• Infections
• Toxic substances
• Nutritional deficiencies
Compromised blood sirculation gas exchange and metabolism
• Placenta disorders
• Cerebral ”stroke” in the fetus
• Birth related disorders in the mother
Neurodevelopmental disorders
• Preterm birth is a risk factor for several
neurodevlopmental disorders.
• The mechanisms involved is largely
unknown
Neurodevelopmental disorders Infection
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Syphilis,
Toxoplasmosis
Rubella (german measles – røde hunder)
CMV-infection
Others
Infections during pregnancy mechanisms for fetal injury
• Fetal infection
• Mother’s infection leads to secretion of
inflammatory mediators, which are
harming the fetus
• Autoimmune mechanism
Toxic factors
• Mercury - high concentrations (Minamata
disease)
• Polutants
• Metabolic products – PKU (Følling
disease)
Toxic substances
– Talidomid
– Antiepileptics
– Alcohol
– Heroin
– Nicotin
Alcohol
• Maternal alcoholism can lead to fetal alcohol
syndrome (FAS), which is associated with mental
retardation, facial deformity, and other problems
Cigarette smoking
• Cigarette smoking during
pregnancy is linked to
retarded growth and low
birth weight
– Cigarette smoking has also
been linked to SIDS
although the ultimate causes
of SIDS are still unknown
– Child behaviour disorders (?)
Some mechanisms for disordered
development of the brain
• Interference with cell division and migration
• Interference with development of synapses,
receptors and transmittor activity
• Interference with normal involution of nerve
tissue and nerve connections
• Altered expression of regulatory genes: Retinoic
acid, Valproate (antiepileptic drug)
Deficiencies
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Lack of iodine
Lack of folate
Lack of certain fatty acids (?)
Thyroid disorders in the mother (and
hence in the child)
Why is it difficult to find out?
• The same environmental factor might
result in different symptoms according to
stage in fetal development
– Rubella, other intrauterine infections
– Cytostatics, other medicins
– In animal experiments: The same toxin may
result in hyperactivity or hypoactivity,
depending on fetal age at exposure
Why is it difficult to find out?
• Various environmental exposure may
result in the same symptoms
• Autistic symptoms may develop after
intrauterin rubella and after major
intrauterine alcohol exposure
Why is it difficult to find out?
• Environmental factor is harmful only for
the genetic vulnerable fetus
• Folic acid supplement is important
primarily for a small group of pregnancies
predisposed to neural tube defects
Neurologic developmental
disorders
• Cerebral palsy, autism, ADHD and other
developmental disorders where the
diagnose at present is based on
presenting symptoms, may be reclassified
completely when causal pathways are
better understood.