Prenatal Development

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• Prenatal Development
• Kari Kveim Lie
• Nasjonalt folkehelseinstitutt,
• Divisjon for epidemiologi

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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

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Leonardo Da Vinci ca 1510
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Prenatal development 2008

• Genes
• Regulatory genes important
• Gene-gene interaction
• Gene-environmental interaction (nature-nurture)

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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

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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

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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 gametes 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

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Conception
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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

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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
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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

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Embryo at 4 Weeks
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Face Development from 5½ to 8 Weeks
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Fetus at 9 Weeks
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Fetus at 11 Weeks
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Fetus at 16 Weeks
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Fetus at 18 Weeks
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Fetus at 20 Weeks
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Fetus at 28 Weeks
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Fetal development
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Formation of genital organs4-7 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

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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

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Gonadal differentiation

• XY fetus SRYproduction
• Development of testicles
• XX fetus no Y chromosome, no SRY Development of
  ovaries

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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

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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

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Development of internal genitalia
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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.

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External genitalia
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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.

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Differentiation of genital organs in brief

• Female development default path
• Male development defeminization and
  masculinization

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Fetal development sex differencesin 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

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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

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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.

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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

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Sex differentiation what could og wrong?

• Genes environment
• Structure - function

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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

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Fetal development
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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

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Brain development

• Migration of cells
• Formation of nerval tracts in the brain
• Formation of synapses
• continues after birth

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Brain development

• Cell division
• Cell migration
• Development of synapses, receptors and
  transmittor activity
• Involution of nerve tissue and nerve connections

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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 system become functional

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Fetal Rest-Activity Cycles

• Become stable during the second half of pregnancy
• Circadian rhythms are also apparent
• Near the end of pregnancy, the fetuss sleep and
  wake states are similar to those of the newborn

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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

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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

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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

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What can go wrong in the central nervous system?

• Genetic defect
• Environmental damage

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What can go wrong?

• Malformation
• Other structural and or functional abnormality
• Metabolic process

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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
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Neural tube defects Norway 1967-2002
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Neurodevelopmental disordersGenetic factors

• Chromosomal disorder
• Single gene disorder
• Gene-gene interaction
• Gene-environment interaction

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Neurodevelopmental disordersEnvironmental factors

• Reduced blood circulation/placenta function
• Infections
• Toxic substances
• Nutritional deficiencies

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Compromised blood sirculation - gas exchange and
metabolism

• Placenta disorders
• Cerebral stroke in the fetus
• Birth related disorders in the mother

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Neurodevelopmental disorders

• Preterm birth is a risk factor for several
  neurodevlopmental disorders.
• The mechanisms involved is largely unknown

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Neurodevelopmental disorders - Infection

• Syphilis,
• Toxoplasmosis
• Rubella (german measles røde hunder)
• CMV-infection
• Others

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Infections during pregnancy - mechanisms for
fetal injury

• Fetal infection
• Mothers infection leads to secretion of
  inflammatory mediators, which are harming the
  fetus
• Autoimmune mechanism

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Toxic factors

• Mercury - high concentrations (Minamata disease)
• Polutants
• Metabolic products PKU (Følling disease)

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Toxic substances

• Talidomid
• Antiepileptics
• Alcohol
• Heroin
• Nicotin

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Alcohol

• Maternal alcoholism can lead to fetal alcohol
  syndrome (FAS), which is associated with mental
  retardation, facial deformity, and other problems

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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 (?)

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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)

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Deficiencies

• Lack of iodine
• Lack of folate
• Lack of certain fatty acids (?)
• Thyroid disorders in the mother (and hence in the
  child)

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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

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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

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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

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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.