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Prenatal Development and the Newborn Siegler Prenatal German measles by mikeholy


									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

•   Genes
•   Regulatory genes important
•   Gene-gene interaction
•   Gene-environmental interaction (nature-
     Phylogenetic Continuity
• The idea that because of our common
  evolutionary history, humans share
  physiologic characteristics with
  other animals.
and apes
share 98%
of the genes
   Prenatal development
Cell division
Cell migration is the movement of cells from
 their point of origin to somewhere else in the
Cell differentiation (from stem cells)
Selective death of certain cells, or apoptosis,
 important in organ development
• 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

• 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

• 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
• 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
Differentiation of genital organs – in

• Female development – default path

• Male development – defeminization and
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
• 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
  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
• Those not converting to male: less succsessful
  psychosocial development
Sex differentiation – what could og
• Genes – environment

• Structure - function
 Sex differentiation what could og
• Defect ormation of gonadal ridges, genital
  tubes and early outer genitalia
• Hormon receptor defect – lack of hormon
• 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
  – 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
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
      – 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
 • Near the end of pregnancy, the
   fetus’s sleep and wake states
   are similar to those of the
• 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
  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
  buffer for
  the fetus
What can go wrong?
• By far the most common
  misfortune in prenatal
  development is spontaneous
  abortion (miscarriage)
• Around 45% or more of
  conceptions result in very early
• The majority of embryos that
  miscarry very early have severe
What can go wrong in the
central nervous system?
  • Genetic defect

  • Environmental damage
          What can go wrong?
• Malformation
• Other structural and
  or functional
• 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 1967-
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
    Neurodevelopmental disorders -

•   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

• Polutants

• Metabolic products – PKU (Følling
            Toxic substances
– Talidomid
– Antiepileptics

– Alcohol
– Heroin

– Nicotin
• 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)

•   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

• 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.

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