1. Prenatal Development Kari Kveim Lie Nasjonalt folkehelseinstitutt,
Divisjon for epidemiologi

2. 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

3. Leonardo Da Vinci ca 1510

4. Prenatal development 2008 Genes Regulatory genes important
Gene-gene interaction
Gene-environmental interaction (nature-nurture)

5. 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

6. 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

7. 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

8. Conception

9. 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

10. 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

11. 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

12. Embryo at 4 Weeks

13. Face Development from 5½ to 8 Weeks

14. Fetus at 9 Weeks

15. Fetus at 11 Weeks

16. Fetus at 16 Weeks

17. Fetus at 18 Weeks

18. Fetus at 20 Weeks

19. Fetus at 28 Weeks

20. Fetal development

21. 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

22. 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

23. Gonadal differentiation
XY fetus: SRYproduction:
Development of testicles
XX fetus: no Y chromosome, no SRY: Development of ovaries

24. 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

25. 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

26. Development of internal genitalia

27. 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.

28. External genitalia

29. 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.

30. Differentiation of genital organs – in brief
Female development – default path
Male development – defeminization and masculinization

31. 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

32. 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

33. 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): , 1997 Mar.

34. 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
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

35. Sex differentiation – what could og wrong?
Genes – environment
Structure - function

36. 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

37. Fetal development

38. 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

39. Brain development Migration of cells
Formation of nerval tracts in the brain
Formation of synapses –
continues after birth

40. Brain development Cell division Cell migration
Development of synapses, receptors and transmittor activity
Involution of nerve tissue and nerve connections

41. 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

42. 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

43. 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

44. 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

45. 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

46. What can go wrong in the central nervous system?
Genetic defect
Environmental damage

47. What can go wrong? Malformation
Other structural and or functional abnormality
Metabolic process

48. Spina bifida
Closing of the neural tube occurs day after conception
I Norway around 60 children are born every year with spina bifida

49. Neural tube defects Norway 1967-2002

50. Neurodevelopmental disorders Genetic factors
Chromosomal disorder
Single gene disorder
Gene-gene interaction
Gene-environment interaction

51. Neurodevelopmental disorders Environmental factors
Reduced blood circulation/placenta function
Infections
Toxic substances
Nutritional deficiencies

52. Compromised blood sirculation - gas exchange and metabolism
Placenta disorders
Cerebral ”stroke” in the fetus
Birth related disorders in the mother

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

54. Neurodevelopmental disorders - Infection
Syphilis,
Toxoplasmosis
Rubella (german measles – røde hunder)
CMV-infection
Others

55. 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

56. Toxic factors Mercury - high concentrations (Minamata disease)
Polutants
Metabolic products – PKU (Følling disease)

57. Toxic substances
Talidomid
Antiepileptics
Alcohol
Heroin
Nicotin

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

59. 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 (?)

60. 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)

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

62. 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

63. 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

64. 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

65. 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.