Teratogenesis

Question 1

What are birth defects?

Answer 1

Structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth or later in life

• Clinically significant birth defects
• Malformation
• Disruption
• Deformation
• Dysplasia

Question 2

Birth defects are…

Answer 2

Multifactorial diseases

Question 3

What is a teratogen?

Answer 3

Teratogen: An agent which produces a permanent structural or functional alteration in an organism exposed during embryonic or fetal life

Question 4

What is teratogenesis?

Answer 4

Teratogenesis: The process by which birth defects are produced

Principles:
➢ Dose of teratogen
➢ Genotype
➢ Time of action of the agent:
increased teratogenicity at critical period of development

Question 5

What are physically and medically important teratogens?

Answer 5

• Physical:
• Ionizingradiation
• Maternal diseases as teratogens:
• Uncontrolled Diabetes
• Drugs/medication:
• Thalidomide
• Valproic acid
• Phenytoin
• Warfarin
• Tetracycline
• Isotretinoin
• Alcohol

Question 6

What illicit substances are teratogens?

Answer 6

• Cocaine

* Marijuana

Question 7

What chemical is a clinically important teratogen?

Answer 7

Methylmercurry

Question 8

What infections are clinically important teratogens?

Answer 8

• Infections:
• Toxoplasma Gondii ( Toxoplasmosis)
• Other (Syphilis, varicella-zoster, parvovirus B19)
• Rubella virus ( German measles) • Cytomegalovirus ( CMV)
• Herpes simplex virus

Question 9

What is congenital toxoplasmosis?

Answer 9

Caused by protozoan toxoplasma gondii an intracellular parasite

Question 10

What is the prognosis of congenital toxoplasmosis ?

Answer 10

Severity related to gestational age and time of infection

Question 11

How is congenital toxoplasmosis managed?

Answer 11

• Antenatal screening

- Treatment during pregnancy reduces the risk of transmission

Question 12

What are the symptoms of congenital toxoplasmosis?

Answer 12

At birth most children are asymptomatic but may develop symptoms later.

Classic signs: Chorioretinitis, hydrocephalus, intracranial calcifications, convulsions.

Question 13

What is congenital syphilis?

Answer 13

Syphilis is caused by the bacteria Treponema pallidum
• Transmission:
• Sexuallytransmitted
• Transplacental→ may occur at any stage of pregnancy

Question 14

What are the clinical manifestations of congenital syphilis?

Answer 14

Clinicalmanifestations:

• Stillbirths(hydropsfetalis),
• Congenital syphilis: deafness, hydrocephalus, intellectual disability, craniofacial anomalies
• Early or late presentation of symptoms

Question 15

How is congenital syphilis managed?

Answer 15

Management
• Prevention:antenatalserologicalscreening
• Treatment with penicillin

• Incidence increasing due to association with HIV infection

Question 16

What are signs of congenital syphilis?

Answer 16

Saddle nose

Saber shins

Hutchinson teeth

Question 17

What is Congenital Cytonegalovirus (CMV)?

Answer 17

• One of the most common viral infections in the fetus.
• Induces abortions if the mother is infected during the early development
• 90% children are asymptomatic at birth
• Up to 10-15% develop symptoms later, notably sensorineural hearing loss
• Other defects : microcephaly, hydrocephalus, microphthalmia, intellectual disability

Question 18

What is the significance of Herpes Simplex in pregnancy?

Answer 18

• Virus that causes cold sores and genital warts
• Abortions in early pregnancy
• In late pregnancy premature birth and malformations can occur
• Fetal infections most frequently occur during delivery
• Mucocutaneous: Eye, mouth and skin eruptions within 48 hours
• CNS: microcephaly, chorioretinitis and mental deficiency
• Disseminated

Question 19

How is Herpes Simplex in pregnancy managed?

Answer 19

Early diagnosis in mother

Antiviral therapy

Question 20

What is congenital Rubella Syndrome?

Answer 20

• “German measles “ Rubella virus infection

Features:
• Cataract and retinopathy
• Cardiopathies: PDA, pulmonary artery stenosis
• CNS : microcephaly and mental deficiency
• Deafness
• Skin lesions
• Prophylaxis with vaccine (MMR)

Question 21

What drugs are teratogens?

Answer 21

• Thalidomide
• Retinoic acid and its derivatives
• Tetracycline
• Anticonvulsants: Lithium, phenytoin
• Alcohol

Question 22

What is the importance of Thalidomide in limb development?

Answer 22

• Thalidomide inhibits Fibroblast growth factors FGFs from the apical ectodermal ridge (AER) of the limbs which leads to the proximal limb tissue not developing, while the distal limb tissue continues to differentiate.
• Inhibits angiogenesis

Question 23

What is Amelia?

Answer 23

Amelia
• Complete absence of limbs
• Suppression of limb bud development in the 4th week
• Thalidomide induced Amelia is more frequent in the lower limb

Question 24

What is Maromelia?

Answer 24

Meromelia ( Phocomelia)
• Partial absence of limbs
• Disturbance of limb development
during 5th week

Question 25

What is the role of tetracyclines in pregnancy?

Answer 25

When used during tooth development (second half of pregnancy) tetracyclines may cause permanent yellow-gray-brown discoloration of the teeth and enamel hypoplasia. The use of tetracycline during pregnancy is generally not recommended, especially during the last half of pregnancy.

Question 26

What is the importance of isotretinoin (retinoids acid) in pregnancy?

Answer 26

* Used for treatment of severe acne * Severely teratogenic even at low doses. * Critical period of exposure – 3rd to 5th week * High doses of vitamin A during pregnancy can produce the same effects. ``` Defects: • spontaneous abortion • neuropsychological impairment • premature birth • neonatal death ``` Prevention p: mandatory contraception

Question 27

What is phenytoin (Dilantin)?

Answer 27

Affects 5-10% of the embryos based on their genotype

Question 28

What is valproic acid?

Answer 28

Valproic acid Drug used in treatment of epilepsy, bipolar disorder and migraines Associated defects: – Spina bifida, ASD, VSD, Cleft palate, Hypospadias, Polydactyly, Craniosynostosis. – Fetal valproate syndrome ( rare) – Increased risk of autism

Question 29

What is Fetal Hydantoin syndrome?

Answer 29

Fetalhydantoinsyndrome. • Mental deficiency, IUGR, ptosis hernias, depressed nasal bridge, microcephaly, epicanthal folds and hypoplasia of nails and distal phalanges

Question 30

What are the anti convulsive drugs?

Answer 30

Phenytoin(Dilantoin) Valproic acid Warfarin Organic mercury

Question 31

What is the importance of Warfarin ?

Answer 31

Warfarin (anticoagulant) inhibits vitamin K epoxide reductase and can cross the placental barrier. • The critical period 6-12 weeks, • Hypoplasia of the nasal cartilages, stippled (dotted) epiphysis CNS defects and fetal hemorrhage • Later trimesters: microcephaly, optic atrophy and some mental disorders.

Question 32

What is organic mercury?

Answer 32

Organic mercury occurs when bacteria interact mercury present in the sediments in water bodies * accumulates in the tissue of aquatic animals like fish(swordfish, shark, kingfish) * Neurotoxic in high concentrations causing loss of nerve cells, decreased brain size and problems with neuronal migration. * Symptoms : spasticity, seizures mental retardation * Congenital Minamata disease

Question 33

What recreational drugs are used as teratogens?

Answer 33

- Alcohol - Tobacco - Cocaine

Question 34

What are the consequences of alcohol during pregnancy?

Answer 34

Alcohol crosses the placenta and remains within the amniotic fluid * Risk of birth defects is directly related to the amount and frequency of consumption * Disrupts DNA and protein synthesis, inhibits cell migration, disrupts metabolic pathways and the transfer of nutrients across the placenta • Spontaneous abortion, preterm delivery and still births Fetal Alcohol Syndrome (FAS)

Question 35

What is fetal alcohol syndrome?

Answer 35

* Growth deficiency * Low IQ (average = 63) * Mild to moderate microcephaly * Facial defects: Short nose, smooth philtrum, thin upper lip * Heart murmur * Small distal phalanges

Question 36

What factors influence cigarette smoking in pregnancy?

Answer 36

* Epigeneticchanges:DNAmethylation * Nicotine:vasoconstrictor;decreased uterine blood flow * CO: impaired oxygen delivery fetus These are all linked to chronic fetal hypoxia

Question 37

What are the defects of cigarette smoking in pregnancy?

Answer 37

``` Defects: • Low birth weight (Women who stop smoking before pregnancy or 2-3 months into pregnancy, reduce their risk of having a low birth weight baby to that of non smoking women! ) • Intra uterine growth retardation (IUGR) • Preterm labor and premature delivery • Placentaldefects • Suddeninfantdeathsyndrome(SIDS) • Conotruncaldefects • Some orofacial ( cleft lip and palate) ```

Question 38

What is cocaine?

Answer 38

Readily crosses the placenta and causes severe vasoconstriction in the fetus * Can lead to low birth weight * Probable neurobehavioral disorders * These babies tend to be easily stimulated and difficult to soothe

Question 39

What is cannabis?

Answer 39

Use of cannabis during pregnancy was not associated with increased risk of perinatal mortality or morbidity * Confounding factors ? Other drugs, alcohol .... * Cannabis use throughout pregnancy may be associated with lower birth weight

Question 40

What is maternal diabetes?

Answer 40

Uncontrolled maternal diabetes mellitus alters the expression of developmental genes and is associated with the following defects: •Macrosomia (large baby) •Impaired growth •Pulmonary disease ( in neonatal period) • CNS • Heart: VSD’s, transposition of the great arteries, ASD’S and Coarctation of the aorta • Skeletal •Metabolic disorders( hypoglycemia, hypocalcemia)