Teratogenicity

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Teratogenicity
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• It is the science dealing with the development of
  congenital malformations.
• A teratogen ( terat monster or ugly animal)
• It is a substance that alters embryonic or fetal
  development resulting in structural or
  functional alterations.
• ? In 1928 Exposure to therapeutic radiation
  during
• pregnancy microcephaly
  baby.
• ? In 1933 Deficiency of vitamin A in the 1st
  month before pregnancy during pregnancy
  anophthalmia (deficiency in eye)
• ? In 1941 German measles ( rubella ) infection
  in pregnancy cause teratogenicity (blindness,
  deafness, mental retardation and death).
• ? In 1944 Malformation due to nutritional
  deficiency.
• ? In 1961 Correlation between Thalidomide (
  used as sedative , hypnotic and antiemetic)
  ingestion in pregnancy phocomelia ( phoco seal
  , melia extremities).

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• Causes of malformations
• 40 Unknown
• 12-25 Genetic defects (Downs syndrome is the
  most common of this group)
• 20 Interactions between hereditary factors and
  environmental factors
• 5-9 Maternal disease (diabetes and seizure) or
  infection (German measles) , chemicals, X-ray and
  drugs.
• Factors That Determine the Effects of Teratogens
• 1-Dose reaching fetus
• 2-Time of drug exposure
• 3-Duration of exposure
• 4-Environmentall factors e.g age or disease of
  the mother

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• Sensitivity to Teratogens according to the stage
  of development
• The attack by the teratogen could be at any stage
  of development as follows
• 1-Pre-implantation Stage (All or Non)
• From fertilization till implantation
• During this stage the embryo is NOT susceptible
  to teratogenic agents which either kill the
  embryo ( embryolethality), or have no effect (
  i.e. in both cases there is NO teratogenicity) .
• 2-Embryonic Stage (stage of organogenesis )
• from the 3rd to the 8th week of gestation .
• 6-7 days after gestation ,implantation occurs
  followed by gastrulation ( formation of ectoderm,
  mesoderm endoderm). It is characterized by
  differentiation and organization. During this
  stage, the embryo is highly susceptible to
  teratogens, it produce major morphological
  changes ( especially face).
• 3-Fetogenesis Stage (stage of histogenesis )
• It is characterized by growth and functional
  maturation. During this stage, the fetus is less
  sensitive to morphologic changes however minor
  structural deviation is possible. The teratogen
  affects mainly growth or functional aspects (
  e.g. intelligence, reproduction)

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• FDA Classifications of Drug Risk
• Animal studies cannot be true predictors of
  teratogenicity due to wide inter- and
  intraspecies variations in the pharmacokinetic
  properties of drugs, including placental
  transfer.
• Only controlled epidemiological studies can
  detect a relationship between environmental
  factors such as drug exposure and pregnancy
  outcomes.
• Drug Risk Category
• A----No fetal risk shown in controlled human
  studies in all trimesters.
• B----Animal studies show risk that is not
  confirmed in human studies during all trimesters.
• C----Fetal risk shown in controlled animal
  studies but no controlled human studies are
  available (OR ) studies in humans are not
  available. Drugs only given if the potential
  benefit outweighs the potential risk to the fetus
• D----Studies show fetal risk in humans
• (Use of drug may be acceptable even with risks,
  such as in life-threatening
• illness or where safer drugs cannot be used or
  are ineffective)
• X----Risk to fetus clearly outweighs any benefits
  from these drugs The drug is contraindicated in
  women who are or may become pregnant.

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• Known teratogens and their effects
• - Aminoglycosides (C) (high dose)Cranial nerve
  damage
• - Androgens (X)...................Masculiniza
  tion of female fetus
• - ACE inhibitors (D).......................Renal
  tubular dysplasia
• - Antineoplastics (D)
• alkylating agents Growth
  retardation, cleft palate
• antimetabolite agents. Growth
  retardation, malformation of ear, eye, nose,
  cleft
• 
  palate, malformation of
  extremities, fingers, brain, skull.
• - Iodides (D).Goiter, fetal
  hypothyroidism
• - Lithium (D)Ebsteins anomaly (
  tricuspid valve defect)
• -Tetracyclines (D)Weakend fetal bone
  and, permanent tooth
  
  discoloration
• -Thalidomide (X)
• - a sedative non-nausiating non-barbiturate
• - greatest danger during days 34-56 of pregnancy
• -phocomelia and amelia
• - deafness ,anomalies of teeth, eyes, intestines,
  heart, kidney

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• Mechanism of action of teratogens
• 1-Interference with nucleic acids ( replication
  , transcription or RNA translation)
• The antimetabolite
  methotrexate.
• alkylating agents Chlorambucil,
  cyclophosphamide.
• Active metabolites of Thalidomide
  
• 2- Inhibition of enzymes
• Methotrexate ( dihydrofolate
  reductase inhbitor DHFRI) prevents
  formation of folinic acid from folic
  acid which is essential for
  embryo.
• 5- flurouracil inhibits
  thymidylate synthase leading to inhibition of
  deoxythymidine
  monophosphate( DTMP )synthesis inhibition
  of DNA synthesis .
• 6- aminonicotinamide ( G6PD
  inhibitor) decrease energy production.

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• 3- Deficiency of energy supply needed to build
  organs
• a- Glucose deficiency
• - Deficiency of glucose in diet
• - G6PD inhibitors ( 6-
  aminonicotinamide) interfer with glycolysis.
  - Drugs affecting Krebs cycle (
  fluroacetate)
• Interference with O2 s supply or utilization
• b- Interference with internal
  respiration
• - CN toxicity cytochrome oxidase
  inhibitor.
• c- Hypoxia
• -CO toxicity (Decrease
  in both O2 delivery osmotic pressure to fetus)
• - Drug induced (
  phenytoin).
• 4-Lack of substrates
• 1-Decrease of vitamines or minerals intake.
• 2-Failiur of absorbtion from GIT as in GIT
  infection e.g. diarrhea or bile acid deficiency.
• 5- Genetic mutation

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• 6- Chromosomal aberrations
• The abnormalities may be in number ( numerical)
  or structure ( structural)
• A-Numerical abnormalities
• Normal no. of chromosomes 23 pairs. Pairs from
  1-22 are called somatic or autosomal chromosomes.
  Pair 23 is called sex chromosomes ( XXfemale)
  ( XY male) Abnormalities in no. may be
  called
• Aneuploidy loss or gain in chromosomes.
• -Monosomy single
  chromosome instead of a pair
• -Trisomy 3 chromosomes
  instead of a pair
• Polyploidy when a complete set of chromosomes
  is gained.
• ?The numerical abnormality may be in the
  autosomes ( 1st 22 pairs) or in the sex
  chromoses ( pair no.23)
• 
  i-Autosomal abnormalities
• Autosomal abnormalities may be caused by X-ray,
  viruses, F in drinking H2O , maternal diabetes
  age
• Trisomy 21 ( Mongolism Downs syndrome)
• It is characterized by mental retardation, heart
  malformations, susceptibles to infections, acute
  leukemia death in childhood.
• Trisomy 17 18
• mental retardation, defects in heart, ears
  finger.
• Trisomy 13 mantal retardation microcephaly.

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• B- Structural abnormalities
• In this case the no. is normal, but there may be
  a breakage or a loss of a part from chromosomes
  mental retardation or deformity.
• E.g. Cri- du chat syndrome ( cat cry
  syndrome).
• It is characterized by mental retardation
  mewing sound crying.
• Structural abnormalities may be caused by atomic
  explosion, radioactive materials, LSD, heavy
  smoking viruses.

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Types of Teratogenes

• 1- pollution
• a) physical
• Atomic and nuclear explosions e.g. Hiroshima
  Nagasakia.
• b) chemical
• lead (pb2)
• from water pipes, or car exhaust miscarriage
  (spontaneous abortion ), stillbirth ( delivery of
  a dead baby ), and increased mortality rate
  during the 1st year of life .
• Carbon monoxide CO
• from cigarette smoking, car exhaust, and
  incomplete combustion of coal. It binds to Hb
  decreasing O2 supply to fetus hypoxia
  spontaneous abortion, stillbirth, growth
  retardation, premature labor.

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• Vinyl chloride
• sperm damage ( working in vinyl industry, their
  babies may be malformed ) .
• Mercury
• Minamata syndrome A plastic factory poured is
  wastes, containing Hg, in Minarnata Bay
  Hg is converted by microorganisms in H2O to
  methyl Hg witch contaminated fish
  eating contaminated fish, the pregnant women gave
  birth to malformed mentally retarded babies .
• 2- infections ( biological pollution )
• a-Viral
• -German measles (Rubella) deafness, blindness,
  cataract, retinopathy, glaucoma, microcephaly,
  mental retardation . Attenuated virus causes
  damage to the fetus, so give vaccine before
  pregnancy by three months
• -Hepatitis, small pox, chicken pox may cause
  abortion, stillbirth, skin diseases, hepatitis
  etc .

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• b-bacterial
• Syphilis hydrocephalus mental retardation,
  deafness, tooth malformation, meningitis CNS
  disturbances .
• Tuberculosis Wt. loss, refusal to suckle,
  hepato-splenomegaly
• c-protozoal
• toxoplasmosis it is transmitted to pregnant
  women by feces of domestic cats birds causing
  hydrocephalus, CNS disturbance, microcephaly,
  hepatosplenomegaly blindness .
• 3- maternal diseases
• - uncontrolled diabetes mellitus, hyperthermia
  thyrotoxicosis(hyperthyroidism)
  teratogenicity toxemia of pregnancy
• 4-Alcohol
• Fetal Alcohol syndrome ( FAS ) growth failure
  delayed development, microcephaly mental
  retardation , defects in the eye, face ( cleft
  palate) , congental abnormalities in heart, skin
  kidneys .

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• 5-Drugs
• -Highly teratogenic drugs as" thalidomide,warfarin
  ,corticosteroids , anticancer drugs .
• -The following drugs are hazardous if given
  during the 2nd or 3rd trimester, some of them are
  hazardous also if given during the 1st trimester
  
• 1-Androgens progesteroneMusculization of
  fetus.
• 2-EstrogensFeminization of male fetus,abnormal
  spermatogenesis.
• 3-Diethylstilbestrol ( DES ) Adenocarcinoma of
  vagia in girls (15-
• 20 years ) whose mothers took DES during the 1st
  trimester .
• 6- malnutrition
• Vit. A anophthalmia .
• Vit. D bone and teeth
  malformation .
• Folic acid malformations .
• Minerals as iron ( anemia ), Ca 2 ( bone
  malformation ) K
• ( pre-term labour ).