Teratogenicity

1. Teratogenicity

2. 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).

3. Causes of malformations 40% Unknown 12-25% Genetic defects (Down’s 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

4. 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)

5. 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.

6. Known teratogens and their effects - Aminoglycosides (C) (high dose)……Cranial nerve damage - Androgens (X)……………...................Masculinization 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)……………………………Ebstein’s 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

7. 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.

8. 3- Deficiency of energy supply needed to build organs : a- Glucose deficiency : - Deficiency ofglucose in diet - G6PD inhibitors ( 6- aminonicotinamide) interfer with glycolysis. - Drugs affectingKreb’s 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 : X-ray ,atomic explosion &radiations DNA damage mutation congenital abnormalities. E.g.: Achondroplasia. It is characterized by congenital abnormality in ossification of cartilage. Features include : * Dwarfism- microcephaly ( small head) *Kyphosis ( arched back)- Polydactylia ( 6 or more fingers in one hand)

9. 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 ( XX=female) & ( 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 = Down’s 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. ii Sex chromosome ( genosomal) abnormalities Turner;s syndrome : (XO)- ( Monosomy 23)

10. 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.

11. 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.

12. *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 .

13. 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 .

14. 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 & progesterone:Musculization of fetus. 2-Estrogens:Feminization 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 ).