Genetics (1) Teratogenicity PDF

Genetics Lecture (1)- teratogenicity  LECTURE 01 Teratogenicity Definitions Terato=monster or ugly animal Teratogen ▪ Is an agent can produce a permanent alteration of structure or function...

Genetics Lecture (1)- teratogenicity  LECTURE 01 Teratogenicity Definitions Terato=monster or ugly animal Teratogen ▪ Is an agent can produce a permanent alteration of structure or function by interfering with normal embryonic or fetal development. ▪ Capability of producing fetal malformation. Teratogenicity Exposure to teratogen ⇨ Teratogenicity ▪ Is the Science that studies the ① Causes Teratology ② Mechanisms ③ Patterns of abnormal development. Dr.Noaman Page 1  Pediatrics Teratogenicity Incidence Key fact  An estimated 303000 newborns die within 28 days of birth every year, worldwide ✓ Due to congenital anomalies (WHO, World Birth Defects Day: 3 March 2021) Birth Defects in Child Principles of Clinical Teratology ① There are NO absolute teratogens. ② Individual differences in susceptibility to teratogens exist. ③ Teratogens act at vulnerable periods of embryogenesis and fetal development. ④ Combinations of exposures to teratogenic agents. ⑤ Teratogenic exposures tend to produce characteristic patterns of multiple anomalies rather than single defects. Critical Periods STAGE OF EXPOSURES OUTCOME (S) All or Non. ▪ Embryonic lethality PRE-IMPLANTATION : FROM FERTILIZATION TILL IMPLANTATION. IMPLANTATION TO TIME OF ORGANOGENESIS ▪ Morphological defects (TO THE END OF 1ST 2 MONTHS) ▪ Functional disorders FETAL → NEONATAL STAGE ▪ Growth retardation (DURING THE SECOND AND THIRD TRIMESTER) ▪ Carcinogenesis Dr.Noaman Page 2  Pediatrics Teratogenicity Mechanism of action of teratogens ▪ Replication, transcription or RNA translation e.g ❶ Interference with nucleic acids methotrexate ▪ Methotrexate ( dihydrofoleate reductase inhibitor ) ❷ Inhibition of enzymes ⇨ prevents formation of folinic acid from folic acid which is essential for embryo. ① Glucose deficiency Deficiency of energy supply needed ❸ ② Interference with internal respiration to build organs ③ Hypoxia ▪ Decrease of vitamins or minerals intake. ❹ Lack of substrates ▪ Failure of absorption from GIT as in GIT infection e.g. diarrhea or bile acid deficiency. ❺ Genetic mutation ❻ Chromosomal aberration Teratogenic agents These factors fall into four major categories:- ① Infectious agents. ② Environmental, Chemicals and Physical Agents. ③ Drugs and Pharmaceuticals. ④ Maternal Disorders. Dr.Noaman Page 3  Pediatrics Teratogenicity 1 INFECTIOUS AGENTS  Congenital infections are well-known causes of defects and psychomotor handicaps.  Common teratogens: Congenital infections(sTORCH) ① Congenital Toxoplasmosis gondii. ② Congenital syphilis (Treponema pallidum). ③ Congenital Cytomegalovirus (CMV). ④ Congenital rubella (German measles). ⑤ Congenital Varicella Zoster (Chicken pox) 6- ⑥ Congenital herpes simplex. ⑦ HIV / AIDS. ⑧ Tuberculosis. 1 Congenital Toxoplasmosis gondii Fetal Toxoplasmosis syndrome 2 Congenital syphilis (Treponema pallidum) Fetal syphilis syndrome. ① Rhinorrhea and conjunctival discharge at birth. ② Maculopapular eruption. ③ Saddle nose. ④ Hutchinson teeth at age 10years. ⑤ Perforation of palate at age 10 years Dr.Noaman Page 4  Pediatrics Teratogenicity 3 Congenital Cytomegalovirus (CMV) Fetal Cytomegalovirus syndrome 4 Congenital rubella (German measles) Fetal Rubella syndrome 5 Congenital Varicella Zoster (Chicken pox)  FVS: most common findings are ① Hypoplasia ② Paresis of an extremity with scarring cicatricial (zigzag) skin lesions in a dermatome distribution ③ Eye findings: microphthalmia, cataracts, choreo-retinitls, optic atrophy, anisocoria.  Gastrointestinal and genitourinary anomalies have been reported.  CNS: ① Microcephaly, hydrocephaly ② Cortical atrophy, ③ Intracranial calcification ④ Motor ,sensory deficits, seizures ⑤ Deafness, psychomotor retardation. Dr.Noaman Page 5  Pediatrics Teratogenicity 6 Congenital herpes simplex  10%maternal infections transmitted to fetus.  Early loss of pregnancy, fetal death.  Symptomatic neonates: ① Microcephaly, intracranial calcification ② Hydranencephaly, chorio-retinitis ③ Psychomotor retardation. ④ Seizures, microphthalmia ⑤ PDA, scarring vesicular rash ⑥ hepatomegaly, hepato- splenomegaly ⑦ osteitis, adrenal failure, ⑧ hypoplastic distal phalanges. Dr.Noaman Page 6  Pediatrics Teratogenicity 2 DRUGS AND PHARMACEUTICALS  Theoretically, all drugs or pharmaceuticals should be considered as possible teratogens during pregnancy should be minimal and limited only to those needed to treat important maternal health conditions category Classification Based on Teratogenic Potential (FDA Drug Risk Classification) CATEGORY CHARACTERISTICS EXAMPLES Folic Acid A Controlled human studies show no risk Thyroxine Acetaminophen B Animal Studies OK no human data Erythromycin Rifampicin C Animal Studies not OK no human data Morphine D Evidence for risk +++ Benefits outweigh risk Antiepileptics Thalidomide X Evidence for risk +++ outweigh Benefits Risks Retinoids Examples ① Angiotensin converting enzyme (ACE) inhibitors as enalapril, captopril, others. ② Antibiotics. ③ Anticonvulsants. ④ Vitamins. ⑤ Hormones: - Oral contraceptives Androgenic agents ⑥ Anticoagulants. ⑦ Corticosteroids ⑧ Acetyl salicylic acid. ⑨ Antiparasitic agent ⑩ Chemotherapy ⑪ Lithium Dr.Noaman Page 7  Pediatrics Teratogenicity 1 Angiotensin converting enzyme (ACE) inhibitors As enalapril, captopril, others  Use during second and third trimester associated with Hypoplasia of skull, Prematuity, IUGR, and PDA. Renal failure, Neonatal hypotension may occur. Oligohydrmnios deformation sequence. 2 Antibiotics Streptomycin, & closely ❶ ▪ 10-15% sensori-neural hearing loss. related aminoglycosides ▪ Weakend fetal bone ▪ Tooth enamel dysplasia ❷ Tetracycline ▪ Permanent tooth discoloration Folate antagonist ▪ May be used alone or in combination with sulfonamides. ▪ It may cause ❸ Trimethoprim ① Cardiovascular defects ② Structural defects ③ Neural tube defects. 3 Anticoagulants : Coumadin (Warfarin) Warfarin embryopathy Dr.Noaman Page 8  Pediatrics Teratogenicity 4 Anticonvulsants  Cleft lip and/or palate  Cardiac defects (VSD, coarctation of aorta, PDA, HLH)  Internal and external anomalies of genitalia  Long fingers and toes  Hyper-convex nails, defects in closure of neural tube (1-2%),  Psychomotor retardation. 5 Vitamins : Vit A With megadoses  Over 15,000 units per day  Manifestation ✓ sirenomelia and oculo-auriculo-vertebral sequences ✓ Genitourinary malformations.  Recommend maximum of 8000 units per day during pregnancy. 6 Corticosteroids 1% risk for cleft palate or adrenal atrophy. 7 Hormones Combined progesterone and estrogen ❶ Oral contraceptive ▪ 2 to 4 fold increase in vater association. ▪ Synthetic progestins were used frequently to prevent abortion (Ethisterone or norethisterone) ❷ Androgenic agents ▪ Have considerable androgenic activity: Musculinization of female genitalia Dr.Noaman Page 9  Pediatrics Teratogenicity 8 Acetyl salicylic acid (aspirin)  In the 1st trimester⇨ cleft palate (in a few percentages) 9 Chemotherapy Multiple fetal malformations 10 Antiparasitic agent: Metronidazol 0  If it used in first trimester, ✓ it may cause fetal malformations,  BUT using it in second and third trimester is acceptable 11 Lithium Ebstein’s anomaly Dr.Noaman Page 10  Pediatrics Teratogenicity 3 ENVIROMENTAL, CHEMICALS AND PHYSICAL AGENTS ① Alcohol (ethyl alcohol) ⑥ Cocaine ② Ionizing radiation ⑦ Lead ③ Toluene (glue sniffing) ⑧ Mercury ④ Tobacco (nicotine) ⑨ Carbon monoxide (CO) ⑤ Maternal hyperthermia ⑩ Pesticides 1 Alcohol (ethyl alcohol) Fetal alcohol syndrome 2 Ionizing radiation  Malformations usually only noted with large doses used for treating malignancies, or doses over 10 rads.  Manifestation ✓ Early loss of pregnancy, microcephaly ✓ Eye anomalies, cataracts ✓ Spina bifida cystica, cleft palate ✓ Skeletal and visceral malformations, ✓ Psychomotor retardation.  Beyond 20W :The fetus is completely developed, it has become more resistant to the developmental effects of radiation. Dr.Noaman Page 11  Pediatrics Teratogenicity 3 Tobacco (nicotine) Dose-related IUGR, fetal loss, neonatal deaths, prematurity. 4 Maternal hyperthermia  Temperature 38.90º or more; ✓ Usually over a 24- hour period or more with inter-current illness ✓ As minimal as 30-45 minutes in sauna, hot tub, very hot bathes or Heavy exercise on hot and humid environments.  Exposure between 4 and 14 weeks: ✓ IUGR, microcephaly, ✓ Hypotonia, microphthalmia, ✓ Midfacial hypoplasia, microganthia, ✓ Cleft lip and/or palate, malformed ears. ✓ Neural tube defects, seizures, psychomotor retardation 5 Lead  Found in old paint and water pipes  ⇧abortions  Anemia  Neurological disorders: ✓ Encephalopathy ✓ Abnormal development of the brain & MR 6 Mercury  Fish, seed corn sprayed with mercury containing fungicide ⇨ Minamata Syndrome (Multiple neurological symptoms) Dr.Noaman Page 12  Pediatrics Teratogenicity 7 Carbon monoxide (CO)  From cigarette smoking, car exhaust, and incomplete combustion of coal.  It binds to Hb,⇨ ↓ 02 supply to fetus hypoxia ⇨ spontaneous abortion, stillbirth, growth retardation & prematurity. 8 Pesticides  Agricultural parental work where the pesticides are massively used ⇨increases the risk of fetal death. 4 MATERNAL DISORDERS  Certain maternal disorders during gestation may adversely affect the fetus.  The outcomes are usually related to the degree of control or severity of the maternal disease.  Examples ① Diabetes mellitus ④ Hyperthyroidism ② Hypothyroidism ⑤ Malnutrition ③ Systemic lupus erythematosus 1 Diabetes mellitus  Outcome varies with with degree of control of maternal diabetes during pregnancy.  Insulin dependent diabetic at higher risk than non-insulin dependent or gestational diabetics.  Increased risk of ① Early loss of pregnancy 8% ② Risk for major malformations of heart (transposition of great vessels), ③ Anencephaly, spina bifida, hydrocephalus, ④ Cleft lip and/or palate, renal anomalies, ⑤ VATER association like findings ✓ Caudal regression sequence similar to sirenomelia sequence. Dr.Noaman Page 13  Pediatrics Teratogenicity 2 Hypothyroidism  Increased risk for loss of pregnancy.  Because fetal thyroid development is independent of maternal thyroxine levels, fetal and neonatal thyroid development and function not affected. 3 Systemic lupus erythematosus  Early loss of pregnancy, congenital heart block. 4 Hyperthyroidism  Usually occurs with Grave's disease.  Increased risk for loss of pregnancy.  If thyroid stimulating globulins present, fetal and neonatal hyperthyroidism.  Treatment with antithyroid medications can result in fetal hypothyroidism. Dr.Noaman Page 14  Pediatrics Teratogenicity 5 Malnutrition ❶ Vitamin A ▪ Anophthalmia ▪ Increased risk for defects in closure of the neural tube. ❷ Folic acid Recommend at least 400 micrograms folic acid daily. ❸ Vitamin D ▪ Bone and Teeth malformation ▪ Iron ⇨ anemia ❹ Minerals ▪ Calcium ⇨ bone malformation ▪ Potassium ⇨ preterm labour What about Fathers?  When toxic substances affect sperm cells, the damaged sperm usually do not survive journey to the egg.  Cocaine may disrupt development of zygote.  Most birth defects result from mother's exposure to toxins.  Men should consider how they contribute to prenatal hazards.  Healthy pregnancy is the responsibility of both men and women. Take home message  Birth Defects Caused By Teratogenic  Exposures Are Preventable.  Prevention of Birth Defects Caused by Teratogenic  Exposures is an Important Public Health Problem. Dr.Noaman Page 15