Pediatrics notes about "Teratogenicity". These notes were published in 2018. You can download them also from - Telegram: https://t.me/pediatric_notes_2018 - Mediafire: http://www.mediafire.com/folder/u5u60m184t9z7/Pediatric_Notes_2018

1. Teratogenicity
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Teratogenicity
Agent can produce permanent alteration of structure or function by
interfering with normal embryonic or fetal development.
Teratogen
(monster or ugly animal)
Capability of producing fetal malformation.Teratogenicity
Science that studies causes, mechanisms and patterns of abnormal
development.
Teratology
1- Multifactorial (42%) → Most common
2- Unknown (37%)
3- Teratogen (10%)
4- Monogenic "single gene" (8%)
5- Chromosomal (3%)
(5 points)
1- Individual differences in susceptible to teratogen exist.
2- There are no absolute teratogens
( depend on: dose, duration, single or multiple exposure, period "trimester")
3- Teratogens act at vulnerable periods of embryogenesis and fetal development
4- Teratogenic exposures tend to produce characteristic patterns of multiple anomalies
rather than single defects
5- Combination of exposures to teratogenic agents → may increase or decrease defect
Definitions:
Incidence of birth defects in childhood:
Principles of clinical teratology
Multifactorial
42%
Unknown
37%
Teratogen
10%
Monogenic
8%
Chromosomal
3%
N.B:
- Exposure to Teratogens in 1st
2 weeks → abortion
- Most vulnerable period to Teratogens: (2: 8 or 10 weeks)

2. Teratogenicity
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Stage of exposures Outcome
A. pre-implantation
(1st
2 weeks)
• Embryonic lethality
B. Implantation to time of organogenesis
(2: 8 or 10 weeks)
• Morphological defects.
C. Fetal stage to neonatal stage • Functional disorders
• Growth retardation
• carcinogenesis
Critical periods:

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(6 points)
1- Chromosomal aberration.
2- Interference with nucleic acids: (replication, transcription or RNA translation).
3- Genetic mutation:
X-ray, atomic explosion & radiations→ DNA damage→ Mutation →Congenital abnormalities
4- Inhibition of enzymes
e.g. Methotrexate Inhibits Dihydrofolate Reductase enzyme
& prevent conversion of folic acid to folinic acid which is essential for embryo
5- Lack of substrates:
- Decrease of vitamins or minerals intake
- Failure of absorption from GIT as in GIT infection e.g. Diarrhea or bile acid deficiency
6- Deficiency of energy supply needed to build organs:
a) Glucose deficiency:
*  Glucose in diet
* G6PD inhibitors e.g. 6-Aminonicotinamide (6-AN)
* Drugs affecting Krebs cycle e.g. Fluoroacetate
b) Interference with internal respiration
* CO toxicity → inhibits Cytochrome oxidase
c) Hypoxia:
* CO toxicity →  O2 delivery + osmotic pressure to fetus
* Drug induced e.g. phenytoin
Mechanism of action of teratogens
DHFR DHFR
Folic acid (−)
methotrexate
�⎯⎯⎯⎯⎯⎯⎯⎯⎯� Dihydrofolate (−)
methotrexate
�⎯⎯⎯⎯⎯⎯⎯⎯⎯� Tetrahydrofolate → Folinic acid

4. Teratogenicity
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( 4 categories )
1- Infectious agents ( sTORCH )
2- Drugs & pharmaceutical
( ACEIs, Antibiotics, Anticoagulants, Anticonvulsants, Thalidomide, vitamin A,
corticosteroid, Hormones, Aspirin, Chemotherapy, metronidazole)
3- physical, chemical & Environmental agents
* Physical: Ionizing radiation – Hyperthermia
* Chemical: Alcohol – Tobacco “ Nicotine “ – Cocaine
* Environmental: Lead – Mercury – CO - pesticides - Toluene
4- Maternal disorders
( DM – Hyper/Hypo thyroidism – SLE - PKU – Malnutrition)
1-Infectious agents (sTORCH)
- Syphilis – Toxoplasma – Rubella – CMV - Herpes simplex –
- Others: Varicella Zoster, HIV, TB, … etc.
 Mainly affect CNS - Eye - Ear & others
I. Congenital Syphilis: (Treponema pallidum)
 Early:
1. Rhinorrhea “snuffles” and conjunctival discharge → At birth
2. maculopapular eruption (involving palms and soles - desquamating)
 Late:
1. Hutchinson teeth → late at age 10ys
2. perforated palate → late at age 10ys
3. Rhagades (thickening and fissures of corners of mouth)
4. Saddle nose
5. Saber shins
Teratogenic agents

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II. Congenital Toxoplasma
1. CNS :
• Intracranial calcification (diffuse)
• Obstructive hydrocephalus
2. Eye : "chorioretinitis , cataract "
3. IUGR
4. GIT : Hepatosplenomegaly,
neonatal Jaundice
5. Blood : Anemia , thrombocytopenia
III. Congenital Rubella: (German measles)
 Congenital Rubella syndrome :
1. Ear: SNHL (Most common manifestation)
2. Eye: "cataract, glaucoma , iris hypoplasia , microphthalmia , Retinopathy “
3. CHD ( peripheral pulmonary artery stenosis 55% - PDA 43% )
4. CNS: Severe hypotonia or hypertonia
5. IUGR - LBW
6. GIT: Hepatosplenomegaly, Jaundice
7. Blood: Thrombocytopenia
8. Skin: Petechiae, ecchymosis
IV. Congenital CMV: “ most common congenital infection”
1. CNS : Intracerebral calcification ( periventricular ) + Microcephaly
2. Eye : “ Chorioretinitis , microphthalmia , optic atrophy , nystagmus , strabismus “
3. IUGR – LBW
4. GIT : Hepatosplenomegaly , jaundice
5. Blood : Thrombocytopenia, hemolytic anemia
6. Skin : Petechiae , Purpura
classic
triad

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V. Congenital Herpes simplex:
1. CNS : Seizures
2. Eye : Microphthalmia
3. CHD : PDA
4. GIT : Hepatomegaly, HSM
5. Skin : scarring vesicular rash
6. Bone : Osteitis + characteristic hypoplasia of distal phalanges.
7. Adrenal failure
VI. Congenital varicella zoster: ( Chicken pox )
1. CNS : Microcephaly , Hydrocephalus , cortical atrophy , intracranial calcification ,
Seizures , deafness , Sensory & motor deficits , psychomotor retardation
2. Eye : “ Chorioretinitis , cataract , microphthalmia , optic atrophy , anisocoria “
3. gastrointestinal & genitourinary anomalies
4. Skin : Scarring (cicatricial) lesions with characteristic "zigzag” pattern in a dermatome
distribution
5. Bone : Hypoplasia & paresis of an extremity “limb malformations and deformations “
VII. HIV/AIDS
1. CNS : Microcephaly
2. Abnormal facies (expression or appearance of face).
3. growth retardation
VIII. TB
1. Weight loss , Refusal to suckle
2. GIT : Hepatosplenomegaly
Q: What is the congenital infections cause brain calcification?
- most frequently observed in Toxoplasma (diffuse), CMV ( periventricular )
- occasionally in patients with congenital HSV infection
- rarely in patients with congenital rubella infection or congenital varicella

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Many of the findings of the TORCH infections are very similar,
so note the most likely presentations:
• Syphilis: osteochondritis and periostitis; skin rash involving palms and soles and is
desquamating; snuffles (mucopurulent rhinitis)
• Toxoplasmosis: hydrocephalus with generalized calcifications and chorioretinitis
• Rubella: the classic findings of cataracts, deafness, and heart defects
• CMV: microcephaly with periventricular calcifications; petechiae with thrombocytopenia
• Herpes: skin vesicles, keratoconjunctivitis, acute meningoencephalitis
• varicella Zoster: Scarring (cicatricial) Zigzag skin lesions

8. Teratogenicity
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2-Drugs & pharmaceuticals:
 Classification based on teratogenic potential :
Category Animal
studies
Human
Data
Examples
A   folic acid, thyroxin
B  ? acetaminophen, erythromycin
C  ? Rifampicin, morphine
D   antiepileptics
X   thalidomide, retinoid
(ACEIs, Antibiotics, Anticoagulants, Anticonvulsants, Thalidomide, vitamin A, corticosteroid,
Hormones, Aspirin, Chemotherapy, metronidazole)
- Theoretically, All drugs should be considered as possible teratogens during pregnancy, So
they should be limited to treat important maternal health conditions
 : NO risk  : risk ? : No adequate studies
Common teratogenic DRUGS :
Benefits > Risk
Risk > Benefit
Benefits > Risk

9. Teratogenicity
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I. ACE inhibitors: “ captopril , enalapril “
- If used during 2nd
and 3rd
trimester will Lead to:
1. PDA
2. Neonatal hypotension
3. Prematurity, IUGR
4. Renal failure
5. Oligohydramnios
6. Hypoplasia of skull
7. Deformation sequence
II. Antibiotics: (Streptomycin, Tetracycline, Trimethoprim)
a. Streptomycin & closely related aminoglycosides
- 10-15% SNHL “Ototoxicity”
b. Tetracycline
- Related to dose and duration of exposure
 If exposure after 4th
month gestation :
1. brown staining on deciduous teeth
2. increased caries
3. diminished growth of long bones
 if exposure later in pregnancy :
- may affect permanent teeth
c. Trimethoprim (folate antagonist)
 Used alone OR in combination with sulfonamides
1. Cardiovascular defects
2. Neural tube defects
3. Structural defects

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III. Anticoagulant: Warfarin “Coumadin“
1. Eye: Microphthalmia , hypertelorism , cataract , optic atrophy , blindness
2. Dysplastic ear
3. Characteristic Hypoplastic nose with deformed nasal cartilage & anteverted nares
4. Macroglossia
5. Hypoplasia of distal & proximal phalanx of index finger
6. Stippling of epiphysis of lumbosacral area & trochanters of femur
7. Short neck

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IV. Anticonvulsant: (phenytoin, Diazepam, Phenobarbital, Carbamazepine, valproic acid)
a. phenytoin “
"phenyl-hydantoin, Dilantin"
 Fetal hydantoin syndrome ( FHS )
1. Profuse coarse hair + hirsutism
2. Eye: Hypertelorism, strabismus, ptosis
3. Low set ear
4. Depressed nasal bridge
5. Wide mouth
6. Short neck
7. Small, widely spaced nipple
8. hypoplasia of nails & terminal digits
b. Diazepam "valium" “
- 1st
trimester exposure → ↑risk for cleft lip + palate

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c. Phenobarbital
- Probably low risk
- Very rarely features similar to FHS reported
 All anticonvulsants are teratogenic
but the anticonvulsant with least Teratogenicity is phenobarbitone
d. Carbamazepine "Tegretol"
 Phenotype similar to FHS
- CNS: Microcephaly
- Psychomotor delay
- Cardiac defects
- Eye: Upward slanting palpebral fissure, epicanthal folds
- Short nose
- Long philtrum
- Nail hypoplasia
- Prenatal & postnatal growth deficiency
e. valproic acid
"Depakene, Depakote" “
 29% Fetal valproic syndrome ( FVS ) :
1. CNS: neural tube defect
2. High forehead , Narrow bifrontal diameter head
“prominent metopic ridge “
3. Eye: Shallow orbits, Epicanthal folds , telecanthus
4. Ear: Minor ear anomalies
5. Flat nasal bridge, short anteverted nares
6. Long thin philtrum, thin upper lip
7. Small mouth “micrognathia“
8. IUGR
 Phenytoin has Similar features with carbamazepine and phenobarbital
 hypoplasia of distal phalanx Caused by :
( Diazepam, phenobarbitone, carbamazepine, phenytoin, Warfarin )

13. Teratogenicity
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V. Tranquilizer, psychotropics “thalidomide “→ Historical
► Effect only between 20-40 days after conception
1. Hydrocephalus
2. Renal & Cardiac anomalies “Tetralogy of Fallot”
3. Eye & ear defects
4. Facial capillary hemangioma
5. Phocomelia “Arms more affected than legs “
6. syndactyly, polydactyly
7. Esophageal or duodenal atresia
8. Normal psychomotor development
VI. Vitamin A
• Maximum Recommended dose during pregnancy : 8000 units per day.
• If used with megadose: > 15,000 units per day will cause:
1. Sirenomelia “anomalies of the lower spine and the lower limbs “
2. Genitourinary malformations.
3. Oculo-auriculo-vertebral sequences
VII. Corticosteroid
- 1% risk for cleft palate or adrenal atrophy
VIII. Hormones
a. oral contraceptive (combined progestogen and estrogens)
- 2 to 4 folds increase in VATER association.
 V = Vertebral defects
 A = Anal atresia (imperforate anus)
 TE = Tracheoesophageal fistula
 R = Renal & Radial defects “Limb defects“
b. Androgenic agents: "synthetic progestin"
- Used to establish pregnancy e.g. Ethisterone - Norethisterone
- But can lead to masculinization of female genitalia (virilization).

14. Teratogenicity
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IX. Acetyl salicylic acids : “ Aspirin “
- If used in 1st
trimester → cleft palate “ In a few percentages “
X. Chemotherapy
Methotrexate → Craniofacial and limb anomalies
XI. Antiparasitic agents & Antimalarials: “metronidazole”
- If used in 1st
trimester → may cause fetal malformations
- If used in 2nd
& 3rd
trimester → safe “acceptable “
XII. Lithium
- Ebstein Anomaly;
(Atrialization of the right ventricle → Huge Right atrium; tricuspid regurge)
3- physical, chemical & Environmental agents:
* Physical : Ionizing radiation – Hyperthermia
* Chemical : Alcohol – Tobacco “ Nicotine “ – Cocaine
* Environmental : Lead – Mercury – CO - pesticides - Toluene
a. Physical Agents
I. Ionizing Radiation
 With large doses for treating malignancy OR dose >10 rem
- Early loss of pregnancy
- Microcephaly
- spina bifida cystica
- Psychomotor retardation
- Eye anomalies, cataract
- Cleft palate
- Skeletal & visceral malformation

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II. Maternal hyperthermia
► Temperature: 38.9o
c or more; usually over 24 h period or more with inter-current
illness
► as minimal as 30-45 minutes in sauna or hot tub.
► Exposure between 4 and 14 weeks (1st
trimester) :
- IUGR
- psychomotor retardation
- Hypotonia, Seizures
- Microcephaly
- Neural tube defects “Encephalocele “
- Microphthalmia
- malformed ear
- micrognathia
- cleft lip + palate
- midfacial hypoplasia
b. Chemical Agents
III. Tobacco “Nicotine “
- passive or active → lapsing effect
- Dose-related IUGR
- Prematurity
- Fetal loss
- Neonatal death
IV. Cocaine
- Exposure occurs in up to 10% of all pregnancies
- Spontaneous abortions, prematurity
- Abruption placenta
- Exposure in 1st
trimester: 15.7 % Vascular disruption with associated porencephaly
- Gastrointestinal, Genitourinary, limb reduction defect
- Psychomotor retardation, Behavioral difficulties

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V. Alcohol (Ethyl alcohol )
 Fetal alcohol syndrome ( FAS ):
a. Growth
- prenatal and/or postnatal growth retardation
b. Facial deformities “ Midface hypoplasia “ (from abnormal frontal lobe development)
- Smooth philtrum
- Thin, smooth vermilion border of the upper lip
- Short palpebral fissures
- ptosis of eyelid
- microphthalmia
- Epicanthic folds
- flattened nasal bridge, Short upturned nose
- cleft lip ( + palate)
- Micrognathia in adolescence,
retrognathia in infancy
- protruding ears
c. CNS deformities
- Developmental delay
- Irritability in infancy
- Hyperactivity in childhood (ADHD)
- Mental retardation
- microcephaly
- meningomyelocele
- hydrocephalus
d. Cardiac deformities
- tetralogy of Fallot
- coarctation of aorta
e. Skeletal abnormalities (Neck deformities)
- cervical vertebral & rib abnormalities
- mild neck webbing
Characteristic

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c. Environmental Agents
VI. Toluene → glue sniffing
 Similar to Fetal alcohol syndrome with :
- prenatal and/or postnatal growth retardation
- Craniofacial deformities
- Microcephaly
- Psychomotor retardation
- Caudal regression sequence
“congenital defect of the lower spinal segments and the neural tube”
VII. Lead → “In old paints, water pipes “
- ↑ Abortion
- Anemia
- Neurological disorders: “encephalopathy, Abnormal development of brain, MR “
VIII. Mercury → “ In fish , seed corn sprayed with mercury containing fungicide “
- Multiple neurological Symptoms
IX. CO → “ Cigarette smoking , car exhaust , incomplete consumption of coal “
- Bind to Hb →  O2 supply to fetus → Hypoxia →
• Spontaneous abortion
• Still birth
• Growth retardation
• prematurity
X. Pesticides → used in parental agricultural work
- ↑ risk of fetal death

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4- Maternal disorders:
( DM – Hyper/Hypo thyroidism – SLE - PKU – Malnutrition)
• The outcomes depends on degree of control & severity of maternal disease
I. Diabetes mellitus
• Outcome varies with degree of control of maternal DM
• Type 1 “IDDM “ is higher at risk than type 2 “NIDDM “ or gestational
- ↑ risk for Early loss of pregnancy
- CHD : TGA ( 8% ) , hypertrophic cardiomyopathy
- Neural tube defect : anencephaly , spina bifida
- Hydrocephalus, holoprosencephaly
- Renal disorders: double ureter, renal vein thrombosis, renal agenesis
- Small left colon syndrome
- VATER association like findings
- Caudal regression sequence similar to sirenomelia sequence
II. Hyperthyroidism
- ↑ risk of loss of pregnancy especially with grave’s disease
- If Thyroid stimulating immunoglobulins (TSI) are present → fetal & neonatal
hyperthyroidism
 N.B. TSI bind with TSH receptors in thyroid glands → continuous ++ thyroid
hormone secretion “outside normal -ve feedback“→ Hyperthyroidism
- Treatment with Antithyroid drugs → fetal hypothyroidism
III. Hypothyroidism
- ↑ risk for loss of pregnancy
- N.B. fetal thyroid development independent of maternal thyroxin levels → Fetal &
neonatal thyroid development & function are NOT affected
IV. SLE
- Early loss of pregnancy
- Congenital heart block

19. Teratogenicity
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V. Phenylketonuria
• Outcome varies with degree of control of maternal phenylalanine levels in pregnancy
• High level of phenylalanine ( >20 mg/dl ) → serious damage to the fetus:
- Mental retardation (the most common finding)
- Psychomotor retardation
- Microcephaly
- CHD
- Spontaneous early miscarriage
- Prenatal onset growth deficiency
- Abnormal facies similar to FAS
VI. Malnutrition
a. vitamin A deficiency
- Anophthalmia
b. folic acid deficiency
- Neural tube defect
► Recommended dose to prevent it : 400 micrograms daily
c. Vitamin D deficiency
- Bone and teeth malformation
d. Calcium Ca
- Bone malformations
e. Potassium K
- Preterm labor
f. Iron
- Anemia

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 Causes of neural tube defect :
1. Trimethoprim (folate antagonist)
2. Sodium valproate
3. prolonged Maternal hyperthermia ( >38.9o
c )
4. Uncontrolled DM
5. Folic acid deficiency
 Treatable causes of mental retardation :
1. PKU
2. Galactosemia
3. Hypothyroidism
4. Craniostenosis
5. Congenital hydrocephalus
 Preventable causes of mental retardation :
1. Hypoglycemia
2. Hyperbilirubinemia
3. CP
What about Father ?
- When toxic substances affect sperm cells, the damaged sperm usually does Not survive
the journey to the egg
- Cocaine may disrupt the 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 & women
Home message
- Birth defects due to exposure to teratogens are preventable
- And their prevention is an important public health problem