Teratogens😍

Teratogens

Most teratogenic period :

Embryonic period 2 wks to 8 wks after fertilization.

Miscellaneous Teratogens

Teratogens	Features
Methotrexate	Clover leaf skull
Sulfanamides	Binds to albumin → Kernicterus'
Indomethacin (> 32 weeks)	PDA → PAH
Misoprostol	Mobius (CN 6, 7)

Pregestational Diabetes

Formation of free radicals Placenta Congenital malformations.

Congenital Malformation in Diabetes

m/c system involved: CVS > CNS

Hairy Pinna

m/c congenital malformation:

VSD > neural tube defect (NTD)

Most specific:

Sacral agenesis/
Caudal regression syndrome

Most severe → Sirenomelia

m/c CVS anomaly: VSD

Most specific CVS anomaly (does not resolve after delivery):

Transposition of Great Arteries (TGA)

m/c CVS finding or lesion (reversible after delivery):

Hypertrophic Cardiomyopathy (HCM)

Ix :

Risk Predictor : HbA1c.

<6.5% No additional risk.
≥6.5% ↑Risk.

Screening : Level 1 USG.

IOC to detect gross congenital anomalies : Level 2 USG.

Note :

Gestational diabetes → Congenital malformations absent.

SLE and Congenital Heart Block

Maternal antibodies involved:

Anti-Ro (SSA)
Anti-La (SSB)

These antibodies cross placenta.

Cause fetal heart damage → leads to congenital heart block.

Radiation

Exposure ≥5 rads.

The recommended thickness of the lead apron to prevent radiation exposure is >0.5mm.

Teratogenic effects :

Microcephaly (M/c).

Growth restriction.

Neurological impairment.

Risk of cancer : Leukemia (M/c).

Fatal dose (≥10 rads exposure).

Mnemonic :

5 Mal growth M Microcephaly L Leukemia Growth restriction p
10 yr death

Accidental X-ray in pregnancy : Not an indication for MTP.

All or none law :

First 2 weeks after fertilization → either

Abortion

Normal fetus

No chance of congenital malformations

Teratogenic Drugs

Alcohol

Fetal Alcohol Syndrome (FAS)

Growth restriction
Abnormal facial features:

Smooth philtrum
Thin vermilion border

Small epicanthal folds

Abnormal brain development: microcephaly
Abnormal behavioral development: cognitive impairment
Mnemonic: Goa's famous beer bar

Phenytoin

Fetal hydantoin syndrome

Midfacial hypoplasia
Upturned nose
Distal digital hypoplasia
Cardiac defects

Cleft Lip/ Cleft Pallet

Bleeding risk in newborn

Neuroblastoma,

Vit K deficiency,

microcephaly,

NTD

HHHHH → Hirsutism, Hypertrophy of gums, Hydantoin syndrome, Hyperglycemia, Hemorrhagic disease of Newborn

Adverse Effects	Details
H - Hirsutism, Hypertrophy of gums	ㅤ
O - Osteomalacia	ㅤ
T - Teratogenicity	Fetal Hydantoin syndrome, Facial clefts
M - Megaloblastic Anemia	↓ Folate
A - Arrhythmia	Only in overdose
L - Lymph node enlargement Pseudolymphoma	ㅤ
I - ↓ insulin	Avoided in DM
K - ↓ Vitamin K	Increased bleeding in the newborn due to ↓Vit K.
A - Ataxias, vertigo	Overdose

ACE Inhibitors/ARBs

Oligohydramnios (2nd trimester)

Renal agenesis

Lithium

Ebstein anomaly

Apical displacement of tricuspid valve

Tricuspid regurgitation
Right atrial enlargement

Neonate:

Floppy baby syndrome,
diabetes insipidus,
hypoglycemia

Retinoid Syndrome in Foetuses (Retinoid Embryopathy)

Isotretinoin

Microtia/Anotia

Cause: Use of synthetic vitamin A derivatives during pregnancy.

1. Craniofacial abnormalities

Small or malformed ears

Cleft palate

Facial asymmetry

2. Central nervous system defects

Hydrocephalus

Microcephaly

3. Cardiac abnormalities

Ventricular septal defects (VSD)

Transposition of the great arteries (TGA)

4. Limb abnormalities

Missing or malformed fingers, toes, or limbs

5. Visual system abnormalities

Small or absent eyes (microphthalmia)

Cataracts

Optic nerve abnormalities

Phocomelia

Thalidomide

Phocomelia (Proximal limb amputation)

Stillbirth

Q. A baby was born with the limb defects shown in the picture below. There is a history of thalidomide ingestion by the mother during her pregnancy. The probable diagnosis is?

Limbs resemble flippers of a seal.

Maternal intake of thalidomide during pregnancy is a risk factor.

Short proximal segments of limbs.

Warfarin → Fetal Warfarin Syndrome

Disala syndrome

Chondrodysplasia
Stippled epiphysis
Nasal hypoplasia
CNS: Corpus callosum agenesis, microcephaly
Cataract

Mnemonic: War (Warfarin) nu poya Michel (Microcephaly) and salar (Disala Syndrome) nu idi kitti mookilum (Nasal hypoplasia) bone (Stipled epiphysis) ilum cartilage (Chondrodysplasia) ilum and killed his cat (Cataract)

Methotrexate

Craniosynostosis (Clover leaf skull)

Tamoxifen (SERM)

Similar to DES

Vaginal adenosis
Craniofacial defects
Ambiguous genitalia
Mother: Endometrial cancer

Note: Minimum time gap between stopping tamoxifen and pregnancy

2 months (ideal: 3 months)

Misoprostol

Moebius syndrome (6th & 7th nerve palsy)

Limb reduction defects.

Mnemonic : Moshoby ; Mismobei (Misoprostol , Mobeius syndrome )

Indomethacin

Premature closure of ductus arteriosus (>32 weeks)

Oligohydramnios

Chloramphenicol

Gray baby syndrome

General Teratogenic Considerations

Distal Digital Hypoplasia/Amputation

Phenytoin
Amniotic band syndrome

Hyperpyrexia in Pregnancy

Microcephaly
NTD
Intellectual disability

Teratogenic Infections

Congenital Syphilis

Follows Kassowitz Law:

If a woman with untreated syphilis has multiple pregnancies:

Risk of fetal infection decreases in later pregnancies.

Not associated with recurrent abortion.

Example in Sequence

1st: Miscarriage at 5th month
2nd: Stillbirth at 8th month
3rd: Congenital syphilis infant who dies in few weeks
4th & 5th: Congenital syphilis infants who survive
Later: 1 or more healthy children may be born

Associated with:

Stillbirth
Polyhydramnios
Hydrops fetalis
Fetal anemia

Mnemonic : S(Still birth) yp(Polyhydramnios) h(Hydrops fetalis)ilis

Varicella Zoster

Congenital Varicella

Teratogenic period:

Infected in 1st trimester

0.4% of babies

2nd trimester → 12-20 weeks (after 3 months till 5 months end)

2% of babies
Congenital / Fetal Varicella Syndrome

Indication for MTP

Clinical features

Cicatricial scarring in zoster like or

Dermatomal distribution around umbilicus.

Limb hypoplasia.

Low birth weight.

CNS involvement:

Microcephaly,
developmental delay,
intellectual disability,
seizures.

Eye involvement:

Chorioretinitis,
cataract,
microphthalmia (small eye).

Renal involvement:

Hydronephrosis.

Autonomic dysfunction:

Swallowing dysfunction,
neurogenic bladder.

Diagnosis of congenital varicella infection

history of varicella during pregnancy.

clinical features in a baby.

Anti-varicella IgM in a baby.

Neonatal Varicella Syndrome

Pregnant female acquires infection 5 days before to 2 days after delivery

Features

Hepatitis
Pneumonia
Skin rash
Meningoencephalitis

Treatment :

Give VZIG
IV Acyclovir to child

For mother :

Oral Acyclovir

Rubella

Congenital rubella syndrome.

Risk of transmission ↑↑↑ → if earliest before 11 weeks of gestation

Least r/o perinatal transmission

Virus excretion → saliva, urine

Mnemonic : Rubee → Blue bee( Blueberry rash)

Sitting in salt and pepper (Salt & Pepper Fundus)
Shiny Pearly eyes → Nuclear pearly cataract
Can't see (Small eyes) can't hear (SNHL) also had some heart disease.
adich Padam (PDA) aakki

Triad of Gregg

PDA
Cataract
SNHL

Complications

Congenital heart diseases:

Most common: Patent Ductus Arteriosus > PS

Least common: Atrial Septal Defect.

Sensorineural hearing loss.

Blueberry muffin lesion:

Bluish red nodular lesions

characteristic of congenital rubella.

Microcephaly, IUGR.

Glaucoma.

Hepatosplenomegaly.

Jaundice.

Thrombocytopenia.

Key Ocular Manifestations:

Congenital nuclear cataract

Nuclear Pearly Cataract
Most common cataract in CRS

Micro-ophthalmos

abnormally small eyes

Salt & Pepper Retinopathy

NOTE:

Salt & Pepper Fundus

Mnemonic: Salt and pepper movie

Ruby (Rubella) → a Star (Stargardts)
Rough (Refsum) Labor (Lebers) who has Syphillis (CS) Raped (RP → Retinitis Pigmentosa) her → got Rid (Thioridazine) of body

Thio Ridazine :

Thio Ridazine → rid of
Brown (Brown vision) Cuteee (QT prolongation) with colorful eyes (RP),

like Salt and Pepper () movie

but ejaculated retrograde ()

Diagnosed by:

Presence of IgM rubella antibodies in the infant shortly after birth
(since IgM does not cross the placenta)
Persistence of IgG antibodies for >6 months
(maternally derived antibody would have disappeared)

Zika

Vector borne teratogen (Aedes mosquito)

Associated with receptors:

TIM 1
TAM-XL

Features:

Microcephaly
Increased limb tone
Club foot

Chicken Tikka (Zika) from Zam Zam (TIM TAM) Club (Club foot)

Pathogen	Transmission	Clinical Features in Fetus/Neonate	Management
Toxoplasmosis	Transplacental	Chorioretinitis, hydrocephalus, intracranial calcifications	Spiramycin for mother; pyrimethamine + sulfadiazine for neonate
Rubella	Transplacental	Congenital rubella syndrome (cataracts, deafness, PDA)	Vaccination pre-pregnancy
Parvovirus B19	Transplacental	Fetal anemia, hydrops fetalis	Intrauterine transfusion if severe
Syphilis	Transplacental	Hepatosplenomegaly, rash, osteochondritis, snuffles	Penicillin for mother and neonate
Zika	Transplacental	Microcephaly, brain defects	Supportive care; mosquito prevention
CMV	Transplacental, perinatal (breast milk)	Sensorineural hearing loss, microcephaly, hepatosplenomegaly	Ganciclovir/valganciclovir for symptomatic neonates
HSV	Perinatal (90%), transplacental (10%)	Skin/eye/mouth disease, CNS disease, disseminated disease	Acyclovir for neonate; C-section if active lesions
HIV	Perinatal (major), transplacental (rare)	Immunosuppression, opportunistic infections	Antiretroviral therapy (ART) for mother; prophylaxis for neonate
GBS	Perinatal	Early-onset sepsis, pneumonia, meningitis	Intrapartum ampicillin/penicillin
Hepatitis B	Perinatal (major), transplacental (rare)	Chronic hepatitis, liver disease	HBIG + vaccine for neonate

TERATOGEN	ASSOCIATED BIRTH DEFECTS/EFFECTS	NOTES
MEDICATIONS	ㅤ	ㅤ
Vitamin A (Toxicity)	Acute toxicity:	Pseudotumor cerebri, Exfoliative dermatitis, Hepatomegaly.
ㅤ	Chronic toxicity: (>50,000 IU/d)	Bony exostoses, Hepatomegaly (Cirrhosis) Calcinosis
ㅤ	Pregnancy:	Teratogenic
Vitamin D	Supravalvular Aortic Stenosis	ㅤ
Statins	VACTERAL Vertebral Anal Cardiac Tracheoesophageal fistula Renal arterial Limb defects	Vaccine Stat
ACE inhibitors/ARBs	Renal failure, oligohydramnios, Hypoplasia of organs, hypocalvaria, Oligohydramnios in 2nd trimester, Renal agenesis	Teratogenicity. C/I in pregnancy.
Alkylating agents	Ear/facial abnormalities, absence of digits	ㅤ
Aminoglycosides	Ototoxicity	"A mean guy hit the baby in the ear.". C/I in pregnancy.
Valproate	Neural tube defects. Spina Bifida Autism spectrum Disorder Coarctation of aorta AS, VSD Pulmonary Atresia	Max teratogenic risk. Category D (Teratogenic risk + Used in pregnancy, Benefit > Risk).
Carbamazepine	Neural tube defects, cardiac defects, cleft palate, skeletal abnormalities.	High-dose folate
Phenytoin	Facial clefts. Fetal hydantoin syndrome: Midfacial hypoplasia, upturned nose, distal digital hypoplasia ± cardiac defects.	High-dose folate
Phenobarbital	Neural tube defects, cardiac defects, cleft palate, skeletal abnormalities.	High-dose folate supplementation Used for seizures in neonates.
Chloramphenicol	Gray baby syndrome	ㅤ
Clarithromycin	Embryotoxic
Penicillamine	Cutis Laxa Syndrome	ㅤ
Diethylstilbestrol (DES)	Vaginal clear cell adenocarcinoma, Congenital Müllerian anomalies. M/c malignancy a/w DES: - Clear cell cancer of cervix and vagina. M/c uterine malformation a/w DES: - Hypoplastic uterus. Most specific uterine malformation a/w DES: - T shaped uterus. Similar effects to Tamoxifen: vaginal adenosis, craniofacial defects, ambiguous genitalia.	Now discontinued. DES exposure does not lead to renal anomalies in female fetuses. Category VII uterine malformation.
Progesterone	Masculanization of female fetus	ㅤ
Fluoroquinolones	Cartilage damage.	C/I during pregnancy or breastfeeding and in children < 18 years old. Inhibits prokaryotic enzymes topoisomerase II (DNA gyrase) and topoisomerase IV.
Folate antagonists	Neural tube defects	ㅤ
Indomethacin	Premature closure of ductus arteriosus.	ㅤ
Isotretinoin	Craniofacial (eg, microtia, dysmorphism), CNS, cardiac, and thymic defects. Microtia/Anotia.	Contraception mandatory. Pronounce “isoteratinoin” for its teratogenicity.
Methimazole	Aplasia cutis congenita (congenital absence of skin, typically on scalp). Choanal/Esophageal teratogenicity.	C/I in 1st trimester DOC for Hyperthyroidism overall & 2nd/3rd Trimester. - Inhibits thyroid peroxidase.
Spironolactone	Can affect external genitalia of a male fetus.	Antiandrogenic OCPs are added when used for female hirsutism.
Sulfonamides	Kernicterus in infants. Hemolysis if G6PD deficient.	ㅤ
Tamoxifen (SERM)	Similar to DES: vaginal adenosis, craniofacial defects, ambiguous genitalia. Can cause endometrial cancer in mother.	Minimum time gap between stopping and pregnancy: 2 months (Ideal: 3 months)
Lithium	Ebstein anomaly. Neonate effects: Floppy baby syndrome, diabetes insipidus.	ㅤ
Misoprostol	Moebius syndrome (6th & 7th nerve palsy).	Used with mifepristone for pregnancy termination or abortion. PGE1-synthetic analog.
Methotrexate	Neural tube defects (as folate antagonist). Craniosynostosis: Clover leaf skull.	Folate deficiency Used in ectopic pregnancy/medical abortion.
Tetracyclines	Discolored teeth, inhibited bone growth. Fanconi syndrome (with expired tetracyclines).	Pronounce “teethracyclines”.
Carbimazole/Methimazole	Choanal Atresia Aplasia CUtis TEF Fetal Goitre	ㅤ
Thalidomide	Limb → Phocomelia → flipper like limbs). Stillbirth.	Pronounce “thalimbdomide”. Pregnancy Category X (High Risk > Benefit).
Trimethoprim	Neural tube defects	ㅤ
Warfarin	DiSala syndrome: • Chondrodysplasia, Stippled epiphysis, Nasal hypoplasia, limb hypoplasia, Mid facial hypoplasia. Optic nerve atrophy, Cataract. CNS defects: Corpus callosum agenesis, microcephaly, cerebral hemorrhage.	Only indication in pregnancy: • Mechanical valve replacement. VKOR inhibitor.
INFECTIONS	ㅤ	ㅤ
Rubella	Classic triad: chorioretinitis, hydrocephalus, and intracranial calcifications, +/− “blueberry muffin” rash PDA, pulmonary artery stenosis, septal defects.	Congenital rubella. Maternal: • Rash, lymphadenopathy, polyarthritis, polyarthralgia.
Syphilis	Stillbirth.	• TORCH infection. • Follows Kassowitz Law. • Not a/w recurrent abortion.
Toxoplasma gondii	Classic triad: chorioretinitis, hydrocephalus, and intracranial calcifications, +/− “blueberry muffin” rash	ㅤ
Varicella Zoster	Stillbirth, Polyhydramnios, Hydrops fetalis, Fetal anemia.	Teratogenic period: 12-20 weeks.
SUBSTANCES	ㅤ	ㅤ
Alcohol	Fetal alcohol syndrome: • Developmental delay, Intellectual disability • microcephaly, • facial abnormalities (smooth philtrum, thin vermillion border, small palpebral fissures, flat nasal bridge), • limb dislocation, • Holoprosencephaly may occur. Heart defects: • VSD, PDA, ASD, tetralogy of Fallot.	ㅤ
Cocaine	Preterm birth, low birth weight, fetal growth restriction (FGR).	Vasoconstriction mechanism.
Tobacco smoking	Preterm birth, low birth weight (leading cause in resource-rich countries), FGR, sudden infant death syndrome (SIDS), ADHD.	Nicotine -> vasoconstriction, CO -> impaired O2 delivery mechanisms.
OTHER EXPOSURES	ㅤ	ㅤ
X-rays	Microcephaly, intellectual disability. Teratogenic exposure, Abortion (with fetal dose ≥10 rads).	Effects minimized by use of lead shielding.
Pregestational Diabetes	M/c system involved: CVS > CNS. M/c congenital malformation: VSD > NTD. Most specific malformation: Caudal regression syndrome/Sacral agenesis. Most specific cardiac malformation: Transposition of great arteries.	Formation of free radicals in placenta mechanism.

MANAGEMENT NOTES

High-dose folate supplementation is recommended when using antiepileptic drugs (valproate, carbamazepine, phenytoin, phenobarbital).

For females on Warfarin who are or plan to be pregnant, the only indication is mechanical valve replacement.

Management involves switching anticoagulants (Warfarin, LMWH, UFH) based on the period of gestation and Warfarin dose.
Heparin does not cross the placenta.

Minimum time gap between stopping Tamoxifen and pregnancy is 2 months (Ideal: 3 months).

William Syndrome

Chromosome 7 micromutation

Elastin Mutation

Results in Williams syndrome

Overfriendly

HyperCalcemia

Elfian facies

Leads to Supravalvular aortic stenosis

Differential BP

Right arm BP > Left arm Bp > Lower Limb

ㅤ	Williams syndrome	Marfan syndrome
Mutations	Elastin Mutation	Fibrillin Mutation
Leads to	Supravalvular aortic stenosis	Dilatation of aortic root ↳ Rupture → Death

ㅤ	ㅤ
Supravalvular AS	• Vitamin D toxicity • William syndrome
Supravalvular PS	• Noonan syndrome

ㅤ	Seen in
GNAS	• Mccune Albright • Cardiac Myxoma
GNAS 1	• Pseudohypoparathyroid/ Albright Hereditary Osteodystrophy
GNAQ	• Sturge Weber (Sporadic)