Teratogenicity

Thalidomide: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Cereblon protein binding → angiogenesis inhibition & cell death

characteristic fetal syndrome / defects: Phocomelia ("seal-like" flipper limbs), amelia, anotia, cardiac defects

Isotretinoin (Retinoids): Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Disruption of retinoic acid signaling in neural crest cells

characteristic fetal syndrome / defects: Retinoic Acid Embryopathy: Microtia, cleft palate, conotruncal heart defects, CNS malformations

Valproic Acid: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Folate antagonism + histone deacetylase (HDAC) inhibition

characteristic fetal syndrome / defects: Neural Tube Defects (Spina Bifida), craniofacial defects, cardiovascular anomalies

Phenytoin: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Oxidative stress via reactive epoxide intermediates

characteristic fetal syndrome / defects: Fetal Hydantoin Syndrome: Microcephaly, cleft lip/palate, hypoplastic nails/digits

Warfarin: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Inhibits Vitamin K epoxide reductase (VKORC1); impairs bone matrix proteins

characteristic fetal syndrome / defects: Fetal Warfarin Syndrome: Nasal hypoplasia, stippled epiphyses, microcephaly, optic atrophy

Tetracyclines: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Chelates calcium ions in mineralizing bone and teeth

characteristic fetal syndrome / defects: Permanent yellow-brown tooth discoloration, enamel hypoplasia, skeletal growth inhibition

ACE Inhibitors / ARBs: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Fetal renal ischemia due to loss of Angiotensin II-mediated efferent vasoconstriction

characteristic fetal syndrome / defects: Renal Dysgenesis, oligohydramnios, pulmonary hypoplasia, skull hypoplasia, neonatal renal failure

Methotrexate: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Competitive inhibition of Dihydrofolate Reductase (DHFR)

characteristic fetal syndrome / defects: Fetal Methotrexate Syndrome: Growth restriction, cranial ossification defects, limb anomalies

Lithium: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Disruption of phosphoinositide signaling during cardiac cardiac looping

characteristic fetal syndrome / defects: Ebstein’s Anomaly (downward displacement of the tricuspid valve into the right ventricle)

Diethylstilbestrol (DES): Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Synthetic estrogen binding to fetal reproductive tract receptors

characteristic fetal syndrome / defects: Clear Cell Adenocarcinoma of the v*gina/cervix in female offspring; T-shaped uterus

Ethanol (Alcohol): Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: Chronic cellular hypoxia, ROS formation, altered neural cell adhesion

characteristic fetal syndrome / defects: Fetal Alcohol Syndrome (FAS): Smooth philtrum, thin upper lip, microcephaly, severe cognitive deficits

Lithium: Primary mechanism, characteristic fetal syndrome / defects

Primary mechanism: PGE1 receptor activation → uterine contractions → focal vascular disruption

characteristic fetal syndrome / defects: Möbius Syndrome: Congenital facial paralysis (CN VI and VII cranial nerve palsies), limb reduction defects

Thalidomide

Historic catalyst for modern teratogenicity testing and drug safety regulations.

Isotretinoin (Retinoids)

Requires strict adherence to iPLEDGE (two negative pregnancy tests before initiation)

Valproic Acid

Highest risk of neural tube defects among all antiepileptic drugs (1-2% risk of spina bifida).

Phenytoin

Supplement with 4 mg/day Folic Acid and monitor therapeutic drug levels.

Warfarin

Crosses placenta easily. Replace with Heparin or LMWH in pregnancy

Tetracyclines

Contraindicated after the 4th month of gestation

ACE Inhibitors / ARBs

Toxic in 2nd and 3rd trimesters

Methotrexate

Potent abortifacient and teratogen.

Lithium

Perform fetal echocardiography at 18-20 weeks gestation.

Diethylstilbestrol (DES)

Delayed teratogenesis: Manifests decades later during reproductive age.

Ethanol (Alcohol)

#1 non-genetic cause of intellectual disability

Misoprostol

Used off-label for labor induction/abortion.