What are examples of teratogenic drugs that pregnant women or women of childbearing age should avoid?

Teratogenic Drugs: Examples and Clinical Guidance

Pregnant women and women of childbearing potential must avoid specific medications with established teratogenic effects, including valproate, warfarin, lithium, isotretinoin, mycophenolate mofetil, ACE inhibitors/ARBs, streptomycin, thalidomide, and methotrexate, as these drugs cause serious structural birth defects and developmental abnormalities.

Established Teratogenic Medications by Category

Anticonvulsants

• Valproate (valproic acid): Causes neural tube defects, decreased IQ in exposed children, and multiple congenital anomalies; contraindicated in pregnancy and requires effective contraception in women of childbearing potential 1
• Phenytoin, carbamazepine, phenobarbital: Associated with congenital anomalies, particularly at higher doses and with polytherapy; monotherapy at lowest effective dose is preferred when anticonvulsants are necessary 2

Anticoagulants

• Warfarin: Causes warfarin embryopathy with characteristic facial and skeletal abnormalities, CNS malformations, and fetal death; absolutely contraindicated during pregnancy 3, 2
• Direct oral anticoagulants (DOACs): Limited human data but animal studies show placental transfer; should be avoided due to potential fetal bleeding risk 2

Cardiovascular Medications

• ACE inhibitors and ARBs: Cause fetal renal anomalies, oligohydramnios, fetal death, and neonatal renal failure; must be discontinued before conception 2
• Atenolol: Associated with lower birth weight and should be avoided 2

Dermatologic Agents

• Isotretinoin: Highly teratogenic causing craniofacial, cardiac, thymic, and CNS malformations; associated with miscarriage; requires strict contraception and pregnancy prevention programs 2

Immunosuppressants

• Mycophenolate mofetil: Teratogenic and must be stopped at least 12 weeks before conception 2
• Methotrexate: Folate antagonist causing neural tube defects and multiple malformations; contraindicated in pregnancy 4

Antimicrobials

• Streptomycin: Documented to cause eighth nerve damage resulting in congenital deafness in 17% of exposed infants (ranging from mild hearing loss to bilateral deafness) 2
• Kanamycin, amikacin, capreomycin: Presumed to share ototoxic potential with streptomycin 2
• Fluoroquinolones: Associated with arthropathies in young animals; should be avoided if possible 2

Psychiatric Medications

• Lithium: Pregnancy Category D; associated with cardiac malformations (particularly Ebstein's anomaly); requires discontinuation and physician contact if pregnancy occurs 5

Endocrine Medications

• Methimazole: Possible teratogenicity in first trimester; propylthiouracil is preferred in first trimester, then switch to methimazole in second/third trimesters 2

Other Medications

• Thalidomide: Classic teratogen causing severe limb reduction defects (phocomelia) and multiple organ malformations 2
• Leflunomide: Teratogenic; requires washout period before conception 6

Teratogenic Mechanisms

The following mechanisms explain how medications cause birth defects 4:

• Folate antagonism: Methotrexate, trimethoprim, some anticonvulsants interfere with folate metabolism essential for neural tube closure 4
• Neural crest cell disruption: Isotretinoin, valproate affect neural crest migration causing craniofacial and cardiac defects 4
• Endocrine disruption: Methimazole, ACE inhibitors alter hormonal pathways affecting organ development 4
• Vascular disruption: Misoprostol, cocaine cause vascular insufficiency leading to tissue necrosis 4
• Oxidative stress: Phenytoin generates reactive oxygen species damaging developing tissues 4

Critical Timing Considerations

• Preimplantation period (0-4 weeks from last menstrual period): All-or-none effect—either miscarriage or complete recovery without malformation 2
• Organogenesis (4-8 weeks embryonic age, 6-10 weeks gestational age): Highest risk period for structural malformations 2
• Continued development (up to 20-22 weeks): Brain, genitalia, and palate remain vulnerable 2
• After 22 weeks: Risk of gross structural abnormality rare, but fetal toxicity and organ dysfunction remain concerns 2

Medications with Reassuring Safety Data

Generally Safe Throughout Pregnancy

• Acetaminophen: Safest analgesic option throughout pregnancy 7
• Penicillins and cephalosporins: Safe antibiotic options 2
• Insulin: Preferred for diabetes management 2
• Inhaled corticosteroids and beta-agonists: Safe for asthma control; budesonide and beclomethasone preferred 2
• Azathioprine, cyclosporine, tacrolimus, prednisolone: Should not be stopped in transplant recipients 2

Safe with Timing Restrictions

• NSAIDs (ibuprofen, diclofenac): Safe in first and second trimesters but must be discontinued after 28-32 weeks due to risk of premature ductus arteriosus closure and oligohydramnios 8

Common Pitfalls and Clinical Caveats

• Antidepressants (SSRIs): Despite concerns, converging evidence suggests observed associations between prenatal antidepressant exposure and neurodevelopmental problems (ASD, ADHD) are largely due to confounding factors rather than causal effects; untreated maternal depression poses significant risks 2
• Combination therapy: Multiple medications utilizing similar teratogenic mechanisms may have additive effects even if individually considered lower risk 4
• Timing of exposure: The same drug may cause different defects depending on gestational age at exposure 2
• Dose-response relationship: Higher doses and polytherapy increase malformation risk for anticonvulsants 2

Preconception Counseling Algorithm

1. Identify all current medications and assess teratogenic potential 2
2. Discontinue known teratogens with adequate washout period (mycophenolate: 12 weeks minimum) 2
3. Switch to pregnancy-compatible alternatives when chronic treatment is necessary 2
4. Optimize disease control before conception to minimize need for medication adjustments during pregnancy 2
5. Ensure effective contraception until medication regimen is optimized 1
6. Provide folate supplementation (at least 0.4-1 mg daily, higher doses for anticonvulsant users) 2