What are the risks of Tretinoin (all-trans retinoic acid) use during pregnancy?

Tretinoin Embryopathy: Risks During Pregnancy

Tretinoin (all-trans retinoic acid) is absolutely contraindicated during pregnancy due to its high teratogenic potential, which can cause severe birth defects including craniofacial, central nervous system, cardiovascular, and skeletal malformations. 1

Teratogenic Effects

• Oral tretinoin has been conclusively shown to be teratogenic in multiple animal studies including rats, mice, hamsters, and subhuman primates 1
• The FDA classifies tretinoin as Pregnancy Category C, indicating that animal studies have shown adverse effects on the fetus, and there are no adequate and well-controlled studies in humans 1
• Tretinoin embryopathy includes a pattern of malformations affecting:
  • Craniofacial structures (high palate, microtia or absent external ears) 1, 2
  • Central nervous system (microcephaly, hydrocephaly, holoprosencephaly) 1, 3
  • Cardiovascular system (anomalies of great vessels) 3
  • Skeletal system (shortened or kinked tail, limb abnormalities, syndactyly, absence of terminal phalanges) 1

Risk Comparison with Related Compounds

• Isotretinoin (13-cis retinoic acid), a closely related compound, is associated with an estimated 20% risk of major fetal malformations with first-trimester exposure 4
• While topical tretinoin has shown less conclusive evidence of teratogenicity than oral forms, its similarity to isotretinoin warrants extreme caution 5, 6
• The risk appears highest during weeks 3-6 of gestation, which corresponds to critical periods of embryonic development 2

Clinical Management Guidelines

• Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, which is rarely if ever the case 1
• For women of childbearing potential:
  • Pregnancy must be excluded by negative pregnancy test within 2 weeks prior to starting therapy 2
  • Effective contraception must be practiced for at least 4 weeks before and during therapy 2
  • In the US, contraception is recommended for 3 years after discontinuation of acitretin (a related retinoid), while European guidelines mandate 2 years 2
• Patients should not donate blood either during or for at least 1 year following discontinuation of therapy 2

Monitoring and Alternatives

• For pregnant women with accidental exposure, comprehensive evaluation including detailed ultrasound examination is recommended to detect possible malformations 7
• For skin conditions typically treated with tretinoin:
  • Safer alternatives should be considered for pregnant women 2
  • Beta-carotene form of vitamin A is preferred over retinol during pregnancy 7
  • For acne treatment during pregnancy, avoid all retinoids including tretinoin 2

Special Considerations

• Although some small studies of topical tretinoin have not shown increased risk of major malformations 5, 6, the structural similarity to isotretinoin and the theoretical risk of systemic absorption make it prudent to avoid all forms of tretinoin during pregnancy 1
• The American Academy of Dermatology recommends discontinuing retinoids at least 1 month before attempting conception 7
• Even with risk management programs like iPLEDGE for isotretinoin, fetal exposures continue to occur, highlighting the importance of absolute avoidance of all retinoids during pregnancy 2