What are the effects of thalidomide (thalidomide) on pregnancy?

Thalidomide Causes Severe Birth Defects in Pregnancy

Thalidomide is a potent teratogen that causes severe birth defects when taken during pregnancy, most notably phocomelia (short limbs) and amelia (absence of limbs), along with other serious malformations affecting multiple organ systems. 1, 2

Major Teratogenic Effects

• Thalidomide causes severe limb malformations, particularly phocomelia (shortened limbs) and amelia (complete absence of limbs), which are the most characteristic defects 2, 3
• External ear abnormalities including anotia (absence of ears), micropinna, and small or absent external auditory canals 2
• Eye abnormalities including anophthalmos (absence of eyes) and microphthalmos (abnormally small eyes) 2
• Congenital heart defects affecting cardiac structure and function 2
• Alimentary tract, urinary tract, and genital malformations 2
• High mortality rate at or shortly after birth, affecting approximately 40% of exposed infants 2

Mechanism of Teratogenicity

• Thalidomide is a thalidomide analogue that binds to cereblon, which forms part of an E3 ubiquitin ligase complex essential for limb development 4
• This binding inhibits the function of the E3 ubiquitin ligase complex, leading to downregulation of fibroblast growth factor 8, a critical regulator of limb development 4
• The drug also has anti-angiogenic properties that may contribute to its teratogenic effects by disrupting normal blood vessel formation during embryonic development 5, 6

Historical Context

• Between 1958 and 1961, approximately 10,000 children worldwide were born with severe deformities after their mothers took thalidomide during pregnancy 7, 6
• Thalidomide was originally developed in 1954 as a sedative and was commonly prescribed to treat morning sickness in pregnant women 4
• This led to one of the biggest medical disasters in history and fundamentally changed drug safety testing and regulations 7
• Rodents are resistant to thalidomide's teratogenic effects, which contributed to the failure to detect its dangers before widespread use in humans 5

Critical Period of Exposure

• The first trimester is the most critical period for thalidomide exposure, particularly days 20-36 after conception when limb development occurs 1, 2
• Even a single dose during this critical window can cause severe malformations 2
• The specific malformations depend on the exact timing of exposure during embryonic development 5

Current Medical Use and Contraindications

• Despite its teratogenic effects, thalidomide is still used for treating conditions like multiple myeloma and erythema nodosum leprosum (leprosy complication) 2, 5
• Thalidomide is absolutely contraindicated during pregnancy due to its severe teratogenic effects 1
• Strict contraception is mandatory for patients of reproductive potential who are prescribed thalidomide 1, 2
• Pregnancy testing and effective contraception are required for patients taking thalidomide or related drugs 2

Comparison to Other Teratogens

• Thalidomide is considered one of the most potent human teratogens known 1, 6
• Unlike some other teratogens that may have dose-dependent effects, even small amounts of thalidomide during critical periods can cause severe malformations 2
• The pattern of malformations caused by thalidomide (particularly the limb defects) is highly characteristic and distinguishable from other causes of birth defects 3

Clinical Implications

• Healthcare providers must be vigilant about avoiding thalidomide in pregnant women or women who may become pregnant 1, 2
• When thalidomide is medically necessary for non-pregnant patients, strict pregnancy prevention programs must be implemented 2
• For cancer patients who become pregnant, thalidomide and related drugs (lenalidomide, pomalidomide) must be avoided throughout pregnancy 1
• If pregnancy occurs during thalidomide treatment, the drug should be immediately discontinued and the patient referred to specialists in reproductive toxicity 2