Medications with Proven Teratogenic Effects in Humans

Alkylating agents

- Malformations of many different organs
- Organogenesis

Amiodarone

- Transitory hypothyroidism (risk of 17%, goiter in some cases) or transitory hyperthyroidism
- From 12th week after LMP

Androgens (danazol, testosterone)

- Masculinization of genital organs in female fetus
- From 9th week after LMP

Angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists

- Renal failure, anuria, oligohydramnios (low amniotic fluid), pulmonary hypoplasia, intrauterine growth restriction, limbs contracture, skull hypoplasia
- After the first trimester

Anticonvulsants (first generation)

- NTD (carbamazepine and valproic acid); oral cleft, skeletal, urogenital craniofacial, digital, and cardiac malformations
- Organogenesis for structural anomalies

Carbamazepine, Phenytoin Phenobarbital, Valproic acid, divalproex

- Major malformations: up to 5%-10% depending on the agent used, with variation with dosage used (10%-15% or more for valproic acid).
- Valproic acid: abnormal neurologic development
- Valproic acid: whole pregnancy for neurologic impairment

Corticosteroids

- Oral cleft (risk of 3-4/1000 vs 1/1000 in general population)
- Organogenesis (most critical period for palate formation: 8 and 11 weeks after LMP)

Diethylstilbestrol

- Girls: cervical or vaginal adenocarcinoma, incidence: 1/1000. Structural genital anomalies (eg, of cervix, vagina)
Boys: genital anomalies, spermatogenesis anomalies
- First and second trimesters

Fluconazole high doses

- Skeletal and craniofacial malformations, cleft palate, cardiac anomaly (with chronic dose ≥ 400 mg/day, not reported with 150 mg single dose
- Not defined, but cases are reported where exposure was throughout pregnancy

Iodine (supraphysiologic dosage)

- Hypothyroidism, goiter
- From 12th week after LMP

Isotretinoin

- Other systemic retinoids (acitretin, bexarotene, etretinate), and high dose of vitamin A (vitamin A > 10,000 IU/day not recommended)
- Spontaneous abortion, CNS, skull, eyes and ears malformations, micrognathia, oral cleft, cardiac malformations, thymus anomalies, mental retardation: estimated risk at 25%-30% (may be higher for neurologic development impairment)
- Isotretinoin and bexarotene, discontinue 1 month before pregnancy, isotretinoin prescribed under a special program called IPLEDGE
- Acitretin: discontinue 3 years before pregnancy
- Organogenesis (risk of teratogenic effect after organogenesis not excluded)

Lithium

- Cardiac malformations: risk of 0.9%-6.8% (higher risks in small studies) (baseline risk-1%)
- Includes Ebstein anomaly
- Cardiac organogenesis (5-10 weeks after LMP)

Methimazole/propylthiouracil

 - Aplasia cutis (absence of skin), choanal atresia, esophageal atresia , omphalocele, minor facial anomalies, growth delay; risk of 2%-4%
- Fetal hypothyroidism in 1%-5% of newborns, goiter
- Organogenesis

Methotrexate

- Spontaneous abortion, CNS, and cranial malformations (large fontanelles, hydrocephalia, incomplete cranial ossification, craniosynostosis), oral cleft, ear, skeletal and limb malformations, mental retardation; discontinue at least one ovulatory cycle before pregnancy
- Organogenesis (8-10 weeks after LMP for structural anomalies but some exceptions reported)

Misoprostol

 Moebius syndrome ± limb anomalies ± CNS anomalies Abortion, preterm birth
- Organogenesis. Throughout pregnancy for abortion/preterm birth

Mycophenolate mofetil, mycophenolic acid

- Anomalies including ear anomalies, oral cleft, micrognathia, ophthalmic, cardiac, and digital anomalies (risk of structural anomalies estimated from 20%-25%); spontaneous abortion (30%-50%)
- Organogenesis (risk unknown after)

Nonsteroidal anti-inflammatory drugs

- In utero closure of ductus arteriosus (constriction is rare before 27 weeks, 50%-70% at 32 weeks [GA]) and neonatal pulmonary hypertension
- Renal toxicity and oligohydramnios possible after prolonged use from second half of second trimester from 20 weeks of gestational age
- Third trimester

Penicillamine

- Cutis laxa (loose skin) Joints and CNS anomalies; Risk probably low
- Not defined

Tetracycline

- Teeth discoloration
- From 16 weeks after LMP

Trimethoprim

- Cardiac and urogenital malformations, NTD, oral cleft, overall risk probably < 6%
- Organogenesis

Warfarin/acenocoumarol

- Before 6 weeks: baseline risk of anomalies
- Taken between 6 and 12 weeks: nasal hypoplasia, epiphysis dysplasia, vertebral malformations, rarely ophthalmic anomalies, scoliosis, hearing loss; risk estimated of 6%-10% and possibly dose-dependent 12 weeks after LMP: rarely, heterogeneous CNS anomalies