What drug is absolutely contraindicated in pregnancy and why?

Drugs Absolutely Contraindicated in Pregnancy

Isotretinoin (Accutane) is absolutely contraindicated in pregnancy due to its severe teratogenic effects, causing major malformations in approximately 20% of exposed fetuses, including craniofacial, cardiac, central nervous system, and skeletal abnormalities. 1, 2

Why Isotretinoin is Absolutely Contraindicated

Teratogenic Mechanism and Malformations

• Isotretinoin causes multiple severe birth defects when used between weeks 3-6 of gestation, affecting skeletal and craniofacial bones, the central nervous system, and auditory, ocular, and cardiovascular systems 3
• The drug is FDA Pregnancy Category X, meaning the risk of use outweighs any possible benefit 1
• First trimester exposure carries an estimated 20% risk of major fetal malformations 2
• Specific abnormalities include renal dysgenesis, cardiac defects, thymic abnormalities, and neural tube defects 1

Strict Contraceptive Requirements

• Women must use two forms of effective contraception simultaneously for at least one month before, during, and one month after isotretinoin therapy 1
• Pregnancy testing is mandatory before initiation and monthly during treatment 1
• The iPLEDGE risk management program requires enrollment and monthly compliance verification 1
• Prescriptions must be obtained within 7 days of a negative pregnancy test 1

Duration of Contraindication

• Women who wish to become pregnant after discontinuing isotretinoin should wait at least 3 years after completion of treatment 3
• This extended waiting period is due to potential spontaneous transformation of acitretin (a related retinoid) into etretinate, which has a half-life of 168 days 3
• Alcohol ingestion promotes conversion to the longer-acting metabolite, though the exact amount needed is unknown 3

Other Drugs Absolutely Contraindicated in Pregnancy

Acitretin (Retinoid for Psoriasis)

• Acitretin is FDA pregnancy category X and absolutely contraindicated in women who plan to become pregnant or who do not use sufficient contraception 3
• Multiple malformations occur particularly if used between weeks 3-6 of gestation 3
• Requires 3-year waiting period before attempting pregnancy after discontinuation 3

Methotrexate

• Methotrexate is absolutely contraindicated in pregnancy and must be discontinued at least 6 months before conception due to its long half-life 3
• The drug interferes with organogenesis and causes major congenital anomalies 3
• Women considering conception should be off methotrexate for 3 months before attempting to conceive 3

ACE Inhibitors and ARBs

• ACE inhibitors and ARBs are absolutely contraindicated during the second and third trimesters of pregnancy 3, 4
• These medications cause fetal renal dysgenesis, oligohydramnios due to fetal oliguria, neonatal anuric renal failure, intrauterine growth retardation, pulmonary hypoplasia, and fetal death 3
• Should be stopped as soon as possible in the first trimester to avoid second and third trimester fetopathy 3
• First trimester exposure does not appear associated with congenital malformations after adjusting for confounders 3

Aldosterone Antagonists

• Aldosterone antagonists are contraindicated in pregnancy because of their anti-androgen effects and potential teratogenesis 3
• Also contraindicated during lactation 3

Valproate and Topiramate

• Valproate sodium is contraindicated during pregnancy as a known teratogen 4
• Topiramato is contraindicated during pregnancy due to its association with adverse fetal effects 4

Common Clinical Pitfalls

Isotretinoin-Specific Issues

• Many women still become pregnant during isotretinoin therapy despite risk management programs, often leading to elective terminations driven by fear rather than actual exposure risk 5, 6, 7
• Most elective terminations (7/8 in one study) were performed due to fear of fetal malformation rather than confirmed exposure during critical periods 5
• Stringent programs like iPLEDGE may increase fear without reducing pregnancy rates 7

Timing Considerations

• The critical window for isotretinoin teratogenicity is weeks 3-6 of gestation 3
• Exposure before this window (9-10 weeks before last menstrual period) has resulted in healthy live births 6
• If pregnancy occurs during treatment, isotretinoin must be discontinued immediately and the patient referred to an obstetrician-gynecologist experienced in reproductive toxicity 1

Medication Alternatives During Pregnancy

• For hypertension: methyldopa, nifedipine, labetalol, diltiazem, clonidine, and prazosin are safe options 3, 4
• Atenolol is not recommended, but other beta-blockers may be used if necessary 3, 4
• Statins should generally be avoided but may be considered in exceptional high-risk cases with shared decision-making 4