Oral retinoids and their metabolites are associated with a significant teratogenic risk and should only be prescribed and dispensed to women under the Pregnancy Prevention Program (PPP).
Isotretinoin is a retinoid (13-cis-retinoic acid) used orally or topically in the treatment of severe acne which has not responded to standard forms of therapy. Oral isotretinoin is a confirmed major teratogen associated with major structural and neurodevelopmental anomalies (isotretinoin embryopathy). Use during pregnancy is contraindicated. A negative pregnancy test and confirmation that effective contraception (preferably two forms) is used prior to, during, and for at least one month after the last dose is required before isotretinoin is provided to women of childbearing potential.
Malformations associated with isotretinoin embryopathy include central nervous system abnormalities (hydrocephalus, cerebellar abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), renal, thymus gland abnormality and parathyroid gland abnormalities.
The absolute risk of congenital malformation following oral isotretinoin therapy is currently unclear. Overall malformation rates in live-born infants from prospectively reported pregnancies range from 5% to 20%, but risk estimation is hampered by the small sample sizes due to the rarity of the exposure, and the fact that rates of elective pregnancy termination are high following gestational isotretinoin exposure, potentially leading to an underestimation of malformation rates. The only (small) study to have attempted to quantify structural malformation risk in different exposure periods found no statistically significant difference in rates of malformation between infants exposed before two weeks gestation and those exposed in the period from 2-9 weeks gestation, with data also suggesting that even brief exposure (less than one week’s duration) may carry a high risk. No minimum dose or duration of treatment has therefore been specified as without risk for congenital malformation. Because of the long half-life of the drug, women are advised to avoid conception for at least one month following discontinuation of therapy. The currently available data are too limited to facilitate an evidence-based assessment of the risk of infant congenital malformation following conception within this period.
Neurodevelopmental delay of varying severity has been reported following exposure to isotretinoin in utero, both in association with congenital anomalies and in exposed infants without structural malformation. The period of risk for impaired neurodevelopment is undetermined and may hypothetically extend throughout gestation, as central nervous system development continues to term. Spontaneous abortion rates appear to be increased above those commonly reported in observational studies, with estimates from more recent prospective datasets in the range of up to 30%. An increased incidence of ectopic pregnancy has also been reported.
A detailed fetal anomaly scan is recommended following all first trimester exposures to isotretinoin. Women should be made aware of the limitations of this investigation and that impaired neurodevelopment may occur in the absence of structural anomalies. When counselling women regarding the teratogenic risk of isotretinoin, possible synergistic effects of other exposures and the effects of prolonged exposure, high dose regimes or inter-individual variation in isotretinoin metabolism should be considered. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.
There are inadequate data to assess fetal risk following exposure during pregnancy to topical isotretinoin. Use during pregnancy cannot therefore be recommended, however, women who are inadvertently exposed during or within the month prior to pregnancy should be reassured that systemic absorption of the drug is generally low and that existing studies show no evidence of a teratogenic risk for topical retinoids as a group. The risk of isotretinoin embryopathy remains unquantified where exposure to supratherapeutic doses of topical isotretinoin occurs, or risk factors which increase absorption of the drug are present.
Discussion with UKTIS is recommended in all cases.
This is a summary of the full UKTIS monograph for health care professionals and should not be used in isolation. The full UKTIS monograph and access to any hyperlinked related documents is available to NHS health care professionals who are logged in.
If you have a patient with exposure to a drug or chemical and require assistance in making a patient-specific risk assessment, please telephone UKTIS on 0344 892 0909 to discuss the case with a teratology specialist.
If you would like to report a pregnancy to UKTIS please click here to download our pregnancy reporting form. Please encourage all women to complete an online reporting form.