Recently, one of our patients who was taking isotretinoin became pregnant. This occurred despite appropriate counseling, a negative pregnancy test result before commencing treatment, and use of the combined oral contraceptive pill Microgynon 30 (Schering Health Care, West Sussex, England) (levonorgestrel, 150 μg, ethinylestradiol, 30 μg). The patient did not want to terminate her pregnancy. The aim of this Critically Appraised Topic is to explore the literature to determine the chance of delivering a healthy child after fetal exposure to isotretinoin; the types of fetal malformations associated with it; and what monitoring should be performed.
Since introduction of the drug in 1982, over 2000 pregnancies in the United States have been affected by fetal exposure to isotretinoin,1 most resulting in spontaneous or elective abortions.2- 6
We searched the Medline and EmBase databases from 1966 to March 2007 using the terms isotretinoin or Accutane or Roaccutane and pregnancy or birth defect.
We found 469 articles in the literature search and chose 2 case series3- 4 that prospectively identified and followed up pregnancies in which the fetus was exposed to isotretinoin for which abortion was not elected.3- 4 We extracted data from these 2 prospective studies to develop our clinical bottom line because these studies are likely to be less biased than the retrospective studies. These 2 studies collected data from a combined total of 151 pregnant women in the United States aged 14 years to older than 35 years whose fetuses were exposed to isotretinoin.
In one study3 of 115 pregnancies, there were 21 spontaneous abortions (18%). Of the 94 live births, 61 were healthy infants (65% of births, 53% of pregnancies), 26 had congenital malformations consistent with isotretinoin embryopathy (28% of births, 23% of pregnancies), and 7 had other problems (7% of births). Therefore, 28% of live births had congenital malformations consistent with isotretinoin embryopathy (95% confidence interval, 19%-37%).3
In the second study4 of 36 pregnancies, there were 8 spontaneous abortions (22%). Of the 28 live births, 23 were healthy infants (82% of births, 64% of pregnancies), and 5 had congenital malformations (18% of births, 14% of pregnancies).
The main abnormalities found in isotretinoin embryopathy are craniofacial, central nervous system, cardiovascular, and thymic.1,3- 4,7- 8
Craniofacial: ear defects, dysmorphism, cleft palate, depressed nasal bridge, hypertelorism;
Central nervous system: hydrocephalus, microcephaly, facial nerve palsy, cortical and cerebellar defects;
Cardiovascular: Fallot's tetralogy, transposition of great vessels, septal defects, aortic arch hypoplasia;
Thymic: ectopia, hypoplasia, aplasia; and
Miscellaneous: spina bifida, limb reduction.
In addition, fetal exposure to isotretinoin is associated with high risk of adverse outcome with respect to mental functioning.9 The United Kingdom National Teratology Information Service10 estimates that in fetal exposure to isotretinoin, 30% of infants with no gross malformations have mental retardation, and up to 60% have impaired neuropsychological function.
The National Teratology Information Service recommends that women who wish to continue their pregnancy after fetal exposure to isotretinoin should have alpha-fetoprotein testing at 16 to 19 weeks' gestation and undergo a targeted ultrasound scan and echocardiography at 20 to 21 weeks' gestation.10 These investigations would give some indication of the risks of structural malformations so that parents can plan support services and, in rare instances, in utero intervention could be performed, if appropriate.
The high rate of fetal exposure to isotretinoin and its serious teratogenicity are clearly illustrated. The US Food and Drug Administration has recently approved the “iPLEDGE” risk management program,11 which is designed to reduce the risk of fetal exposure to isotretinoin. However, it is also important that dermatologists prevent pregnant women from taking the medication (document proof of no pregnancy) and prevent women who are taking it from getting pregnant (use of 2 forms of birth control).
There is no dose of oral isotretinoin that is safe for use in pregnant women3,12 and, consequently, there are no published studies of women who took isotretinoin throughout pregnancy. Therefore, information about safety must be obtained from studies in which isotretinoin was taken for acne during some portion of pregnancy.13
Reported outcomes of retrospectively and prospectively ascertained cases differ considerably.3 Therefore, we have based our conclusions on data from prospective studies because of the strong likelihood of bias (especially reporting bias) associated with retrospective studies. Published prospective outcome data are available for only a small proportion of pregnancies in which the fetus was exposed to isotretinoin because most of these pregnancies are not reported in the literature.
The level of fetal exposure to isotretinoin varies from pregnancy to pregnancy so it is possible that isotretinoin-related problems may be higher for women who continue taking isotretinoin for a longer duration before discovering that they are pregnant. However, there is insufficient data to address this issue. There is little information about the timing of spontaneous abortions, either in weeks or trimesters. There is little follow-up data on infants with no gross malformation to determine the risk of developmental disabilities later in life.
In pregnancies in which the fetus is exposed to isotretinoin,
The risk of spontaneous abortion is approximately 20%;
In pregnancies that progress, 65% to 82% of neonates appear normal at birth, but there is insufficient data to determine how many will later develop isotretinoin-related problems;
There is an 18% to 28% risk of isotretinoin embryopathy;
There is no safe level of exposure: any exposure can cause malformation;
The main abnormalities are craniofacial, cardiac, central nervous system, and thymic; and
Women who choose to continue their pregnancy require careful support and monitoring.
Finally, it is important that dermatologists prevent pregnant women from taking isotretinoin and prevent women who are taking it from getting pregnant.
Our patient ceased taking isotretinoin as soon as she discovered that she was pregnant, at approximately 6 to 7 weeks' gestation. We discussed with her the evidence regarding isotretinoin and birth defects. She elected to continue with her pregnancy and underwent regular ultrasound scans, performed by her obstetrician. She delivered a healthy baby girl, with no apparent birth defect. At age 18 months, her daughter was developing normally.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and
Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early
dhildhood mortality and growth failure data and their association with maternal
Thank you for submitting a comment on this article. It will be reviewed by JAMA Dermatology editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more
Subscribe for full-text access to content from 1998 forward and a host of useful features
Activate your current subscription (AMA members and current subscribers)
Purchase Online Access to this article for 24 hours
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 5
Customize your page view by dragging & repositioning the boxes below.
and access these and other features:
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.