Isotretinoin and Pregnancy - A Continued Risk for Birth Defects

Siobhan M. Dolan, MD, MPH


November 01, 2004

In September 1982, the US Food and Drug Administration (FDA) approved the drug isotretinoin (Accutane) for use in the treatment of severe recalcitrant nodular acne. Accutane, taken orally over 20 weeks, was shown to be highly effective in treating this serious form of acne. However, within a year and a half of its approval, 29 cases of "adverse reproductive outcomes among women taking isotretinoin during the first trimester of pregnancy" were reported in the Morbidity and Mortality Weekly Report (MMWR).[1] Of the 34 exposed women reported, 19 experienced spontaneous miscarriage, and 10 babies were born with congenital malformations now understood to be the fetal isotretinoin syndrome.

Smith's Recognizable Patterns of Human Malformation[2] reports that retinoic acid embryopathy, also known as Accutane embryopathy or fetal isotretinoin syndrome, consists of a set of malformations involving the central nervous system, head and face, and heart. Isotretinoin (13-cis-retinoic acid) is a synthetic retinoid or vitamin A derivative. The retinoids are involved in the HOX signaling pathways that are used to pattern the branchial arches (pharyngeal arches) during the fourth week of embryonic development. It is not surprising, therefore, that the derivatives of the pharyngeal arches are affected by isotretinoin exposure during pregnancy, namely the central nervous system (CNS), craniofacial features, and cardiac structures.

Children with the isotretinoin syndrome often demonstrate facial asymmetry; serious external ear abnormalities, including microtia (small ear), anotia (no ear), or stenosis of the external ear canal; micrognathia (small jaw); flat depressed nasal bridge; and ocular hypertelorism (widely spaced eyes). The cardiovascular abnormalities commonly seen include conotruncal malformations, such as transposition of the great vessels and tetralogy of Fallot. Effects on the CNS can lead to hydrocephalus and microcephaly as well as to an IQ in the subnormal range and learning disabilities. Thymic aplasia and parathyroid abnormalities can also be part of this syndrome.

In 1988, a manufacturer-sponsored program called the pregnancy prevention program (PPP) was put in place to prevent birth defects from the use of Accutane.[3] The program provided educational materials for physicians and patients and also facilitated contraceptive use for women on Accutane by reimbursing for the contraceptive counseling. Also as part of the PPP, women who were taking isotretinoin were asked to enroll in the Boston University Accutane Study (BUAS). Enrollment was voluntary and the BUAS estimated that about 40% of women taking isotretinoin enrolled. Over the course of the study period, 1989 to October 1999, approximately 500,000 women enrolled. Among that group there were 958 pregnancies. A large proportion of the pregnancies, 834, ended in termination (either elective, spontaneous, or due to ectopic pregnancies), 110 resulted in live births, and 14 had unknown outcomes. Of the 60 infants with available medical records, 8 had congenital abnormalities.[4]

Concerns about exposure to isotretinoin during pregnancy continued through the late 1990s and into 2000. Roche, the manufacturer of Accutane, began a second program called SMART (The System to Manage Accutane Related Teratogenicity) in 2002. SMART includes patient information and labeling materials (booklets, video, and medication guide), consent forms, and yellow qualification stickers that providers need to affix to prescriptions indicating that patients have met all criteria for receiving Accutane prescriptions.

The guidelines for Accutane usage are as follows:

  1. Isotretinoin is teratogenic, causes birth defects, and is Category X, meaning that there is no indication for its usage during pregnancy. In addition, it should not be taken while nursing.

  2. Patients should take 2 pregnancy tests before starting isotretinoin and take a monthly pregnancy test while on the medication.

  3. Two forms of birth control should be used starting 1 month before treatment, during the entire course of treatment, and for 1 month after ceasing treatment with isotretinoin. Even if one of the forms of contraception is hormonal, a second form should be used.

  4. Providers should be knowledgeable about the use of isotretinoin and should read the educational materials and sign a letter of understanding before prescribing the medication. Yellow stickers are given to providers to affix to the prescriptions for isotretinoin. The yellow sticker indicates that the patient has met all criteria for receiving the medication, signed informed consent, and followed the pregnancy testing recommendations.

  5. Pharmacists should dispense isotretinoin only when the yellow sticker is affixed to the prescription. Only a 30-day supply of medication should be dispensed at a time, to remind patients to take a pregnancy test monthly, before getting another 30-day supply.

  6. Providers and consumers should realize that isotretinoin is a potent drug with the potential to cause birth defects and reserve its use for severe recalcitrant nodular acne. Isotretinoin is not for use in mild forms of acne and should not be shared among family members. Isotretinoin should not be purchased over the Internet without appropriate education and safeguards.

The SMART program continues to be a voluntary program and, unfortunately, pregnancies continue to be exposed to and affected by isotretinoin, an entirely preventable cause of birth defects. The March of Dimes has called for tighter controls on the use of Accutane and other recently available generic forms of isotretinoin. Early in 2004, March of Dimes urged the FDA to mandate a single, stringently monitored and restricted program for isotretinoin, such as the highly effective system created for thalidomide when it was licensed in 1998. Such a system would require provider registration and monitoring of prescriptions. Rather than simply being voluntary recommendations, many of the same safeguards around pregnancy testing and contraceptive use would be mandatory.

Most recently, there have been concerns that isotretinoin might be linked to depression and suicide in both men and women, adding to the list of potentially devastating consequences of isotretinoin. Congressman Bart Stupak, from Michigan's First Congressional District, has a keen personal interest in this issue because of his son's suicide while on the medication isotretinoin. He has advocated strongly for tighter regulation of isotretinoin (see

In conclusion, isotretinoin is a serious and powerful drug and should be used with great caution (see Table ). Women in their reproductive years might well be concerned about their complexions and might desire isotretinoin for the potential improvement they might experience on their skin. Clinicians must keep in mind that approximately 50% of pregnancies in this country are unplanned, and therefore isotretinoin should be used with extreme caution so as to avoid inadvertent exposure and the occurrence of birth defects.


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