By Lauren Walker, BS, and Michael Collins, PhD
Annually, approximately 50 million people in the United States are affected by acne vulgaris. Acne can develop at any age, though it is most common in teenagers and young adults. Individuals suffering from moderate to severe acne such as nodular cystic acne often turn to prescription medications for relief. One class of treatments, retinoids, works to prevent the development of new blemishes while helping to clear existing ones. Vitamin A (retinol) and its derivatives are essential for proper embryo development. However, orally taken retinoid treatments have been associated with severe teratogenicity risks when taken during pregnancy, such as severe structural malformations of the newborn’s craniofacial, cardiac, thymic, and central nervous systems. As a result, they have traditionally been available by prescription-only with strict controls regarding prescribing to women who could get pregnant. All that changed in July 2016. Differin® Gel 0.1% is now the first retinoid-based acne medication to be approved by the FDA for over-the-counter (OTC) use. But before you start calling all of the pregnant women you know warning them about this gel, let’s take a closer look as to why this change occurred…
Having acne stinks – most people know this. But what is less known is that it can impart adverse psychological effects on acne patients such as poor self-image and anxiety. Acne blemishes form when hair follicles in the skin become congested. Generally, blemishes occur on the face, neck, back, chest, and/or shoulders and can range from mild pimples to painful cysts that form deep under the surface of the skin—as is the case with cystic acne. Acne blemishes can also cause permanent scarring. Prescription and OTC options with a variety of active ingredients are available to treat acne.
The Rise of Retinoids
One mainstay of prescription treatments is vitamin A (retinol) and vitamin A derivatives (i.e., retinoic acid, isotretinoin), often referred to as “retinoids.” In the early 1980s, isotretinoin—the active ingredient in Accutane—was identified as a highly effective treatment for severe nodular cystic acne. Isotretinoin is a natural metabolite of vitamin A commonly found in the blood stream. Its discovery as a cystic acne treatment was also accompanied by reports of adverse pregnancy outcomes including increased risk of spontaneous abortion and severe birth defects in newborns. The characteristic birth defect pattern associated with Accutane teratogenicity involved defects of the craniofacial, cardiac, thymic and central nervous system structures, as was first described in 1985 by Dr. Edward Lammer. Accutane and similar drugs were subsequently classified by the FDA as a Pregnancy Category X drug, indicating that female patients who are or may become pregnant or who are breast-feeding should not be prescribed or use the drugs. In light of this history why, then, has a retinoid drug been approved for OTC use?
A chemical’s route of exposure is instrumental in dictating its toxicity. Just ask Teratology Society colleague, Dr. Sarah G. Obican, who was on the review board that approved Differin® for over-the-counter use. “The route has to do at least in part with the dose that reaches the fetus,” she explains.
In the case of retinoids, the bioavailability of the compounds and their associated teratogenic effects are mediated by how the mother is exposed. Oral treatments with retinoids lead to rapid absorption into the blood via the digestive tract. Once taken up by the blood, retinoids can be quickly distributed through the body and ultimately cross the blood-placental barrier and reach the developing embryo. In contrast, topical retinoid applications feature significantly reduced and slower systemic absorption through the skin into the bloodstream. Overall, much less active ingredient enters the blood and thus topical application offers a less risky acne treatment option. All tested retinoids have significantly less absorption through the dermal route than through the gastrointestinal route. But what if the patient’s skin barrier is compromised as is frequently the case for cystic acne sufferers? The structure of the active ingredient in Differin®, adapalene, includes a phenoxy-adamantyl group, which results in even lower percutaneous transport compared to other retinoids and consequently reduced blood concentrations. “There is a very large margin of safety between the concentrations achievable in patients, even with overuse of the drug, and concentrations associated with adverse developmental events,” assures Dr. Anthony Scialli, another Society colleague who participated in the approval process.
To Use or Not to Use During Pregnancy
Topically applied retinoids—first approved for prescription use by the FDA in 1971—have become one of the pillars of first-line acne treatment. Despite the reduced teratogenicity risk posed by Differin® Gel 0.1%, women who are pregnant, planning to become pregnant, or breast-feeding should still consult a doctor before use. “Together doctors and patients can make a decision to use by reviewing the needs of the woman, discussing treatment options plus understanding all of the available data,” says Dr. Obican.
Retinoids and Beyond
Since the identification of isotretinoin teratogenicity, studies of the relationship between different retinoid compounds and adverse pregnancy outcomes have provided a broader understanding of the biological impact of retinoids. Most critically, such research has identified less risky retinoid compounds and less risky treatment approaches. Considering that about half of all pregnancies in the United States are unplanned, it is by no means trivial that such alternative treatments are now available. Retinoids are only one of the many chemicals that are the subject of current research aimed at identifying and understanding how birth defects arise. As evidenced by the history of retinoid teratogenicity studies, birth defects research is vital in that it helps us to understand the risks posed by different chemicals and agents with the ultimate goal of preventing birth defects and protecting baby’s health.
About the Authors
Lauren Walker is a PhD Candidate studying environmental toxicology at the University of California, Riverside. Michael Collins is a Professor in the Interdepartmental Program in Molecular Toxicology and in Environmental Health Sciences at the University of California, Los Angeles.
About the Teratology Society
Scientists interested or are already involved in research related to topics mentioned in this blog are encouraged to join the Teratology Society, the premier source for cutting-edge research and authoritative information related to birth defects and developmentally-mediated disorders. Teratology Society members include those specializing in cell and molecular biology, developmental biology and toxicology, reproduction and endocrinology, epidemiology, nutritional biochemistry, and genetics, as well as the clinical disciplines of prenatal medicine, pediatrics, obstetrics, neonatology, medical genetics, and teratogen risk counseling. In addition, the Teratology Society publishes the scientific journal, Birth Defects Research. Learn more at www.Teratology.org. Find the Teratology Society on LinkedIn, Facebook, and Twitter.