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Caution advised in interpretation of US FDA risk classification for dermatological medications during pregnancy

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Caution advised in interpretation of US FDA risk classification for dermatological medications during pregnancy
Jillian W Wong1,2 MS, Misha M Heller3,4 MD, Jenny E Murase1,5 MD
Dermatology Online Journal 18 (10): 15

1. University of California, San Francisco, Department of Dermatology, San Francisco, California
2. University of Utah School of Medicine, Salt Lake City, Utah
3. Harbor-UCLA Transitional Year Medicine Program, Torrance, California
4. Emory University Department of Dermatology, Atlanta, Georgia
5. Palo Alto Medical Foundation Group, Department of Dermatology, Mountain View, California


Prescription and non-prescription medications are frequently used by women of childbearing age. As many as 40 to 80 percent of women receive at least one prescription drug during pregnancy. It is essential to understand the potential teratogenicity of medications and offer pregnant women appropriate counseling. Available classification references include the Swedish Catalogue of Approved Drugs, the US Food and Drug Administration, the Australian system, and the Evidence-Based Medicine system.

Prescription and non-prescription medications are frequently used by women of childbearing age. Studies have shown that as many as 40 to 80 percent of women receive at least one prescription drug during pregnancy [1-6]. Approximately half of all pregnancies in the United States (US) are unplanned, and therefore, there are potentially hundreds of thousands of women each year who expose their fetuses to medications before they recognize that they are pregnant [7]. Fetuses may be exposed to medications during organogenesis, which occurs between two to eight weeks after conception when fetuses are most susceptible to harmful effects of drug exposure [8, 9, 10, 11]. Even if the pregnancy is planned, many pregnant women may need medications for chronic medical conditions diagnosed prior to pregnancy, for pregnancy-induced conditions such as nausea and emesis, and/or for acute medical conditions such as those requiring surgery with general anesthesia. Therefore, it is crucial that pregnant women are offered appropriate counseling regarding the potential teratogenicity of medications.

Three of the most widely accepted international pregnancy classifications are the FASS (Swedish Catalogue of Approved Drugs), the US FDA (Food and Drug Administration), and the Australian system [12]. Interestingly, when comparing these three, only one-quarter of medications appear in the same risk category. This is because of the difference in safety data interpretation: the US system focuses on animal data, whereas the European and Australian systems focus on human data availability. One study compared the US and European systems, interviewing 934 MDs and pharmacists, and revealed that the European system was favored by a large majority over the FDA system [13]. The first most cited reason for this response was that the US focuses too much on animal data. The second most cited reason was that there appears to be a readiness of the US system to label medications new to the market as Category B drugs (safe to use in pregnancy). If a medication has not been on the market for a long time and there have not been many animal or human studies, it will remain a Category B drug until there are sufficient data to prove that the medication shows fetal risk. The philosophy of the US FDA system is that of “innocent until proven guilty.” Therefore, newer medications, some of which physicians consider potent or “high risk,” often appear as Category B.

Besides the FASS and FDA, there are alternative references to guide clinicians and patients in choosing appropriate drug therapy in pregnancy. In the book, Drugs During Pregnancy and Lactation: Treatment options and risk assessment [14], a consortium of physicians active in teratological societies in the US and Europe, practicing in a variety of fields of medicine, created a highly regarded system focused on an “Evidence-Based Medicine” (EBM) approach to counseling and advising patients. The EBM system divides pregnancy into three time intervals: the embryonic period (first trimester), fetal period (second and majority of third trimester), and peripartum (last month of pregnancy) [14]. There are five categories for assessment at each pregnancy time frame:1 (drug of first choice), 2 (drug of second choice), S (single dose or low dosages are tolerable), T (potentially teratogenic or toxic), and C (contraindicated).

We believe that this new EBM system may be a preferable counseling tool for three reasons. First, the EBM highlights differences of use/concern within a pregnancy. Risk changes throughout the pregnancy from the first trimester to immediately prior to childbirth. One example is the use of the antihistamine diphenhydramine commonly prescribed for pruritus and allergies. The EBM indicates that diphenhydramine is safe in the embryonic and fetal periods, but it should be considered potentially toxic in the peripartum period because, at high doses, it has oxytocin-like effects that can stimulate uterine contractions. Furthermore, it increases the risk of retinopathy of prematurity in pre-term infants. Another example is the classification of antifungal medications. The FDA system labels both nystatin and clotrimazole as Category C drugs (risk cannot be ruled out for use in pregnancy). Instead, the EBM system indicates that nystatin is preferred over the imidazole derivatives in the first trimester because the oral medications have a slightly increased risk of congenital anomalies [14].

Second, the EBM takes into consideration how long a medication has been used and the supporting data available regarding safety. This system gives more weight to drugs that have been available longer and have stood the test of time. In contrast, the FDA system often designates a newer medication as category B, sometimes in cases in which providers may consider the medication to be higher risk or if animal studies are limited. For instance, the recently developed tumor necrosis factor alpha (TNF-α) inhibitors, including infliximab (Remicade ®), etanercept (Enbrel ®), and adalimumab (Humira ®), are all classified as Category B. Although biologics have been tested in animal reproduction studies, no animal fertility or carcinogenic studies have been performed. Despite its less than extensive animal testing, biologics remain Category B drugs. In contrast, topical corticosteroids, including over-the-counter hydrocortisone, have been used for several decades in pregnant women, yet they are classified as Category C. They are classified accordingly because animal studies have indicated potential fetal harm when administered systemically (not topically) at very high dosages. Thus, the FDA system seems to suggest that biologics (Category B drugs) would be better than topical corticosteroids (Category C drugs) for treatment of psoriasis patients in pregnancy.

Third, the EBM tends to be more reasonable and coincide with common sense. This can be illustrated with the previous example because most providers would consider hydrocortisone to be a safer option than the potent IV infusion immunosuppressant infliximab for psoriasis, but the US FDA system indicates infliximab (Category B drug) is a safer choice than hydrocortisone (Category C drug), likely because of a paucity of animal studies for infliximab.

When using the FDA risk classification as a source to determine if medications may be used in pregnancy, it is important to remember that drugs labeled as Category B or C can be misleading. New medications labeled as Category B drugs should be cause for concern and should be prescribed with caution. However, well-established medications labeled as Category C, which demonstrate little evidence of fetal toxicity, may be included among possible therapeutic options for use in pregnancy. We encourage dermatologists to compare the US, European, Australian, and EBM safety classifications in order to make an informed decision of how to optimally counsel their female patients of childbearing age who are pregnant or are considering pregnancy in the future when medication use is required.


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© 2012 Dermatology Online Journal