Problematic in pregnancy?
Dermatologists discuss the safety of common dermatologic drugs in pregnant patients.
Feature
By Jan Bowers, Contributing Writer, June 1, 2023
Few mourned the end of the FDA’s pregnancy risk letter categories for prescription and biologic drug labeling in 2015. In addition to being an oversimplified distillation of available safety data, “the letter classifications were artificial and, in fact, often wrong,” said Bruce Strober, MD, PhD, FAAD, clinical professor of dermatology at Yale University School of Medicine. “Cyclosporine is safe in pregnancy, but I recall its letter classification was a C, and therefore not indicative of a drug that you should feel totally confident about. The letter labels were probably never updated, and thus didn’t reflect years of use in the real world.”
The new format for package inserts that went into effect with the implementation of the Pregnancy and Lactation Labeling Final Rule requires information for a pregnancy exposure registry summary, if one exists for the drug; a risk summary based on animal data; clinical considerations; and a description of the data referenced in the risk summary. Separate sections addressing lactation and male and female fertility are also required. The shift from letter categories to more detailed, data-driven risk assessments helps the physician formulate “the key counseling points that you need to state when you’re advising a patient about pregnancy,” said Jenny E. Murase, MD, FAAD, associate clinical professor of dermatology at the University of California, San Francisco.
“Ideally, your staff can ask about pregnancy plans as part of the intake, and flag it so that the dermatologist remembers to have the discussion. That’s really very important, particularly for systemic therapy.”
Dr. Murase is the lead author of a CME series in the Journal of the American Academy of Dermatology on the safety of dermatologic medications in pregnancy and lactation (doi: 10.1016/j.jaad.2013.09.010). Dr. Strober contributes to the online clinical decision support tool UpToDate on the topic of psoriasis treatment in pregnancy (see sidebar). Both were speakers at the 2023 AAD Annual Meeting session titled, “The Pregnant Pause: How to evaluate and treat your pregnant patients.” DermWorld discussed their approach to counseling and treating pregnant patients with some of the most common dermatologic disorders.
Both dermatologists emphasized the importance of talking with patients about how pregnancy might impact their treatment before pregnancy occurs. “About 50% of pregnancies in the United States are unplanned. I feel the onus is on us as dermatologists to have the discussion with any woman of childbearing age about what the implications of a pregnancy might be,” said Dr. Murase. “Ideally, your staff can ask about pregnancy plans as part of the intake, and flag it so that the dermatologist remembers to have the discussion. That’s really very important, particularly for systemic therapy.”
Acne
Topical retinoids are very frequently prescribed to treat acne in women of childbearing age, particularly teenagers. These agents have been very thoroughly evaluated for risks to the fetus, Dr. Murase said, “but the websites of many malpractice lawyers show that they’re looking for people who were prescribed topical tretinoin and had some kind of birth defect, and I think prescribing them, in general, makes dermatologists kind of nervous.” With patients at risk of permanent scarring from cystic acne, Dr. Murase said she explains that treating a small area of their face using a topical tretinoin will not substantially change their vitamin A levels, “and they’re probably getting more vitamin A exposure in through their prenatal vitamins than they would through use of the topical retinoid. Then it’s up to them to make the decision.” Another topical retinoid, tazarotene, caused fetal malformations in experimental animals and is contraindicated in pregnancy.
Over-the-counter topical acne therapies are generally considered safe, Dr. Murase said. She noted that benzoyl peroxide is quickly converted to benzoic acid in the skin, “which is a food additive and certainly a very safe option. Any of the salicylic acid washes for acne would also be fine, as they don’t involve very high doses and have not been shown to be absorbed at significant levels.” In contrast, “there’s just very little data for glycolic acid; that’s a problem.”
Because isotretinoin, spironolactone, and oral contraceptives are all contraindicated in pregnancy, for a systemic therapy “you’re left primarily with the antibiotics,” said Dr. Murase. “If you have more of an acne rosacea pattern, amoxicillin is a good choice. If it’s more of an acne vulgaris, then cefadroxil is an excellent choice since all cephalosporins have a rate of congenital malformations that’s consistent with the general population, but the rate of cefadroxil is lowest as reported in the Briggs. That’s why I tend to prescribe it, even though it’s very likely that things like cephalexin are fine to use too.” A preference for erythromycin “is a kind of lore that’s been passed down through generations of practitioners for pregnant or breastfeeding women, but it has been shown to potentially increase rates of pyloric stenosis in the infant,” Dr. Murase said. “There was also an increased risk of atrial and ventricular septal defect relative to the general population. So, I don’t routinely prescribe erythromycin in pregnancy if I can help it. I try to focus on the classes that are a bit safer.” Overall, for cystic acne, “I really think antibiotics are the way to go for a patient who is pregnant. Low-dose intralesional triamcinolone shots for large acne cysts would be another safe therapeutic approach.”
Atopic dermatitis
One common therapeutic agent used to treat atopic dermatitis illustrates the importance of discussing pregnancy with patients before they become pregnant. “JAK inhibitors are being prescribed very frequently by dermatologists, and I don’t know how often physicians are having the discussion about contraception,” said Dr. Murase. “The JAK inhibitors are small molecules that will cross the placenta, and I think there’s consensus that those should not be used in women of childbearing age; or if they are, have them on contraception.” Light therapy, topical steroids, and antihistamines are safe in pregnancy, Dr. Murase noted, “but I have every woman of childbearing age who is on light therapy take a prenatal vitamin daily just so [the therapy] doesn’t deplete folic acid stores. Light will photo-degrade vitamins, and low folic acid will cause neural tube defects.”
Dupilumab, approved by the FDA in 2017, doesn’t have enough registry data to confirm its safety, Dr. Murase said, “but so far there are no signals, and the antibodies really don’t cross the placenta until primarily late second and third trimester.” Because dupilumab is approved for six-month-old infants, it is very likely safe throughout pregnancy, “but until there are enough patients in the registry you really can’t make that statement,” Dr. Murase remarked. Without an effective remedy, some patients will suffer from “fatigue, stress on the body, incessant itch, the risk of infection if the skin is open and oozing; that is more of a concern than dupilumab.” She is comfortable prescribing dupilumab throughout a pregnancy if, after a thorough review of the current data, the patient chooses to receive the therapy. “I’ll go over what we know to date, and the majority of patients will say I want to do this, even if we don’t have definitive data, because I’m so miserable.” Once there is more registry data for it, tralokinumab — approved less than two years ago — “will probably have a very similar safety profile to dupilumab,” Dr. Murase said. “It’s an IL-13 blocker; dupilumab is IL-4 and IL-13.”
Keeping current with drug safety
Now that the FDA has replaced its pregnancy risk letter categories with more complex and detailed labeling requirements, how can dermatologists access safety information quickly?
“If they’re looking for a text resource, the Briggs [Briggs G, Towers C, Forinash A. Briggs Drugs in Pregnancy and Lactation: A Reference Guide to Fetal Neonatal Risk. 12th ed. Wolters Kluwer; 2022] is a pretty big, comprehensive textbook,” said Jenny A. Murase, MD, FAAD. The Briggs text is also available online and as a smartphone app. “Another excellent resource is an evidence-based medicine guide published by Schaefer and colleagues [Schaefer C, Peters P, Miller R, eds. Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment. 3rd ed. Elsevier; 2015],” Dr. Murase added.
Electronic health record systems may or may not be especially helpful. “My EHR will just say ‘caution in pregnancy’ or something non-specific,” Dr. Murase noted. “But a lot of the EHRs will be attached to resources that provide information on medications, drug-drug interactions and things like that, and those will often have a comment on pregnancy and lactation.”
Bruce Strober, MD, PhD, FAAD, cited the new drug package labeling as helpful, but pointed out that data regarding the drug’s safety in pregnancy “might not be more current than what was submitted at the time of FDA filing.” His preferred resource is UpToDate, a 30-year-old clinical decision support tool to which he contributes an entry about psoriasis treatment in the context of pregnancy, co-written with Miriam Pomeranz, MD, FAAD. “It’s a subscription service with information covering all of medicine. The dermatology articles, often written by dermatologists, are very thorough.”
Finally, the FDA publishes a list of pregnancy exposure registries on its website, as well as links to additional resources for information on drugs and pregnancy.
Psoriasis
Topical steroids are generally safe for use in pregnancy, Dr. Strober said. “I would also put topical immunomodulatory drugs like pimecrolimus and tacrolimus in that category. Topical calcipotriene is fine too. For the most part, if it’s used on limited body surface areas, there should not be a problem with vitamin D overabsorption and calcium metabolism. The newer drugs — roflumilast and tapinarof, for example — we have too little data for a full-fledged endorsement, but because they’re so minimally absorbed when used topically, I have a sense they’re probably safe in the context of psoriasis.” Dr. Strober said he doesn’t find topical retinoids to be effective in treating psoriasis, “but it’s an old argument, if topical retinoids of any type, whether they’re used for psoriasis or acne, are truly posing a risk because of systemic absorption. And my guess is that it’s minimal, as long as you keep the body surface area of application to a very limited area: 5% or less.”
Two oral therapies for psoriasis, acitretin and methotrexate, are contraindicated in pregnancy. Cyclosporine is safe for pregnancy, and “is always something you should consider when a pregnant woman presents with a psoriasis flare. It’s been shown that it doesn’t have any teratogenic potential,” said Dr. Strober. “Just use it with the caveat that it has its own toxicities, hypertension and renal toxicity.” Regarding apremilast, “I don’t think there are enough data for me to make an endorsement.” Apremilast was classified as pregnancy category C under the former system because animal studies revealed dose-related increases in embryo-fetal death.
Among biologic therapies for psoriasis, “the TNF inhibitors have the most data, and the sense is that they’re safe for pregnant women,” Dr. Strober said. “Certolizumab is the preferred TNF blocker because it doesn’t cross the placenta. It’s not really a monoclonal antibody; it’s an engineered pegylated protein. So that’s your first choice. And then the other TNF blockers — adalimumab, etanercept, infliximab, and golimumab — they’re all safe in pregnancy.” The safety data come from many sources, primarily epidemiologic, and frequently involving women with inflammatory bowel disease, he added, noting that severe untreated inflammatory conditions can themselves lead to negative pregnancy outcomes. Other classes of biologics have less data to support their use in pregnancy, Dr. Strober said. “The IL-12/23 inhibitor, ustekinumab, IL-17 inhibitors [secukinumab, ixekizumab, brodalumab], and IL-23 inhibitors [guselkumab, rizankizumab, tildrakizumab]; all the data to date suggest that all the biologics of those classes are safe. In the end, I have used every biologic in every class in the setting of pregnancy without issue.”
While certolizumab may be the preferred biologic for pregnancy, Dr. Strober said he allows women who become pregnant while on any biologic to remain on that same therapy throughout their pregnancy if they choose to do so. “It’s always a discussion, as you lead up to pregnancy, to make sure she’s aware of the potential outcome of getting pregnant while on a biologic. There’s a risk that when you switch therapies, you lose good control of the psoriasis.” Dr. Strober remarked that as opposed to small molecules like cyclosporine, “biologics are somewhat ideal for breastfeeding, because extraordinarily little is actually bioavailable to the nursing infant. And that might be important because sometimes in the postpartum period, psoriasis flares.”
Infections and infestations
Dermatologists have a variety of effective antibiotics to deploy against bacterial infections in a patient who is pregnant, Dr. Murase said. “We use cephalosporins as the primary therapy. Dicloxacillin would be a good first-line choice; it’s not a cephalosporin, but it’s in that beta-lactam class. So, you could use it for impetigo, or for staph infection. We give it a lot to breastfeeding women for mastitis; that’s driven by Staphylococcus aureus. We also use clindamycin.”
Syphilis and the herpes simplex virus are both TORCH infections that can cause congenital malformations in a fetus exposed in utero. TORCH refers to Toxoplasmosis, Other (such as syphilis, hepatitis B, varicella, and mumps), Rubella, Cytomegalovirus, and Herpes simplex. “Penicillin is the first-line therapy for syphilis, and it’s very, very safe,” said Dr. Murase. “For HSV, the treatment is acyclovir. Some patients are worried about risks from the medication, but you want to make it really clear to the patient that these infections pose far more risk to the fetus than the therapy.” Patients with HSV can take acyclovir throughout the pregnancy for recurrent flares, then start prophylaxis at 36 weeks gestation to protect the baby in case of a vaginal delivery. For human papillomavirus, “we try to do non-medicated therapy, so liquid nitrogen is definitely the way to go if we can treat it with that,” Dr. Murase said. Podophyllin is contraindicated in pregnancy, as it can harm both mother and fetus.
In treating fungal infections in a pregnant patient, Dr. Murase makes a distinction between disorders that are purely cosmetic, such as onychomycosis, and those that can cause severe itching and discomfort. “If it were me, I’m going to wait until after the pregnancy to treat my toenail fungus,” she remarked. “But I’ve had patients with such severe itching from tinea pedis that it was difficult for them to sleep and function. On the rare occasion, I’ve used an oral antifungal. But for the most part, we have such good topical treatment that there’s little justification for using the oral instead of the topical.” All imidazole derivatives are not advised during pregnancy, nor is oral griseofulvin. “Nystatin is not absorbed by skin or mucous membrane, so that’s a very good choice.” A recent study in JAMA Dermatology (doi: 10.1001/jamadermatol.2020.0142) addressed the lack of data surrounding the safety of oral and topical terbinafine in pregnancy. Evaluating more than 1.5 million pregnancies in Denmark, the authors found no increased risk of major malformations or spontaneous abortions among women who received oral or topical terbinafine.
Infestations are a class of disorders that should be treated with non-medicated therapy, if possible, Dr. Murase said. “You can put Cetaphil on the scalp if you get lice, then apply heat with a hair dryer. If occlusive therapy fails, you can apply a 5% permethrin cream.” Permethrin cream can also be used against scabies. Crotamiton is likely safe but not as effective, and lindane is contraindicated in pregnancy.
Fertility
While no dermatologic drugs have been shown to affect a woman’s ability to conceive, a handful of systemic agents have been implicated in reducing sperm count and/or motility. Methotrexate should be stopped for three months prior to conception because of its negative impact on sperm count and DNA integrity, Dr. Murase said. In an article published online in UroToday.com (Feb. 6, 2014) discussing dermatologic medication effects on male fertility, Dr. Murase and co-authors Jillian Wong Millsop, MD, and Mona Malakouti, MD, FAAD, also singled out finasteride (at the 5mg/day dose used to treat androgenic alopecia) and ketoconazole (along with the other azole antifungals) as agents that should be considered for discontinuation, particularly if attempts at conception have failed. More recently, a JAAD review (doi.org/10.1016/j.jaad.2018.09.031) focused on drugs from the former FDA pregnancy categories D and X for potential impact on male fertility and teratogenicity. Evidence of possible negative effects on fertility was found for colchicine, cyclophosphamide, finasteride, and tetracycline. Regarding methotrexate, the authors noted that the prescribing information alludes to “reported negative effects [on male fertility] without cited studies.” Drugs identified as having potential teratogenicity were finasteride, cyclophosphamide, doxycycline, and thalidomide.
