C. Zip, MD, FRCPC
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Although the developing fetus was once considered protected from the outside world, we now know that it can potentially be affected by any medication given to the mother. Despite this knowledge, use of medications during pregnancy is common and pregnant women often present for treatment of dermatological disease. Therapeutic options available for these patients will be discussed.
pregnancy, congenital malformations
Two drugs given in the middle of the 20th century to pregnant women changed the attitude of physicians about the use of medications during this period. Diethylstilbestrol and thalidomide use in early pregnancy led to disastrous consequences for the exposed offspring, consequences that were not causally linked for years. These events led to the development of the US FDA Pregnancy Categories (see Table 1) that are now assigned before a drug is released.
Despite awareness that any medication taken during pregnancy can potentially affect the fetus, a recent multinational survey indicated that 86% of women took an average of 2.9 medications during pregnancy.1 This article will review options for the treatment of a variety of common dermatological disorders during pregnancy (see Table 2).
|A||No fetal risk in controlled studies|
|B||No risk to human fetus despite possible animal risk or
no risks in animal studies but human studies lacking
|C||Human risk cannot be ruled out. Animal studies may or
may not show risk
|D||Evidence of risk to human fetus|
|X||Contraindicated in pregnancy|
Table 1: FDA Pregnancy Categories for Drugs.
Acne and Rosacea
Topical therapy is preferred for the treatment of acne during pregnancy.2 Topical erythromycin (category B), clindamycin (category B) and benzoyl peroxide (category C) are considered safe in pregnancy. Use of topical tretinoin (category C) is not advised due to case reports of congenital malformations in infants whose mothers used tretinoin during the first trimester of pregnancy.3,4 Moreover, some of these malform ations are consistent with those observed in retinoic acid embryopathy. However, the fetal risk, if any, from inadvertent exposure in early pregnancy appears to be very low.5 Use of adapalene (category C) and tazarotene (category X) is also not recommended.
Topical metronidazole (category B) is minimally absorbed and considered safe in pregnancy. Topical azelaic acid (category B) is also minimally absorbed and likely safe in pregnancy.
Tetracyclines (category D) are associated with deciduous tooth staining when taken after the first trimester, decreased bony growth, and maternal liver toxicity. However, inadvertent exposure in the first few weeks of pregnancy is extremely unlikely to be harmful.6 Erythromycin (category B) has long been considered safe in pregnancy. However, two recent Swedish studies have reported an increased risk of cardiovascular malformations with the use of oral erythromycin in early pregnancy.7,8
Oral isotretinoin (category X) is a well-known teratogen. However, it is safe for women to conceive 1 month after this medication is stopped.
|Acne||Topical clindamycin, erythromycin, benzoyl peroxide|
|Rosacea||Metronidazole, azelaic acid|
|Psoriasis||Topical corticosteroids, calcipotriol, broad band UVB|
|Dermatitis||Topical corticosteroids, chlorpheniramine or diphenhydramine|
|Genital human papillomavirus infection||Liquid nitrogen, trichloroacetic acid|
|Herpes simplex virus infection||Acyclovir|
|Fungal infections||Topical antifungals|
|Bacterial infections||Penicillins, cephalosporins after first trimester, azithromycin|
Table 2: Safe treatments for dermatological disorders during pregnancy.
Topical corticosteroids (category C) have been widely used during pregnancy, although intrauterine growth retardation was reported in an infant whose mother applied 40mg/day of topical triamcinolone beginning at 12 weeks of gestation.9 Calcipotriene (category C) is approximately 6% absorbed when the ointment form is applied to psoriatic plaques and is likely safe in pregnancy for the treatment of localized psoriasis.10
Broadband ultraviolet B phototherapy is considered the safest therapy for extensive psoriasis during pregnancy, although overheating during treatment should be avoided. PUVA is a potential teratogen because it is known to be mutagenic and to induce sister chromatid exchanges. However, adverse outcomes have not been reported in studies of women exposed to PUVA during pregnancy.11,12
Methotrexate and acitretin are both in pregnancy category X. Methotrexate can be used in women with childbearing potential who are using effective contraception. Pregnancy should be avoided for at least one ovulatory cycle after this medication is discontinued. Acitretin should not be prescribed for women of childbearing potential.
There are limited data on the safety of biologics used for the treatment of psoriasis during pregnancy. Animal reproduction studies of alefacept 13 (category B), a mouse analogue of efalizumab,14 and etanercept (category B)15 have shown no evidence of teratogenicity. No congenital malformations have been reported in the offspring of the few women who inadvertently became pregnant while taking alefacept or efalizumab (category C) in clinical trials. More data are available on the outcome of pregnancies exposed to etanercept given its utilization for the treatment of rheumatoid arthritis. Preliminary data from the Organization of Teratology Information Services (OTIS) study of pregnancy outcomes of women with rheumatoid arthritis exposed to anti-TNF therapy included information on 29 women exposed to etanercept. Spontaneous abortion, termination, and malformation rates were similar to those in the diseased and nondiseased control groups.16
In some studies first trimester exposure to systemic corticosteroids (category C) has been associated with intrauterine growth retardation and a small increase in the incidence of cleft lip with or without cleft palate.17,18 However, when needed, the maternal benefits of short courses of oral corticosteroids appear to outweigh the fetal risks, especially when given beyond the first trimester.
The topical calcineurin inhibitors, tacrolimus and pimecrolimus, are in pregnancy category C. Use of oral tacrolimus in pregnant organ transplant recipients has not been associated with fetal loss or teratogenicity thus far.5 Pimecrolimus has shown no evidence of teratogenicity in animal studies.19 To date, there have been no reports of adverse effects on pregnancy with topical use of either tacrolimus or pimecrolimus.
Chlorpheniramine and diphenhydramine (both category B) have been considered the antihistamines of choice for oral and parenteral use, respectively, in pregnancy,20 although one case-control study showed an association between the use of diphenhydramine in the first trimester and cleft palate.21 Antihistamines in general have been linked to retrolental fibroplasia in premature infants when taken in the last 2 weeks of pregnancy.
For the treatment of genital warts, trichloroacetic acid and physical modalities such as cryotherapy are felt to be safe in pregnancy. Imiquimod (category B) is minimally absorbed, and animal studies, as well as very limited data of use in pregnant women, have not shown adverse fetal effects.22,23 Podophylline and podophyllotoxin (category C) are not recommended for use in pregnancy because of fetal abnormalities and deaths associated with maternal use.24,25 Acyclovir, famciclovir and valacyclovir are all pregnancy category B, and pregnancy registries exist for each of these agents. No adverse effects on the fetus or newborn have been attributed to their use in pregnancy, but because we have more data on the use acyclovir in human pregnancy, some authors consider it to be the drug of choice when indicated in pregnancy.
The use of topical antifungals is considered safe in pregnancy because of negligible percutaneous absorption. Animal reproduction studies involving oral terbinafine (category B) have shown no abnormalities, but human pregnancy data are lacking.5 Oral fluconazole (category C) taken during the first trimester at a continuous daily dose of 400mg/day
or more appears to be teratogenic and associated with a pattern of abnormalities involving the head and face, bones, and heart.26
Smaller doses of fluconazole, as used for treatment of vaginal candidiasis, have been associated with minimal or no risk of fetal abnormalities. The available data pertaining to human use of itraconazole (category C) indicates no significant risk for major abnormalities. However, because of concern regarding the use of fluconazole, a structurally related triazole antifungal, avoidance of itraconazole is suggested in the first trimester.
Penicillins, cephalosporins and azithromycin are all pregnancy category B and are generally considered safe in pregnancy. However, a large surveillance study of Michigan Medicaid recipients conducted between 1985 and 1992 observed a possible association between certain cephalosporins (cefaclor, cephalexin, ceftriaxone and cephadrine) and congenital malformations when taken in the first trimester.5
Medications that are considered safe in pregnancy are available for the treatment of common dermatological disorders. Knowledge of these medications is important when considering treatment options for both pregnant patients and women of childbearing potential.
- Collaborative Group on Drug Use in Pregnancy.Medication during pregnancy: an intercontinental cooperative study. Int J Gynaecol Obstet 39(3):185-96 (1992 Nov).
- Koren G, Pastuszak A, Ito S. Drugs in pregnancy. NEngl J Med 338(16):1128-37 (1998 Apr).
- Navarre-Belhassen C, Blanchet P, Hillaire-Buys D,Sarda P, Blayac JP. Multiple congenital malformations associated with topical tretinoin. Ann Pharmacother32(4):505-6 (1998 Apr).
- Colley SM, Walpole I, Fabian VA, Kakulas BA. Topical tretinoin and fetal malformations. Med J Aust 168(9):467 (1998 May).
- Briggs GG, Freeman RK, Yakke SJ. Drugs in Pregnancy and Lactation. 7th ed. Philadelphia (PA): Lippincott Williams and Wilkins (2005).
- Rothman KF, Pochi PE. Use of oral and topical agents for acne in pregnancy. J Am Acad Dermatol 19(3):431-42 (1988 Sept).
- Kallen BA, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 17(3):255-61 (2003 May-June).
- Kallen BA, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in humans? Reprod Toxicol 20(2):209-14 (2005 Jul-Aug).
- Katz VL, Thorp JM Jr, Bowes WA Jr. Severe symmetric intrauterine growth retardation
associated with the topical use of triamcinolone. Am J Obstet Gynecol 162(2):396-7 (1990 Feb).
- Tauscher AE, Fleischer AB Jr, Phelps KC, Feldman SR. Psoriasis and pregnancy. J Cutan Med Surg 6(6):561-70 (2002 Nov/Dec).
- Stern RS, Lange R. Outcomes of pregnancies among women and partners of men with a history of exposure to methoxsalen photochemotherapy (PUVA) for the treatment of psoriasis. Arch Dermatol 127(3):347-50 (1991 Mar).
- Gunnarskog JG, Kallen AJ, Lindelof BG, Sigurgeirsson B. Psoralen photochemotherapy
(PUVA) and pregnancy. Arch Dermatol 129(3):320-3 (1993 Mar).
- Amevive® (alefacept) Product Monograph, Biogen Idec Canada Inc, 2004.
- Raptiva® (efalizumab) Product Monograph, Serono Canada Inc., 2005.
- Enbrel® (etanercept) Product Monograph, Immunex Corporation, 2005.
- Chambers CD, Johnson DL, Lyons Jones K. Pregnancy outcome in women exposed to anti-
TNF-alpha medications: the OTIS rheumatoid arthritis in pregnancy study [Abstract 1224]. Arthritis Rheum 50(9): S479-80 (2004 Sept).
- Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 86(3):242-4 (1999 Sept).
- Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts:
a case-contol study. Teratology 58(1):2-5 (1998 Jul).
- Elidel® (pimecrolimus) Product Monograph, Novartis Pharmaceuticals Canada Inc., 2003.
- Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 78(2):157-9 (1997 Feb).
- Saxen I. Letter: Cleft palate and maternal diphenhydramine intake. Lancet 1(7854):407-8 (1974 Mar).
- Maw RD. Treatment of external genital warts with 5% imiquimod cream during pregnancy: a case report. BJOG 111(12):1475 (2004 Dec).
- Einarson A, Costei A, Kalra S, Rouleau M, Koren G. The use of topical 5% imiquimod during
pregnancy: a case series. Reprod Toxicol 21(1):1-2 (2006 Jan).
- Karol MD, Conner CS, Watanabe AS, Murphrey KJ. Podophyllum: suspected teratogenicity from topical application. Clin Toxicol 16(3):283-6 (1980 May).
- Chamberlain MJ, Reynolds AL, Yeoman WB. Medical memoranda. Toxic effect of podophyllum application in pregnancy. Br Med J 3(823):391-2 (1972 Aug).
- Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 22(2):336-40 (1996 Feb).