Acne during pregnancy – Topical antimicrobials and retinoids

INTRODUCTION

Pregnancy can influence the course of acne. In a study of over 400 pregnant women, after delivery, 75% of women reported improvement in acne, 13% reported no change, and 12% reported worsening of their acne (1). Dermatologists will often be consulted for gestational acne, since many physicians are hesitant to prescribe these medications during pregnancy. In some cases, the patient will have been advised to stop their prior acne treatment. But for female patients with severe disease that can lead to scarring, treatment can continue during pregnancy (2).

Since 1979, the U.S. Food and Drug Administration (FDA) has categorized drugs that may be used by pregnant women from category A “controlled studies show no risk” to category X “contraindicated in pregnancy” (Table 1). Since controlled studies in pregnant women are usually not available, many drugs are interpreted as category C “risk cannot be ruled out” (3). The following is a review of the agents used to treat acne in pregnancy.

TOPICAL ANTIMICROBIALS

Topical therapy is the preferred treatment for acne during pregnancy. Topical erythromycin (category B), clindamycin (category B), and benzoyl peroxide (category C) are considered safe in pregnancy (4). When using clindamycin, approximately 5% of topical clindamycin hydrochloride is systemically absorbed and even less topical clindamycin phosphate is absorbed. Although rare, there are reports of pseudomembranous colitis from topical clindamycin formulations (5). Similarly, approximately 5% of topical benzoyl peroxide is absorbed in the skin. The final metabolic product of benzoyl peroxide, benzoate, is excreted

unchanged in the urine. Thus, systemic effects in pregnant patients and/or the fetus are not observed (5). Azelaic acid (category B) has not shown mutagenicity, teratogenicity, or embryotoxicity in animals (6). For patients with rosacea, topical metronidazole (category B) is an option. It is minimally absorbed and is also considered safe in pregnancy (4).

Table 1

FDA Drug Risk Classification System for Acne Medications

Drug

classification

Definition

Medication

A

Controlled studies show no

Zinc salts

В

fetal risk No evidence of risk to human

Azelaic acid,

fetus

erythromycin,

С

Risk to human fetus cannot be

clindamycin, metronidazole Adapalene, benzoyl

ruled out

peroxide, salicylic

D

Positive evidence of risk to

acid, tretinoin, Tetracycline

X

human fetus; however, potential benefits may outweigh the potential risk Contraindicated in pregnant

Isotretinoin, tazarotene

TOPICAL RETINOIDS

The three main categories of topical retinoids include tretinoin (category C), adapalene (category C), and tazarotene (category X). Topical retinoids are not recommended for use in pregnant patients despite data suggesting that percu-taneous absorption is minimal (1). There have been no reports of infants born with congenital malformation after maternal topical application of tretinoin (5,7). Tretinoin (all-trans-retinoic acid) is the isomer of isotretinoin applied topically. There is documented conversion to 13-cis-retinoic acid after percu-taneous absorption (7). Rothman and Pochi note that, in humans, less than 5% of topical tretinoin is absorbed after one application. They postulate that “if a patient applies 0.1% tretinoin, 1 gm daily, to her skin and one-third is absorbed, it is equivalent to ingesting about 12 IU/kg/day. For a 60 kg woman this amounts to 720 IU/day. Prenatal vitamins contain 5000 IU of vitamin A, that is, seven times the amount of vitamin A expected to be absorbed after topical use of tretinoin.

Thus it is highly unlikely that topically applied tretinoin could induce a teratogenic effect” (5). In addition, photodegradation of tretinoin occurs and about 50% of the applied retinoid is recoverable in the subsequent face washing (7). Thus, no elevation in baseline risk for birth defects has been observed with tretinoin. On the other hand, there have been reports of ocular congenital anomaly associated with adapalene use (6). Tazarotene is the only topical reti-noid designated category X. In experimental animals, it has been associated with malformations including spina bifida, hydrocephalus, reduced fetal body weight, and skeletal ossification. Since the level of exposure that can lead to teratogenicity is unknown, topical tazarotene is contraindicated in pregnant patients (6).

OTHER TOPICAL TREATMENTS

Topical salicylic acid (category C) is widely used in over-the-counter acne treatment. Although topical salicylic acid penetrates the skin easily, there are no published reports of teratogenicity. Data on possible side effects from topical salicylic acid is taken from information on oral salicylates. Oral salicylates rapidly cross the placenta and are slowly eliminated from the fetus. A large prospective study of over 50,000 pregnant women concluded that there is no increased rate of malformations among babies born to mothers who ingested salicylates during their pregnancy. Thus, topical salicylates are unlikely to be teratogenic (5). Oral salicylates block cyclooxygenase in platelets, which is essential for platelet aggregation. There are reports of decreased platelet aggregation and impaired hemostasis in infants born to mothers who took aspirin during the last weeks of pregnancy. Though no data exists, concerns about possible infant bleeding tendencies from topical salicylic acid have been raised (5).

Because of the hormonal nature of acne, cysts can increase during this time. Intralesional kenalog can be helpful for large inflammatory lesions. To minimize the risk of atrophic scarring, it should be injected into the center of the lesion until the redness blanches (2).

SYSTEMIC TREATMENTS

When systemic therapy for acne is warranted, erythromycin (category B) is the agent of choice (2,3,6). Erythromycin crosses the placenta poorly resulting in low fetal tissue levels, but it can concentrate in the fetal liver (5). Of note, erythromycin estolate has been associated with hepatotoxicity in 10% to 15% of pregnant patients after prolonged use (3). For this reason, erythromycin estolate should be avoided in pregnancy because it appears to cause more liver toxicity than other erythromycin formulations.

Tetracyclines (category D) are not recommended in pregnancy. While they are not known to be teratogenic, they have a negative effect on developing bones and teeth (3). The major concerns related to the use of tetracyclines during pregnancy include development of acute fatty liver of pregnancy in the mother, abnormalities in tooth development, and reversible effects on bone growth in infants. Calcification of the deciduous teeth of children occurs from the fourth month of gestation until 6 to 14 months after birth. Calcification of the per-manent teeth begins 4 to 6 months after birth and ends around ages 5 to 12 years. Consequently, maternal tetracycline ingestion does not affect permanent denti-tion. Overall, tetracycline given during the second or third trimester results in deciduous teeth staining and possible enamel hypoplasia (5). For women of childbearing potential who inadvertently take tetracycline during the first weeks of pregnancy, it is unlikely to be teratogenic, but should be discontinued due to its effect on the developing teeth and bones of the fetus.

Zinc salts (category A) are an alternative systemic treatment for acne in pregnancy. Zinc inhibits chemotaxis, 5oc-reductase and tumor necrosis factor-oc production, and modulates integrin expression, mainly ICAM-1 and VLA-3 (2,8). These activities play a role in its anti-inflammatory properties. Dreno et al. performed a multicenter, randomized double-blind controlled trial comparing the efficacy of zinc (30 mg) versus minocycline (100 mg). They found that at three months, the efficacy of zinc was 17% lower than minocycline with respect to the mean change in lesion count (8). In clinical trials evaluating zinc salts in acne versus placebo, zinc salts were more effective in six out of nine studies (8). A large retrospective analysis of more than 2500 pregnant women in France evaluating zinc salts for acne found no abnormalities, congenital malformations, harmful effects, or risk to the fetus associated with zinc use (9). Zinc is typically dosed at 200 mg daily without food, and side effects include nausea and gastric pain (2).

In patients with severe inflammatory acne, short courses of oral steroids can be used after the first trimester. Discussion with the patient’s obstetrician prior to initiating therapy is essential (2). Oral isotretinoin (13-cis-retinoic acid) is a category X medication and is contraindicated in pregnancy. It is a potent teratogen in humans, and female patients must avoid pregnancy for four weeks after stopping isotretinoin (2).

REFERENCES

1. Nussbaum R, Benedetto A. Cosmetic aspects of pregnancy. Clin Dermatol 2006; 24:133 141.

2. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003; 49:S1 S38.

3. Hale EK, Pomeranz MK. Dermatologic agents during pregnancy and lactation: an update and clinical review. Int J Dermatol 2002; 41:197 203.

4. Zip C. A practical guide to dermatological drug use in pregnancy. Skin Therapy Lett 2006; 11(4):1 4.

5. Rothman K, Pochi P. Use of oral and topical agents for acne in pregnancy. J Am Acad Dermatol 1988; 19:431 442.

6. Hammadi A, Al Haddab M, Sasseville D. Dermatologic treatment during pregnancy: practical overview. J Cutan Med Surg 2006; 10(4):183 192.

7. Bologa M, Pastuszak A, Shear N, et al. Dermatologic drugs in pregnancy. Clin Dermatol 1992; 9:435 451.

8. Dreno B, Moyse D, Alirezai M, et al. Multicenter randomized comparative double blind controlled clinical trial of the safety and efficacy of zinc gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris. Der matology 2001; 203:135 140.

9. Dreno B, Blouin E. Acne, pregnant women and zinc salts: a literature review. Ann Dermatol Venereol 2008; 135(1):27 33.

Jean-Paul Marat

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