Pregnancy and dermatologic therapy
Dermatologists should be familiar with medication safety in pregnancy to be able to prescribe safely and confidently to pregnant women or women who may become pregnant during the course of treatment for dermatologic conditions. Topical medications should be considered first-line therapy for pregnant women, but certain systemic medications are safe to use in pregnancy and may be prescribed if necessary. Dermatologic surgery may be performed during the second trimester of pregnancy with proper positioning, but elective procedures should be delayed until the postpartum period.
Key words: dermatologic surgery, dermatologic therapy, medication safety, pregnancy, systemic medications, topical medications
Drug classification for pregnancy
Birth defects related to the use of diethylstilbestrol and thalidomide in the mid-20th century led to the development of the Food and Drug Administration (FDA) Pregnancy and Lactation Categories.2 One of 5 categories is assigned to each drug before it is released.3 Because of the impossibility of conducting controlled studies with medication use in pregnant women, these categories reflect a risk-benefit ratio based on animal studies or epidemiologic data.4 The classifications are included in Table I.3Table I. US Food and Drug Administration pregnancy risk categories
| Category | Description |
|---|---|
| X | Contraindicated in pregnancy; there is no reason to risk use of drug in pregnancy |
| D | Positive evidence of risk to human fetus, but benefits may outweigh risks of drug |
| C | Risk cannot be ruled out; human studies have not been performed; animal studies may or may not show risk; potential benefits may justify potential risk |
| B | No risk to human fetus despite possible animal risk; or no risk in animal studies and human studies not done |
| A | Controlled studies show no fetal risk |
Timeline for risk
When prescribing a medication, it is important to determine whether a patient is actively preventing pregnancy with contraception, trying to conceive or not preventing pregnancy, or is currently pregnant in a specific trimester and/or period of development (preimplantation, embryonic, or fetal).1For sexually active women not on contraception, there is an 85% chance of becoming pregnant within 1 year.7 Avoiding potentially teratogenic agents during the embryonic period, which is the second through the eighth week after conception when organogenesis occurs, is especially important.1 Because some women will not have a positive home pregnancy test result until up to 5 weeks after conception, these patients should be treated with medications that are safe during pregnancy.1 Although the highest period of risk is during organogenesis, certain structures, such as the brain, teeth, and bones, remain susceptible after 9 weeks. Thus, some medications that do not cause harm during organogenesis may cause complications later in pregnancy.1
Topical medications during pregnancy
For most dermatologic conditions in pregnancy, topical treatments remain the safest choice and should be considered first-line therapy. Table II summarizes the pregnancy classifications and risks of each topical medication.Table II. Pregnancy classifications and risks of topical medications for dermatologic therapy
| Medication | Pregnancy category | High-risk period | Risks/comments |
|---|---|---|---|
| Retinoids | |||
 Tretinoin | C | First trimester | Possible teratogen in first trimester, absorption minimal |
| Adapalene | C | First trimester | Possible teratogen in first trimester, absorption minimal |
| Tazarotene | X | Entire pregnancy | Retinoid-like anomalies in animal studies |
| Antibacterials | |||
| Clindamycin | B | None | |
| Erythromycin | B | None | |
| Metronidazole | B | None | |
| Dapsone | C | End of third trimester | Theoretical risk of neonatal hyperbilirubinemia if used near time of delivery |
| Mupirocin | B | None | No large studies available |
| Neomycin | B | None | No large studies available |
| Polymyxin B | B | None | No large studies available |
| Nonantibacterial antiacne products | |||
| Sodium sulfacetamide | C | None | |
| Benzoyl peroxide | C | None | |
| Salicylic acid | C | None | Do not apply over large areas under occlusive dressings, 9-25% absorbed |
| Azelaic acid | B | None | <4% Absorbed |
| Immunosuppressants | |||
| Corticosteroids | C | Third trimester with high doses | Possible risk of low birth weight in some studies with excessive absorption |
| Tacrolimus | C | None | Data in human beings limited |
| Pimecrolimus | C | None | Data in human beings limited |
| Antipsoriatics | |||
| Calcipotriene | C | None | Skeletal abnormalities in animal studies, no such findings in human studies |
| Anthralin | C | None | No evidence of systemic absorption, no studies during pregnancy in human beings or animals |
| Antifungals | |||
| Clotrimazole | B | None | |
| Oxiconazole | B | None | |
| Econazole | C | None | Limited data |
| Ketoconazole | C | None | Limited data |
| Ciclopirox | B | None | |
| Naftifine | B | None | |
| Terbinafine | B | None | |
| Butenafine | B | None | |
| Nystatin | B | None | |
| Antiparasitic | |||
| Permethrin | B | None | Has been used extensively in pregnancy |
Acne and rosacea
For acne and rosacea, a plethora of topical medications are available, most of which are safe for use during pregnancy. The topical retinoids tretinoin and adapalene are category C. Some studies suggest that topical tretinoin is teratogenic in the first trimester,8, 9, 10 but another study contradicts that finding.11 Absorption is minimal, and risk is unlikely, but alternative treatments should be considered in the first trimester if they are available.12 Adapalene, also category C, has minimal absorption, so use during pregnancy could be considered once the benefits and risks have been discussed with the patient.12 Data suggest that the potential risk of teratogenicity of both agents is only during the first trimester, and no problems have been reported in studies where use occurs in the second and third trimester.12 A practical approach would be to consider treatment with these agents after the first trimester in consultation with the patient’s obstetrician. Topical tazarotene, on the other hand, is category X because of retinoid-like anomalies found in animal studies, so it is contraindicated.12Antibacterial topical agents used for acne and rosacea include clindamycin, erythromycin, and metronidazole, all of which are category B and safe throughout pregnancy.12 Topical dapsone, a category C medication, has been used safely as an oral medication in pregnancy for both leprosy and dermatitis herpetiformis, and no fetal risks are reported in the literature.12 There is a theoretical risk of neonatal hyperbilirubinemia when used near the time of delivery, so the prescribing physician should consider stopping treatment before the last month of pregnancy.12 Topical sodium sulfacetamide, on the other hand, is a category C medication that is not associated with hyperbilirubinemia, so its use is not contraindicated anytime during pregnancy.12 The nonantibacterial antiacne product benzoyl peroxide is category C because human studies have not been conducted, but it is considered safe to use during pregnancy and is a treatment of choice for acne in pregnant patients.1, 4, 12 Salicylic acid, another nonantibacterial antiacne product, is also category C. Although this is an nonsteroidal anti-inflammatory drug, which is generally contraindicated in pregnancy because of the potential for oligohydramnios and early closure of the ductus arteriosus in the third trimester,1 the systemic absorption is estimated to be between 9% and 25%.13, 14, 15 Because of its minimal absorption, there is a very low teratogenic potential,16 and pregnant women should simply be advised not to apply topical salicylic acid for prolonged periods over large areas or under occlusive dressings, which would enhance systemic absorption. Azelaic acid is pregnancy category B because animal studies show no adverse effects, and less than 4% of the applied dose is systemically absorbed.4, 12, 15
Psoriasis and atopic dermatitis
For inflammatory skin conditions such as psoriasis, topical corticosteroids are considered first-line therapy in pregnant patients. A detailed review of pregnancy and psoriasis was performed by Tauscher et al17 in which they outlined a stepwise approach for treatment. For localized disease in pregnancy, they recommended topical corticosteroids as first-line therapy followed by stepwise therapy with topical calcipotriene, anthralin, and tacrolimus.1 Although all of these topical medications are category C, there are many data on corticosteroid use for a variety of medical conditions in pregnancy, so they are currently the preferred first-line therapy.The absorption, and therefore the safety in pregnancy, of topical corticosteroids is related to a number of factors, including the vehicle of administration, amount applied, occlusion, and sites of application.4 A practical approach to therapy with topical corticosteroids in pregnant women would be to advise them not to apply large amounts over extensive areas or under occlusive dressings to avoid excessive absorption16 because of certain studies that associate such use with a risk of low birth weight.12
In pregnancy, topical calcipotriene should be considered the next step in therapy for psoriasis. Topical calcipotriene is FDA pregnancy category C, and although skeletal abnormalities have occurred in animal studies, no such findings have been shown in human beings.12 Practical usage limits and avoidance of occlusive dressings as described above for topical steroids will likewise help avoid systemic absorption and lower the risk of vitamin D toxicity. If both topical steroids and calcipotriene fail, alternative options for topical treatment are anthralin and tacrolimus.1 There are no studies on the use of anthralin during pregnancy in human beings or animals, but because there is also no evidence of systemic absorption after topical application, its use is not contraindicated.16 Likewise, data in human beings are limited for tacrolimus, but there have been no problems reported from topical use during pregnancy.12, 16 Both anthralin and tacrolimus are pregnancy category C, and until more data are available on their use in pregnancy, they remain third- and fourth-line treatment options.
Pimecrolimus is a common topical treatment for atopic dermatitis. Similar to tacrolimus, it is a category C medication and no problems have been reported from its use during pregnancy, but data are limited.12 If topical corticosteroids fail, pimecrolimus would be an acceptable topical treatment for atopic dermatitis during pregnancy.
Topical antimicrobials
For bacterial infections, topical antibiotics such as mupirocin, neomycin, and polymyxin B are not associated with teratogenicity.12 Large studies have not been conducted on any of these, but they are considered safe to use during pregnancy.12Topical antifungals are considered a safer alternative to oral antifungals during pregnancy. Of the imidazoles, the 2 preferable options are clotrimazole and oxiconazole, which are both category B.4 All other topical imidazoles, including econazole and ketoconazole, are category C because of limited data, but no specific adverse effects from the use of these topical imidazoles have been reported.12 Topical ciclopirox, naftifine, terbinafine, butenafine, and nystatin are all category B because there have been no problems reported from topical use during pregnancy.12
Topical permethrin is the drug of choice for scabies and lice occurring in pregnancy and is poorly absorbed. It has been used extensively with minimal adverse effects reported, thus it is category B.12
Systemic medications during pregnancy
Although systemic medications should only be used when absolutely necessary during pregnancy, it is important to know the safety ratings of systemic treatments for common dermatologic conditions, especially for patients who may become pregnant during the course of treatment or in circumstances where delaying or interrupting treatment until pregnancy is completed is not advisable. Table III summarizes the pregnancy classifications and risks of each systemic medication.Table III. Pregnancy classifications and risks of systemic medications for dermatologic therapy
| Medication | Pregnancy category | High-risk period | Risks/comments |
|---|---|---|---|
| Antibiotics | |||
| Tetracyclines | D | Second and third trimester | Dental staining and enamel hypoplasia in second and third trimester, has been associated with acute fatty liver of pregnancy |
| Erythromycin | B | First trimester | Hepatotoxicity rare with prolonged use in pregnancy, possible increased risk of cardiovascular malformations in early pregnancy |
| Azithromycin | B | None | |
| Penicillins | B | None | |
| Cephalosporins | B | None | |
| Retinoids | |||
| Isotretinoin | X | Entire pregnancy | Increased fetal loss in first trimester, microtia, external ear canal stenosis, cleft palate, hydrocephalus, cardiac outflow tract defects |
| Acitretin | X | Entire pregnancy | Craniofacial, cardiac, thymic, and central nervous system malformations |
| Diuretic/antiandrogenic | |||
| Spironolactone | C | After 8 wk | Delayed sexual maturation of female rat fetuses and feminization of male rat fetuses in animal studies; risk to human fetus is only theoretical, as case reports show no adverse effects in human pregnancy |
| Antirheumatics/antimetabolites | |||
| Methotrexate | X | Entire pregnancy | Increased risk of miscarriage, micrognathia, developmental delays, craniosynostosis, small low-set ears, limb abnormalities, and growth retardation |
| Hydroxychloroquine | C | None | Not associated with a specific congenital malformation |
| Immunosuppressants | |||
| Cyclosporine | C | None | No specific birth defects, data on long-term outcomes lacking |
| Corticosteroids | C | Third trimester with high doses | Potential for growth retardation and inhibition of endogenous corticosteroid production when used in high doses |
| Mycophenolate mofetil | D | Entire pregnancy | Increased risk of miscarriage and anomalies of distal limbs, heart, esophagus, kidney, external ear, and face |
| Phototherapy | |||
| Broadband ultraviolet B phototherapy | - | First 28 d of pregnancy | Avoid overheating during therapy |
| Biologics | |||
| Adalimumab | B | None | Limited data |
| Etanercept | B | None | Limited data |
| Infliximab | B | None | Limited data |
| Antihistamines | |||
| Cetirizine | B | None | Potential sedation of neonate in nursing mothers |
| Diphenhydramine | B | None | Potential sedation of neonate in nursing mothers |
| Loratadine | B | None | Potential sedation of neonate in nursing mothers |
| Chlorpheniramine | B | None | Potential sedation of neonate in nursing mothers |
| Antifungals | |||
| Terbinafine | B | None | Do not electively use to treat onychomycosis during pregnancy per manufacturer |
| Griseofulvin | C | Entire pregnancy | Increased risk of skeletal and central nervous system anomalies and fetal loss |
| Ketoconazole | C | Entire pregnancy | Sexual ambiguity of a male fetus, can interfere with pregnancy implantation |
| Itraconazole | C | None | Lowest teratogenic potential of all imidazoles |
| Fluconazole | C | None | Single-dose use confirmed safe |
| Antiparasitic | |||
| Ivermectin | C | None | Teratogenic to animals in high doses |
Acne
Acne is a common condition that is generally unaffected by pregnancy.1 The 2 most common systemic medications used to treat acne are antibiotics and isotretinoin. Isotretinoin is category X and should be avoided during pregnancy or in those patients trying to conceive.18 Increased fetal loss may result from first-trimester use, and specific malformations including microtia, stenosis of the external ear canal, cleft palate, hydrocephalus, and cardiac outflow tract defects may occur with use later in pregnancy.1 The risks of systemic retinoid exposure during embryogenesis have been extensively reviewed, and a detailed discussion is beyond the scope of this review article. We would direct interested readers to the included references.19, 20, 21, 22, 23, 24, 25, 26, 27, 28Tetracyclines are known to deposit in developing bones and teeth during the second and third trimester, resulting in enamel hypoplasia and a yellowish staining of the teeth that will darken over time.12, 29 Tetracyclines have also been associated with acute fatty liver of pregnancy, which is a potentially fatal syndrome that occurs in the third trimester.4 Interestingly, tetracyclines have not been associated with congenital anomalies during the first trimester,12 so as long as they are discontinued as soon as pregnancy is suspected, there is very little risk. However, because of multiple concerns with use during the second and third trimester, they are classified as category D and should be avoided during later pregnancy. Erythromycin is category B and is considered safe in pregnancy; however, hepatotoxicity may rarely occur with prolonged use of the erythromycin ethylsuccinate formulation in pregnant patients.4 In addition, 2 Swedish studies have reported an increased risk of cardiovascular malformations when erythromycin was used early in pregnancy.30, 31 Alternative antibiotics in later pregnancy are azithromycin, penicillins, and cephalosporins, all of which are pregnancy category B.5
Spironolactone, an antiandrogenic drug that competitively inhibits 5α-reductase and aldosterone, is often prescribed off-label for acne.32 Pregnancy category C, spironolactone caused feminization of male rat fetuses and delayed sexual maturation of female rat fetuses in animal studies, but those effects have not been observed in human beings.1 The differentiation of the urogenital tract does not occur until after 8 weeks, so any theoretical risk would occur after that point,1 but 2 case reports of 5 pregnancies where spironolactone was used by the mother showed no abnormalities in the 2 female and 3 male children.33, 34
Psoriasis
Psoriasis, a chronic inflammatory skin condition, affects 2% to 3% of the population,35, 36 and data show that 44% of patients with psoriasis were female and of reproductive age.17 It is expected, then, that all dermatologists will encounter pregnant patients and patients of childbearing age with psoriasis. Approximately 50% of women with psoriasis will improve during pregnancy, but it can worsen in up to 20%.1 Topical treatments are first-line therapy for psoriasis, but systemic treatments may be required for moderate to severe disease.Oral retinoids, such as acitretin, that are used to treat psoriasis cause craniofacial, cardiac, thymic, and central nervous system malformations and are contraindicated in pregnancy.16 Like all oral retinoids, acitretin is a category X medication.
Methotrexate, a folic acid antagonist used to treat inflammatory skin disorders such as psoriasis, is also used as an abortifacient for conditions such as ectopic pregnancy, so it is contraindicated in pregnancy. Aside from an increased risk of miscarriage, associated malformations include micrognathia, developmental delays, craniosynostosis, small low-set ears, limb abnormalities, and prenatal growth retardation.37, 38
Cyclosporine, a category C medication used for moderate to severe psoriasis, acts as a selective immunosuppressant by inhibiting T lymphocytes.16 It has mainly been studied in pregnant organ transplant recipients, making it difficult to separate the effects of cyclosporine from those of other medications.16 No specific birth defect has been attributed to cyclosporine, but data on long-term outcomes are lacking.4 For pregnant patients, its benefits outweigh any theoretical risks, and it appears to be safe for the fetus.1
Broadband ultraviolet B phototherapy is considered safe during pregnancy, with no adverse outcomes reported in studies.39, 40 For extensive psoriasis during pregnancy, this appears to be the safest systemic therapy, but overheating during treatment should be avoided because of an increased risk of neural tube defects if hyperthermia occurs during neural tube formation in the first 28 days of gestation.1, 2
Data are currently limited on biologic agents such as adalimumab, etanercept, and infliximab, but all are listed as pregnancy category B. Pregnancy registries have been established for these medications, but given the limited data, the benefits of therapy should be carefully weighed against any unknown risk to the fetus.12 Currently, no specific congenital malformations have been attributed to any of the above medications when used at any time during the pregnancy.
Atopic dermatitis
For atopic dermatitis during pregnancy, topical medications should be prescribed initially, but the occasional use of systemic steroids may be considered in severe or refractory cases. Pregnancy category C, oral steroids appear to be safe when used in moderate doses and for the shortest duration possible.5 Some potential problems with high doses of systemic corticosteroid use during pregnancy include intrauterine growth retardation and inhibition of endogenous corticosteroid production.6, 41, 42, 43, 44 Some studies have shown an association between orofacial clefts and corticosteroid use in pregnancy, but a recent publication by Hviid and Molgaard-Nielsoen45 shows no such association. When faced with a patient with a severe atopic dermatitis flare, either systemic corticosteroids or cyclosporine would be acceptable choices, as neither is associated with an increase in congenital malformations when used in pregnancy for other conditions such as asthma and autoimmune disease.1Mycophenolate mofetil, an immunosuppressive agent used to treat moderate to severe refractory atopic dermatitis, has been assigned a pregnancy category D because of an increased rate of spontaneous abortions and certain congenital malformations including anomalies of the distal limbs, heart, esophagus, and kidney as well as external ear and facial abnormalities such as cleft lip and palate.16 Mycophenolate mofetil should be avoided during pregnancy and in women who are not actively preventing pregnancy.
For conditions such as atopic dermatitis, antihistamines may be used for itching. Most antihistamines, including cetirizine, diphenhydramine, loratadine, and chlorpheniramine are pregnancy category B and are safe to use.12 It is important to note that antihistamines should be avoided during lactation in nursing mothers if possible because of possible sedating effects on the neonate.12
Connective tissue disease
For pregnant women with severe discoid lupus or systemic lupus erythematous, the systemic medication hydroxychloroquine is category C and has not been associated with a specific congenital malformation. Because stopping hydroxychloroquine can precipitate a lupus flare, most experts recommend continuing therapy if it is currently in use when a patient becomes pregnant.1 When faced with a patient with cutaneous lupus who is not at risk for a systemic flare and who is either pregnant or trying for pregnancy, short-term oral steroids along with topical steroids may be a better treatment option because more data are available regarding corticosteroid use in pregnancy.Fungal and parasitic infections
For fungal infections during pregnancy, oral antifungals pose greater risks than topical agents.4 That said, terbinafine is a category B medication because of a low risk for fetal harm in animal studies and is the systemic treatment of choice for a dermatophyte infection during pregnancy. The manufacturer does recommend not using oral terbinafine electively to treat onychomycosis during pregnancy.12The other major antifungals, griseofulvin and the imidazoles, are all pregnancy category C. In animal studies, griseofulvin showed an increased risk of skeletal and central nervous system anomalies and of fetal loss.1, 4 Certain studies indicate an increased risk for conjoined twins as well,1, 12 so griseofulvin use during pregnancy is not recommended. Ketoconazole can inhibit androgen synthesis, increasing the risk of sexual ambiguity of a male fetus.1 It can also impair progesterone secretion and interfere with early pregnancy and implantation,4 so it should not be used during pregnancy. The newer imidazoles itraconazole and fluconazole, both category C, have been the subject of large cohort studies that indicate neither is teratogenic.1 Some studies suggest that fluconazole should be avoided in prolonged high doses to avoid the risk of malformations, but multiple studies have confirmed the safety of a single oral dose, typically used by obstetricians to treat vaginal candidiasis.4, 12 Itraconazole has the lowest teratogenic potential because it has minimal effect on the steroid hormones.12
Finally, because it is teratogenic to animals in high doses, the category C medication ivermectin should be avoided as a treatment for scabies in lieu of permethrin, a safer topical FDA category B medication.12
Dermatologic surgery during pregnancy
Most experts agree that nonemergent surgery during pregnancy be performed during the second trimester (weeks 13-24) or postpartum to avoid the possible risk of spontaneous abortion in the first trimester or preterm labor in the third trimester.46 If possible, the patient should be placed in the left lateral position to avoid compression of the vena cava by the pregnant uterus, but positioning on the right side is an acceptable alternative to avoid supine positioning.46 Alcohol and chlorhexidine preparations for the surgical site are acceptable to use during pregnancy, but povidone-iodine absorption through mucous membranes has been associated with fetal hypothyroidism.47, 48, 49 and hexachlorophene has been reported to cause fetal central nervous system toxicity.47, 48Most dermatologic procedures can be performed using local anesthetics. Lidocaine and prilocaine are both category B medications, and multiple studies have shown no increased risk of adverse effects in the fetus.46 Local anesthetics do cross the placental barrier, but the only potential risk to the fetus would be in the case of injection of excessive amounts or inadvertent arterial injection.50 Risks to the fetus in that case would be central nervous system or cardiac toxicity.46 Local anesthetics such as mepivacaine and bupivacaine increase the risk of fetal bradycardia,51 so lidocaine and prilocaine would be the anesthetics of choice.
Epinephrine is often added to lidocaine in small concentrations as a vasoconstrictor to reduce bleeding at the operative site. It is a category C medication because of decreased uterine blood flow with use during animal experiments.46 Considering the dilution and small amounts used during dermatologic procedures, potential risk is probably outweighed by the benefits of decreased bleeding during procedures, so epinephrine is considered safe when used judiciously.46
With regard to antibiotics and pain control, medications that are category A and B should be first-line. Antibiotics were previously discussed in the section on systemic medications. For pain control, acetaminophen is category B and is first-line. Opioid narcotic pain medications are all category C because of the risk of neonatal respiratory depression from high doses used near the time of delivery and the risk of neonatal withdrawal from chronic maternal use.12 If opioids are necessary for pain control, they should be used in the lowest dose and for the shortest possible duration to avoid fetal withdrawal.1 Also, pain medications including nonsteroidal anti-inflammatory drugs should be avoided because of the risk of oligohydramnios and premature closure of the ductus arteriosis.1
Procedures such as cryotherapy, laser ablation, and application of trichloroacetic acid that involve local destruction of lesions without anesthetics are safe to perform during pregnancy.1 Podofilox, 5-fluorouracil cream, and interferon are not recommended during pregnancy, however, because of concerns regarding maternal and fetal safety.1
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