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N O V E M B E R 2 0 0 3
Members of the
Dermatological Drugs in Pregnancy
Division of Dermatology
By MOHAMMED AL-HADDAB, MD, DENIS SASSEVILLE, MD, FRCPC Three percent of all children born in the United States have a major structural malforma-
tion that is detectable at birth1 and at least 10% of birth defects are thought to result from
maternal drug exposure.2 The approach of the medical community to using medication during
pregnancy has changed dramatically since the early 1960s, largely because of the epidemic of
phocomelia that followed the introduction of thalidomide and the late occurrence of vulvo-
vaginal neoplasias in the female offspring of women who had received diethylstilbestrol dur-
ing pregnancy. Since 1975, the U.S. Food and Drug Administration (FDA) has assigned
pregnancy risk factors to all drugs used in the United States (Table 1). Unfortunately, many
drugs have not been adequately researched during pregnancy and, because of ethical consid-
erations, probably will not be in the future.4
While many drugs pose minimal risk during pregnancy and lactation, dermatologists are
often reluctant to prescribe any drugs during this period because many common dermatolog-
ical conditions do not necessitate immediate therapy. Some patients are therefore denied
effective treatment for their cutaneous condition because of excessive caution on the part of
their physicians. On the other hand, when treating patients during pregnancy and lactation,
dermatologists must be familiar with the potential effects that certain medications may have
on the developing fetus or the nursing infant. When a drug commonly used to treat a specific
dermatological condition is potentially teratogenic, there are often alternatives that are safer
to use in the pregnant or lactating patient.5
After a brief summary of maternal pharmacokinetics and fetal development, this issue of
Dermatology Rounds will review the safety of dermatological medications during pregnancy.
The authors have decided on an approach by “disease” rather than by “drug” and challenge
the reader to a quiz focusing on a series of clinical situations at the end of the article.
Enjoy your reading!
Centre universitaire
Maternal pharmacokinetics
de santé McGill
The 4 basic processes that govern the ultimate action of a drug are absorption, distribution, McGill University
biotransformation, and excretion.6 The physiological changes that occur throughout pregnancy Health Centre
may considerably alter these fundamental functions. High levels of progesterone in pregnancyare responsible for delayed gastric emptying, decreased gastrointestinal motility, and hyper- McGill University Health Centre
emesis gravidarum. The normally rapid absorption of lipophilic drugs is not modified, but hydrophilic, slowly transferred, and ionized drugs are more completely absorbed than in the non-pregnant state and display a greater toxicity.7 The extracellular volume increases by up to 50% in the latter half of pregnancy, an expan- sion that directly affects the distribution of most drugs. Thus, larger loading doses are usually required to achieve similar plasma levels than during the nonpregnant state. Protein binding decreases so that, at equilibrium, concentrations of pharmacologically-active free drugs may be higher.8 The editorial content of Dermatology Hepatic blood flow is unmodified by pregnancy, but progesterone increases the activity of Rounds is determined solely by the Division of Dermatology, McGill hepatic microsomal enzymes, which causes faster inactivation of many drugs.7 Cardiac output Table 1: FDA Pregnancy Drug Risk Categories
Table 2: Teratogenic effects of synthetic
retinoids
Positive evidence for risk to human fetus.
Craniofacial
Risk cannot be ruled out. Animal studies animal risk. Or: no risks in animal studies, Controlled studies show no fetal risk.
Central nervous system
Unrated: No pregnancy category has been assigned.
• Obstructive hydrocephalus• Non-obstructive hydrocephalus and glomerular filtration rates increase by 30%-50% during pregnancy. In the absence of toxemia and fluid retention, drugs that are eliminated by the renal route will clear more rapidly and have a shorter half-life.9 Cardiovascular system
Fetal development
• Tetralogy of Fallot• Transposition of the great vessels The implantation stage of fetal development extends from day 1 to day 17 after conception. At this stage, all cells are pluripotent and administration of toxic drugs tothe mother will result in abortion rather than in fetal Skeletal system
malformations.The embryonic stage spans the second to eighth week of pregnancy. Organogenesis occurs during this critical period when teratogenic drugs are most like- ly to exert their deleterious effects. The fetal stage coversthe period between the eighth week of pregnancy andparturition. Adverse effects of drugs given in this period Psoriasis
include delayed somatic and psychomotor development, Topical corticosteroids (category C) can generally be as well as abnormal differentiation of genitalia. In the utilized with relative safety during pregnancy since only perinatal period, drugs may cause a variety of side effects approximately 3% of the medication in topical prepara- related to their pharmacologic activity, such as sedation, tions is absorbed following 8 hours of contact with nor- respiratory distress, hypotonia, jaundice, bleeding, etc.
mal skin.11 Calcipotriene (category C) is likewise safe forthe treatment of localized psoriasis during pregnancy, as A review of dermatological agents and their effects
approximately 6% of the drug is absorbed systemically during pregnancy
when the ointment is applied to psoriatic plaques.11 Acne
The general feeling about anthralin and tar is that Isotretinoin is classified as category X and is well these agents should be avoided during pregnancy.9 As known for its teratogenic effects during pregnancy PUVA is mutagenic and induces sister chromatid (Table 2). Although tetracycline (category D) does not exchange, it is considered a potential human teratogen.12 appear to be teratogenic when administered in the first When this therapeutic modality is needed, topical trimester, there is a risk of fatty liver atrophy in the PUVA should be chosen. For patients with localized dis- mother and deciduous dental staining in offspring when ease of the palm and soles, topical PUVA does not give administered later in gestation. Erythromycin (category rise to detectable blood levels of 8-methoxypsoralen.13 B) is the agent of choice when a systemic antibiotic is Ultraviolet B phototherapy is the safest treatment for Topical therapy is the preferred method of treat- Systemic corticosteroids in high doses have caused ment for pregnant women with acne. Topical ery- cleft palate in experimental animal models and low birth thromycin (category B), clindamycin (category B) and weight in humans.14 Placental 11-hydroxygenase meta- benzoyl peroxide (category C) were recommended as bolizes the short-acting agents prednisone, prednisolone, the treatments of choice in a recent review.10 Topical and methylprednisolone, and the fetus is exposed only to metronidazole (category B) is another safe alternative.
approximately 10% of the maternal dose. There is no Tretinoin (category C) has been considered as alternative evidence that either prednisone or methylprednisolone therapy in pregnancy.10 Tazarotene (category X) should are teratogenic in humans.15,16 Acitretin (category X) not be used in pregnant patients, although 6 women and methotrexate (category X) are absolutely contra- exposed to it during pregnancy had healthy babies.5 Pruritus and pruritic conditions
recent study suggests that mebendazole does not repre- The first-generation H -antihistamines are consid- sent a major teratogenic risk in humans when used in the ered relatively safe in pregnancy. Promethazine and doses recommended for pinworm (Enterobius vermicu- hydroxyzine are category C, while chlorpheniramine, laris) infestation.24 Thiabendazole (category C) has not diphenhydramine, and cyproheptadine are category B.
been associated with adverse effects in human pregnancy, Hydroxyzine is not thought to be associated with birth but its safety is not clearly established. The newer alben- defects.3,17 Among the second-generation H -antihista- dazole has shown some teratogenicity in animals and its mines, cetirizine and loratadine are the only two non- use is contraindicated in pregnancy.
sedating agents in FDA category B, while fexofenadine iscategory C.5 The H -inhibitor cimetidine (category C) Analgesics
has antiandrogenic effects when administered at high Acetaminophen (category B) in therapeutic doses is doses and carries the potential risk of feminization of a safe for short-term use during all stages of pregnancy.
male fetus when given to a pregnant patient. Doxepin Non-steroidal anti-inflammatory agents such as ibupro- (unrated) should be avoided, especially close to the time fen, ketoprofen, naproxen, and indomethacin are consid- of delivery because it can induce ileus, cardiac dysryth- ered to be FDA category B. However, when used in the mias, irritability, and respiratory distress in the newborn.18 third trimester or near delivery, they are classified ascategory D because of the reported association with Bacterial infections
oligohydramnios, prolonged labour, and premature clo- Penicillins, cephalosporins, erythromycin, and azi- sure of ductus arteriosus.5 These effects are secondary to thromycin are all FDA category B and considered safe in the inhibition of prostaglandin synthesis. A recent meta- pregnancy. Sulfonamides are classified as category B for analysis showed no evidence of an overall increase in most of the gestation period, but are considered category congenital malformation due to aspirin except for a D when used near term because of the risk of hyper- possible increased risk of gastroschisis when exposure bilirubinemia and kernicterus. Quinolones (category C) should be avoided in pregnancy because they have dele-terious effects on growing cartilage.3 Local anesthesia
There is no contraindication to the use of lidocaine Fungal infections
(category B) with or without epinephrine (category B) Topical antifungals are relatively safe in pregnancy.
during pregnancy for routine dermatological biopsies Ketoconazole (category C) may cause sexual ambiguity in the developing male fetus by inhibiting androgensynthesis.5 Itraconazole (category C) appears to be safe Clinical situations
in pregnancy according to a recent prospective cohort Case 1: A 42-year-old woman with dermatitis her-
study.19 The allylamine terbinafine (category B) is proba- petiformis is treated and well-controlled with dapsone bly even safer. Amphotericin B (category B) remains the (avlosulfone) 100 mg orally per day. She has no children drug of choice for systemic invasive mycotic infections, and wants to become pregnant. What is your advice? whether they are life-threatening or less severe.20 Case 2: A 37-year-old woman suffering from
Behcet’s disease and treated with colchicine presents to Viral infections
the clinic with a positive pregnancy test. Based on the Trichloroacetic acid and physical modalities such as date of her last menstrual period, you estimate a gesta- cryotherapy, electrodesiccation, and laser vaporization tional age of 7 weeks. Will you recommend an amnio- are effective alternatives that are thought to be safer during pregnancy than imiquimod (category B) and Case 3: A 25-year-old woman has discoid lupus
podophyllin (category C) for the treatment of genital erythematosus of the scalp, well controlled with oral warts.9,21 Five hundred and fifty-two women exposed to hydroxychloroquine. She comes to your office in tears, acyclovir (category C) during the first trimester of preg- saying, “Doctor, I am 14 weeks pregnant and I stopped nancy demonstrated no increased rate of birth defects.22 taking the medication 3 weeks ago. I want to keep my Published information is scanty on the newer antivirals child, but I don’t want to lose my hair, what am I sup- such as famciclovir (category B) and valacyclovir (cate- Case 4: A 32-year-old primigravida, in her 26th
week of pregnancy, comes to the emergency room with Parasitic infestations
fever and a generalized pustular eruption of sudden Permethrin (category B) and precipitated sulfur are onset, consistent with pustular psoriasis or impetigo her- considered safe during pregnancy. Ivermectin (category C) is teratogenic in animals at high doses and should be Case 5: A 30-year-old woman, known for recurrent,
avoided during pregnancy pending further studies.23 A moderately severe erythema multiforme, on suppressive acyclovir therapy, is planning to get pregnant in the pregnant patients with cutaneous involvement only, near future. She wants to know if acyclovir can the risks probably outweigh the benefits. Other cause potential fetal adverse effects. What are her therapeutic modalities, such as potent topical or intralesional corticosteroids, should be considered as Case 6: A 29-year-old Vietnamese woman, a
newly landed immigrant, is 11 weeks pregnant and Case 4: Fulminating generalized pustular psori-
presents to the dermatology clinic with a skin lesion asis in pregnancy is best treated with prednisolone, on the dorsum of her right hand that has slowly the drug that carries the least hazard for the fetus.28 been enlarging over a few months. A skin biopsy In a 4- to 5-year follow-up of children whose moth- confirms the diagnosis of tuberculosis verrucosa ers had received cyclosporin-A (category C) during cutis. How should this patient be treated? pregnancy, no structural malformations or signifi- Case 7: A 27-year-old woman in her 18th week
cant learning disabilities were noted.29 Several stud- of pregnancy presents with severe candidal vaginitis ies have reported no problems in infants whose and intertrigo not responding well to topical antifun- mother or father had been treated with oral 8- gals. Can you safely treat her with a systemic agent? methoxypsoralen (category C) and UVA in the Case 8: A 38-year-old healthy woman comes to
preconceptional period or during early pregnancy.
the clinic with her 47-year-old husband who is on However, these studies were small. It has been sug- methotrexate for psoriasis and psoriatic arthritis.
gested that women who become pregnant during or They are planning to have a baby and ask you if after PUVA treatment should be offered prenatal methotrexate will adversely affect their future child karyotyping to rule-out the possibility of chromoso- Case 9: A 20-year-old woman, with moderately
Case 5: Acyclovir (category C) is not terato-
severe atopic dermatitis that is well-controlled by genic in animals, but it causes fetal death, growth topical tacrolimus, wants to become pregnant. She retardation, and malformations in rats at mater- asks if it is safe to continue the medication during notoxic doses. Use in human pregnancies has not been associated with adverse fetal effects. Briggsstates that there are insufficient available data to Answers to the clinical situations
establish the safety of this medication and that its Case 1: Briggs states that the use of dapsone
use for recurrent herpes simplex infection is not a (category C) during pregnancy poses no major risk convincing indication.18 In pregnancy, acyclovir should to the fetus. Numerous women have conceived nor- be restricted to severe infections. In cases of recur- mal offspring while receiving dapsone for leprosy.
rent, widespread, and incapacitating erythema mul- Stopping therapy during the last month of pregnancy tiforme, the use of acyclovir is probably justified.
may minimize a theoretical risk of neonatal Case 6: Isoniazid, rifampin, ethambutol, and
pyrazinamide have an excellent safety record in Case 2: The children of 116 women taking
pregnancy and are not associated with human fetal colchicine (category D) for familial Mediterranean malformation. Streptomycin should not be used fever were followed. Among 225 completed preg- since 1 in 6 infants will have hearing loss and nancies, an unusual frequency of fetal abnormalities vestibular problems. Tuberculin testing is safe, while could not be found. Colchicine therapy during BCG vaccine should be avoided in pregnancy.
pregnancy does not apparently harm mother or Among the second-line agents used for treating drug-resistant tuberculosis, ciprofloxacin (category Case 3: Both chloroquine and hydroxychloro-
C) has the best safety profile, despite its potential quine (unrated) accumulate in the fetal eye and are retained in ocular tissue for at least 5 months. The Case 7: Fluconazole (category C) in high doses
terminal half-life of hydroxychloroqine is 1 to 2 has been associated with human malformations.18 months.18 Cases of fetal retinal degeneration and First trimester exposure to low doses of fluconazole severe cochleo-vestibular dysfunction have been does not appear to increase the prevalence of mis- recorded, but other authors have not found a carriages, congenital anomalies, or low birth weight.31 greater risk of malformation. Some argue that the Case 8: Both males and females should avoid
risk of an exacerbation of collagen vascular disease methotrexate if pregnancy is anticipated, at least also puts the fetus at risk and that continuation of 3 months for males, and 1 menstrual period for antimalarials during pregnancy should be seriously considered.27 This course of action appears to be Case 9: In a recent study, after topical applica-
justified in systemic lupus erythematosus, but in tion, tacrolimus (category C) was undetectable in Table 3: A summary of FDA Pregnancy and Lactation Categories for some systemic and
topical medications (Refer to Table 1 for meaning of letter designation).
Antibiotics
Parasiticides
Antihistamines
Analgesics
Miscellaneous
Local anesthetics
Antifungals
Antineoplastic/
Immunosuppressants
Antivirals
80% of collected blood samples. In the other 20%, 4. Black RA, Hill A. Over-the-Counter medications in pregnancy.
Am Fam Physician 2003;67(12):2517-2524.
measurable levels of tacrolimus were transitory and 5. Hale EK, Keltz Pomeranz M. Dermatological agents during not associated with adverse events.33 The drug pregnancy and lactation. An update and clinical review. Int J appears reasonably safe for topical use during preg- nancy except for widespread application to areas 6. Juchau MR Faustman-Watts E. Pharmacokinetic considera- tions in the maternal-placental-fetal unit. Clin Obstet Gynecol where the integrity of the cutaneous barrier is signi- ficantly compromised (eg, Netherton Syndrome).11,34 7. Livezey GT, Rayburn WF. Principles of perinatal pharmacolo- gy. In: Rayburn WF, Zuspan FP, eds. Drug Therapy in Obstetricsand Gynecology. 3rd ed. St.Louis: Mosby-Year Book;992:3-11.
Conclusion
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2nd ed. Norwalk, CT: Appleton & Lange;1992:68-79.
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routinely prescribes (Table 3). The pregnant patient 10. Koren G, Pastuszak A, Itu S. Drugs in pregnancy. N Engl J Med ultimately needs to decide if she wants to expose her fetus to a systemic drug. An informed decision 11. Tausher AE, Fleischer AB Jr., Phelps KC, Feldman SR. Psoria- sis and pregnancy. J Cutan Med Surg 2002;6:561-570.
about whether or not to treat a woman during 12. Stern R S, Lange R. Outcome of pregnancies among women pregnancy should be based on the potential risks of and partners of men with a history of exposure to PUVA for the drug versus the degree to which the condition the treatment of psoriasis. Arch Dermatol 1991;127:347-350.
13. Pham C T, Kuo J Y. Plasma levels of 8-Methoxypsoralen after affects the woman’s health and well-being.
topical paint PUVA. J Am Acad Dermatol 1993;28:460-466.
14. Pirson Y, Van Lierda M, Ghysen J, et al. Retardation of fetal References
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Arch Dermatol 2001;137:747-750.
6-11 February 2004
62nd Annual Meeting of the
Abstracts of Interest
American Academy of Dermatology
Drug administration for the pregnant or lactating woman:
A reference guide for dermatologists.
Dermatologists are occasionally faced with the problem of appro-priate systemic drug administration to the lactating or pregnantwoman. The physician’s responsibility is to be aware of the potential Change of address notices and requests for subscriptions risk of prescribing a specific therapeutic agent, to inform the mother for Dermatology Rounds are to be sent by mail to P.O. Box of this risk, and to administer an alternate, less deleterious drug, if 310, Station H, Montreal, Quebec H3G 2K8 or by fax to available. The purpose of this review is to provide guidelines for (514) 932-5114 or by e-mail to [email protected].
dermatologists who must consider the risk to the fetus or neonate of Please reference Dermatology Rounds in your correspondence.
drug administration to the pregnant woman or lactating mother.
Undeliverable copies are to be sent to the address above.
J Am Acad Dermatol 1990;23:87-103.
This publication is made possible by an educational grant from Novartis Pharmaceuticals Canada Inc.
2003 Division of Dermatology, McGill University Health Centre, Montreal, which is solely responsible for the contents. The opinions expressed in this publication do not
necessarily reflect those of the publisher or sponsor, but rather are those of the authoring institution based on the available scientific literature. Publisher: SNELL Medical
Communication Inc. in cooperation with the Division of Dermatology, McGill University Health Centre. ™Dermatology Rounds is a Trade Mark of SNELL Medical Communication
Inc. All rights reserved. The administration of any therapies discussed or referred to in Dermatology Rounds should always be consistent with the recognized prescribing information
in Canada. SNELL Medical Communication Inc. is committed to the development of superior Continuing Medical Education.

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