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BJD

R EV IE W AR TI C LE British Journal of Dermatology

Evidence-based (S3) guideline on topical corticosteroids in pregnancy


C.-C. Chi, G. Kirtschig,* W. Aberer, J.-P. Gabbud, J. Lipozencic, S. Karpati, U.-F. Haustein,** T. Zuberbier and F. Wojnarowska
Department of Dermatology and Centre for Evidence-Based Medicine, Chang Gung Memorial Hospital at Chiayi, Chang Gung University College of Medicine, 6, Sec West, Chia-Pu Rd, Puzih, Chiayi, 61363, Taiwan *Department of Dermatology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands Department of Dermatology, University of Graz, Graz, Austria Dermatology and Venereology, Bern, Switzerland University Department of Dermatology and Venereology, Zagreb University Hospital Center and School of Medicine, Zagreb, Croatia Department of Dermatology, Venereology and Dermato-oncology, Semmelweis University, Budapest, Hungary **Department of Clinical and Experimental Dermatology, University of Leipzig, Leipzig, Germany Allergy-Centre-Charite, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Berlin, Germany Nufeld Department of Clinical Medicine, University of Oxford, Oxford, U.K.

Summary
Correspondence
Ching-Chi Chi. E-mail: chingchi@cgmh.org.tw

Accepted for publication


23 June 2011

Funding sources
No external funding.

Conicts of interest
T.Z.: consultant for Ansell, Bayer Schering, DST, Fujisawa, HAL, Henkel, Kryolan, Leti, MSD, Novartis, Procter and Gamble, Sano-Aventis, Schering Plough, Stallergenes, and UCB; the others, none. DOI 10.1111/j.1365-2133.2011.10513.x

Women with skin conditions may need topical corticosteroids during pregnancy. However, little is known about the effects of topical corticosteroids on the fetus. A guideline subcommittee of the European Dermatology Forum was organized to develop an evidence-based guideline on the use of topical corticosteroids in pregnancy (http://www.euroderm.org/edf/images/stories/guidelines/EDF-Guidelineon-Steroids-in-Pregnancy.pdf). The evidence from a Cochrane Review suggested that the major possible adverse effects on the fetus of topical corticosteroids were orofacial clefts when used preconceptionally and in the rst trimester of pregnancy, and fetal growth restriction when very potent topical corticosteroids were used during pregnancy. To obtain robust evidence, a large population-based cohort study (on 84 133 pregnant women from the U.K. General Practice Research Database) was performed, which found a signicant association of fetal growth restriction with maternal exposure to potent very potent topical corticosteroids, but not with mild moderate topical corticosteroids. No associations of maternal exposure to topical corticosteroids of any potency with orofacial cleft, preterm delivery and fetal death were found. Moreover, another recent Danish cohort study did not support a causal association between topical corticosteroid and orofacial cleft. The current best evidence suggests that mild moderate topical corticosteroids are preferred to potent very potent ones in pregnancy, because of the associated risk of fetal growth restriction with the latter.

Topical corticosteroids are the principal therapy for eczematous dermatoses1 and are also effective in treating inammatory dermatoses such as discoid lupus erythematosus,2 bullous pemphigoid3 and chronic palmoplantar pustulosis.4 Women with these chronic inammatory dermatoses may continue to need topical corticosteroids during pregnancy. Moreover, women with specic dermatoses of pregnancy, e.g. polymorphic eruption of pregnancy, pemphigoid gestationis and atopic eruption of pregnancy, also require topical corticosteroid treatment.5 However, little is known about the effects of topical
2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp943952

corticosteroids on the fetus. Pharmacology references such as the British National Formulary do not give specic advice on prescribing topical corticosteroids in pregnancy. Topical corticosteroids are often labelled in the prescribing information only as: should be used during pregnancy only if the potential benet justies the potential risk to the fetus. This lack of knowledge may have a negative impact on the wellbeing of the mother and fetus. Treatment decisions are almost always a trade-off between potential benets and harms. Lack of information and clarity regarding the risk of

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944 Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al.

topical corticosteroids leads to physicians uncertainty and often results in nonprescribing, and causes pregnant women excessive concerns of possible fetal harm, followed by weakened adherence to the regimen and compromised therapeutic effectiveness. A survey of 250 heads of dermatology departments throughout Europe showed that 30% had concerns about the prescribing of topical corticosteroids in pregnancy and 91% limited their prescribing.6 On the other hand, there may be overprescribing of topical corticosteroids with adverse effects on the fetus. A general assumption is that low-potency topical corticosteroids, like hydrocortisone acetate, are safe to be used during pregnancy; however, this might be wrong. Despite the lack of sufcient safety information, many women still use topical corticosteroids during pregnancy; and surveys from Australia, Denmark, Finland, the Netherlands, U.K. and U.S. showed usage of topical corticosteroids by 286% of pregnant women.613 The uncertainty of the safety of topical corticosteroids in pregnancy highlights the need for an evidence-based guideline in making an informed clinical decision. In 2008, a guideline subcommittee of the European Dermatology Forum was organized to develop an evidence-based (S3) guideline on the use of topical corticosteroids in pregnancy. An S3 guideline is based on a consensus derived from a systematic search of the literature with critical appraisal of evidence levels and a systematic decision process.14 Two workshop meetings were held to establish a consensus for the development and implementation of the guideline. At the rst meeting it was established that no best practices from national groups existed.

Table 1 Levels of evidence dened by the Oxford Centre for Evidence-Based Medicine15 1a Evidence obtained from systematic review (with homogeneity) of RCTs 1b Evidence from individual RCT with a narrow condence interval 1c Evidence from all or none studies (all patients died prior to introduction of an intervention, but some now survive on it; or some patients died prior to introduction of an intervention, but all now survive on it) 2a Evidence obtained from systematic review (with homogeneity) of cohort studies 2b Evidence from individual cohort study or poor-quality RCT (e.g. < 80% follow-up) 2c Evidence obtained from outcomes research or ecological studies 3a Evidence obtained from systematic review (with homogeneity) of casecontrol studies 3b Evidence from individual casecontrol study 4 Evidence from case series, poor-quality cohort or casecontrol studies 5 Expert opinion without explicit critical appraisal, or based on physiology, laboratory research, or rst principles RCT, randomized controlled trial.

Evidence for harm from animal studies


Corticosteroids have been shown to be teratogenic in animals and have fetotoxic effects. Systemic corticosteroids have induced cleft palate in rabbits, mice, rats and hamsters.1619 The incidence of sex organ anomalies in mice was found to correlate with the dose of corticosteroids topically applied to the eyes.20 Prenatal administration of dexamethasone caused an irreversible deciency of hippocampal neurons, high plasma cortisol at the circadian baseline, and post-stress concentrations in juvenile rhesus monkeys.21 After prenatal administration of one to four doses of betamethasone 05 mg kg)1 at 7-day intervals, starting from 3 weeks before delivery, the birth weight of fetal lambs was found to be reduced (by 15% after one dose, 19% after two doses, and 27% after three and four doses).22 It has been shown that considerable amounts of betamethasone 7,21-dipropionate appeared in the fetal blood of mice and rabbits after topical application to the mothers skin.23 Topical corticosteroids were found to be teratogenic in animal studies. Diorasone diacetate cream induced cleft palate when applied topically to the chest skin of pregnant rats at a dose of 0001 mg kg)1 daily, which is only one-third of the comparable human topical dose. When the application dose was increased to 05 mg kg)1 daily, the treated rats had a higher stillbirth rate than the controls.24 Rabbits given a topical dose of diorasone diacetate 0016 mg kg)1 daily had depressed fetal growth, external anomalies (319%), cleft palate (222%) and visceral defects (455%).25 In summary, the animal data show partially dose-dependent teratogenic effects in rodents depending on absorption and
2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp943952

Disclaimer
This guideline was developed by the European Dermatology Forum (available in a more detailed form at http://www. euroderm.org/edf/images/stories/guidelines/EDF-Guideline-onSteroids-in-Pregnancy.pdf). The recommendations reect the best data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations in this report. It may be necessary or even desirable to depart from these recommendations in special circumstances. Just as adherence to guidelines may not constitute defence against a claim of negligence, so deviation from them should not be necessarily deemed negligent.

Levels of evidence and grades of recommendation


Much has been written in recent years on the need for clinical guidelines and the criteria they should meet for development and application, as well as evidence and recommendations to be used in their support. We used the levels of evidence and grades of recommendation dened by the Oxford Centre for Evidence-Based Medicine (Tables 1 and 2).15

Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al. 945 Table 2 Grades of recommendation dened by the Oxford Centre for Evidence-Based Medicine15
Potential of desired effects

Topical corticosteroids therapeutical index


30
CP

A Consistent level 1 studies B Consistent level 2 or 3 studies, or extrapolations from level 1 studies C Level 4 studies, or extrapolations from level 2 or 3 studies D Level 5 evidence, or troublingly inconsistent or inconclusive studies of any level Extrapolations are where data are used in a situation that has potentially clinically important differences from the original study situation.

25 20 15 10 5 0 0 5 10 15 20
HC MPA/MF/ PC HCB

BMV

TRI

Potential adverse effects

systemic levels. In addition, there is evidence of fetal growth restriction and an increased rate of fetal death.

Pharmacology and pharmacokinetics in the mother


Systemic effects of topical corticosteroids largely depend on the extent of percutaneous absorption, and subsequently on pharmacokinetic pathways for systemically administered corticosteroids. They bind to plasma proteins in varying degrees, are metabolized primarily in the liver and excreted in the kidney and they cross the placenta in pregnant women. Skin absorption and bioavailability of topical corticosteroids in pregnancy The extent of percutaneous absorption, and thus the potential for systemic exposure, is determined by many factors including: the chemical compound itself; the vehicle; the integrity of the epidermal barrier; the use of occlusive dressings; the surface area and regional anatomical variation treated; application frequency and prolonged use; the metabolism; and pregnancy (there may be variation in different trimesters).26 Systemic effects of topical corticosteroids largely depend on the extent of percutaneous absorption, which varies from < 05% to 7% when applied to intact skin27,28 and also on systemic bioavailability (see Fig. 1). Inammation and or other disease processes in the skin may increase percutaneous absorption. Less than 05% of the applied methylprednisolone aceponate is percutaneously absorbed through intact skin; however, removal of the epidermal barrier by stripping increased the absorption to 154 77%.28 In addition, the percutaneous absorption of 1% hydrocortisone cream during exacerbation of atopic dermatitis can be 1131 times that in remission.29 Hydrocortisone and other topical corticosteroids have different systemic bioavailability, depending on lipophilicity, degradability and other pharmacokinetic properties. Even hydrocortisone, the least potent corticosteroid, can suppress the adrenals after percutaneous absorption in patients with severe skin disease.30 Clobetasol propionate ointment, a very potent topical corticosteroid, can result in adrenal insufciency
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Fig 1. Therapeutic index of topical corticosteroids (modied from Luger et al.62). BMV, betamethasone valerate; CP, clobetasol propionate; HC, hydrocortisone; HCB, hydrocortisone butyrate; MF, mometasone furoate; MPA, methylprednisolone acetate; PC, prednicarbate; TRI, triamcinolone acetonide.

at doses as low as 2 g daily)1 for 1 week.27 This has also been described with newer topical lipophilic corticosteroids (i.e. mometasone furoate, uticasone propionate and methylprednisolone aceponate) under extreme conditions,31,32 but was not veried for mometasone furoate under more moderate conditions (10 g daily)1)33 nor in a study in psoriatic patients (15 g daily)1).34 The vehicle may help to enhance penetration and promote systemic absorption. The use of occlusive dressings, wellhydrated skin, application on large surface areas, and prolonged use are conditions which augment systemic absorption. Drug penetration is higher on the face, in intertriginous areas, and especially in the perineum. During pregnancy, alterations in the skin hydration and blood ow may change the systemic availability of topical corticosteroids.35 However, for ethical reasons, no specic studies on topically applied corticosteroids in pregnant women have been conducted. Data from nasal and inhaled corticosteroids may not be directly applicable. The data on mometasone furoate and uticasone propionate used by these routes are reassuring,3638 but direct extrapolation to cutaneous application is not possible. On theoretical grounds, the newer lipophilic corticosteroids (i.e. mometasone furoate, uticasone propionate and methylprednisolone aceponate), which have more favourable local and systemic side-effect proles, should perhaps be preferred,39,40 but direct data supporting this are still awaited. Metabolism of corticosteroids After absorption of corticosteroids, 90% or more of cortisol in plasma is reversibly bound to two plasma proteins: corticosteroid-binding globulin (CBG or transcortin) and albumin. Only the unbound fraction can enter cells to mediate corticosteroid effects. CBG is an a-globulin secreted by the liver with high afnity for corticosteroids but relatively low total binding capacity, whereas albumin has low afnity but

946 Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al.

relatively large binding capacity. At normal or low concentrations of corticosteroids, most of the hormone is bound. At higher corticosteroid concentrations, the capacity of protein binding is exceeded, and a greater fraction of the corticosteroid exists in the free state. A special state of physiological hypercorticism occurs during pregnancy. The elevated circulating oestrogen levels induce CBG production, and this leads to increased total plasma cortisone. The physiological signicance of these changes with regard to exogenous corticosteroids remains to be established. Biologically active adrenocortical corticosteroids and their synthetic congeners are metabolized in the liver and elsewhere to water-soluble compounds that are excreted via the kidneys.

Evidence from human studies


The data available as to possible fetal harm from maternal usage of topical corticosteroids were limited. In a recent Cochrane review published in 2009,48 the authors systematically searched 12 databases including the Cochrane Skin Group Specialised Register, the Cochrane Pregnancy and Childbirth Group Specialised Register, CENTRAL, MEDLINE, EMBASE, LILACS, CINAHL, British Nursing Index, SCI-EXPANDED, BIOSIS Previews, Conference Papers Index, and Conference Proceedings Citation Index-Science using a search strategy incorporating generic names of topical corticosteroids and adverse pregnancy outcomes. They identied seven relevant studies, including two cohort and ve casecontrol studies which covered a total of almost 660 000 subjects (Table 4). A consumer (patient representative) assisted in the preparation of the Cochrane review to help ensure its relevance and readability. The available data were inconclusive and primarily on orofacial cleft (level of evidence: 2a). Most of the studies found no signicant associations between maternal use of topical corticosteroids and adverse pregnancy outcomes including mode of delivery, congenital abnormality, preterm delivery and stillbirth, but these studies all had drawbacks.4953 However, a signicant association between topical corticosteroids and orofacial cleft was found in one small casecontrol study;54 and a signicant association between maternal use of very potent topical corticosteroids and low birth weight was found in another small cohort study.55 The limited available data identied by the Cochrane Review highlighted the need for further large-scale studies, and a large population-based cohort study56 has been performed using the U.K. General Practice Research Database (GPRD) which covers 55% of the U.K. population.57 The cohort study compared pregnancy outcomes between 35 503 pregnant women prescribed topical corticosteroids during the period from 85 days before last menstrual period (LMP) to delivery or fetal death with 48 630 unexposed women (Table 4).56 The topical corticosteroids prescribed were stratied for potency as shown in Table 5. No signicant associations of maternal exposure to topical corticosteroids with orofacial cleft and its two categories, cleft lip palate and isolated cleft palate, were found. Maternal exposure to potent very potent topical corticosteroids was found to be signicantly associated with fetal growth restriction {adjusted risk ratio (RR) 208 [95% condence interval (CI) 140310]; number needed to harm (NNH) 168} (level of evidence: 2b). There was a 3% increase in the RR for fetal growth restriction associated with every 30 g (a regular tube) increase of potent very potent topical corticosteroids prescribed during pregnancy. In contrast, no similar association between maternal exposure to mild moderate topical corticosteroids and fetal growth restriction was found. No associations of maternal exposure to topical corticosteroids of any potency with preterm delivery and fetal death was found.56
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Placental metabolism
The fetal effects of corticosteroids depend on their efciency of penetration through the placenta (Table 3). The key enzyme metabolizing corticosteroids in the placenta is the highly expressed 11b-hydroxysteroid dehydrogenase (11bHSD) which converts cortisol (hydrocortisone, the active form) to cortisone (biologically inactive). Therefore, 11bHSD plays an important role in regulating the amount of maternal cortisol that crosses the placenta to reach the fetal compartment and in protecting the baby from potential harm.41 It is assumed that hydrocortisone is safe for use in pregnancy because of its low potency and high metabolism in the placenta, but a study of the maternalfetal cortisol transfer in the fetalplacental unit before abortion showed that 15% of 3 H-cortisol crossed the placenta unmetabolized42 and another study found a linear relation between maternal and fetal serum cortisol concentrations.43,44 Only one-eighth to onetenth of prednisolone crosses the placenta to reach the fetus.45 By contrast, dexamethasone, methylprednisolone and betamethasone are less metabolized by 11bHSD as about 67%, 45% and 30%, respectively, cross the placental barrier.46 Fluticasone propionate and budesonide are not metabolized by placental 11bHSD,47 and therefore high amounts of them may cross the placenta. There are no studies available on the other corticosteroids.
Table 3 Placental metabolism and transfer of various corticosteroids Metabolized by placental 11b-hydroxysteroid dehydrogenase Prednisolone Hydrocortisone Betamethasone Methylprednisolone Dexamethasone Fluticasone 85

Placental transfer 1012% 15% 2833% 446% 67%

In summary, it is difcult to predict the effects of topically applied corticosteroid used by the mother on the unborn child, as there are so many independent factors. Clinical trials are unethical and therefore have never been conducted.

2011 The Authors Setting Population-based, using the dataset Hungarian CaseControl Surveillance of Congenital Abnormalities 20 830 cases of CAs, 35 727 controls Prenatal log book, questionnaire and interview Adjusted OR with 95% CI of maternal corticosteroid ointment treatment in 14 CAs group Number of participants Ascertainment of exposure Outcome measures Results Based on the local population in North Jutland, using Danish Medical Birth registry 363 primiparous, singleton pregnant women exposed to topical corticosteroids within 30 days before conception and or during pregnancy, 9263 controls receiving no prescriptions Single teaching hospital 48 cases with nonsyndromic cleft lip or palate, 58 controls An association between cleft lip palate and maternal corticosteroid ointment treatment in the whole pregnancy [adjusted OR 221 (95% CI 111439)] and in the rst month of gestation [OR 419 (95% CI 1471197)] was revealed. However, the adjusted OR was not signicant in the second and third months of gestation, which are the critical periods for CAs (but the OR statistic was not reported). Also, no signicant association between maternal corticosteroid ointment use and other major or mild CAs was found No increased risk of LBW, malformations, PharmacoCrude and adjusted OR preterm delivery and stillbirth among the epidemiological with 95% CI for LBW, exposure group. The adjusted OR (95% prescription database malformations, preterm CI) for LBW, malformations and preterm delivery and stillbirth delivery among women receiving weak medium strong corticosteroids were 07 (017285), 093 (023380) and 104 (056192), respectively, and those of strong very strong corticosteroids were 123 (045337), 056 (014228) and 099 (054184), respectively. The crude OR for stillbirth among women receiving prescription of topical corticosteroid during pregnancy was 26 (95% CI 083805) A signicant increase in the prevalence of Retrospective OR with 95% CI of topical maternal rst-trimester use of topical interview corticosteroid use in the rst corticosteroid among cases with syndromic trimester of pregnancy for cleft cleft [adjusted OR 186 (95% CI lip or palate, using univariate and multiple regression analysis 129270), P = 0032]

Table 4 Studies on the safety of topical corticosteroids in pregnancy

First author, publication year, citation no.; country; funding source

Study design

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Czeizel, 1997;49 Hungary; not reported

Casecontrol study

Mygind, 2002;50 Denmark; Western Danish Research Forum for Health Sciences, Danish Medical Research Council, and Foundation of Hrslev

Retrospective cohort study

Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al. 947

Edwards, 2003;54 Australia; not reported

Casecontrol study

Table 4 (Continued)

First author, publication year, citation no.; country; funding source Setting Population-based, Swedish Medical Birth Registry Number of participants Ascertainment of exposure Outcome measures Results

Study design

Kallen, 2003; Sweden; K.A. Wallenberg Foundation

51

Register analysis

No signicant association between topical corticosteroid use in the rst trimester of pregnancy and orofacial clefts [RR 201 (95% CI 055515)]

Pradat, 2003;52 multinational; not reported Multicentric database, Malformation Drug Exposure Surveillance (MADRE)

Casecontrol study

149 932 women Prospective with rst-trimester interview at the rst drug exposure, antenatal care visit containing 1094 (usually week exposed to topical 1012) corticosteroid 11 150 cases with Reported by congenital malformations, participating containing 982 cases of researchers cleft palate or lip Expected number of cases with orofacial cleft, compared with observed number as RR (observed expected) with 95% CI based on exact Poisson distribution MantelHaenszel OR with 95% CI after stratication by registry

948 Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al.

Mahe, 2007;55 Senegal; not reported 34 of 99 women with exposure to potent topical corticosteroids (28 clobetasol propionate, 60 g monthly). Compared with nonusers of very potent topical corticosteroids 1110 infants with cleft lip cleft palate and 4079 control infants Interviewed at 69 months pregnancy, local area only

Cohort study Single maternity hospital

Plasma cortisol, pregnancy outcome: mode of delivery, gestational age, birth weight, placental weight, status of newborn and mother; v2 and Fishers two-tailed exact test, KruskallWallis H test

No correlations of rst-trimester exposure to topical corticosteroids with cleft palate or lip [OR 052 (95% CI 016164)], cleft palate [OR 0 (95% CI 0341)], and cleft lip palate [OR 073 (95% CI 023237)] Increased frequency of mild vaginal bleeding (P = 0031), decreased birthweight (P = 0046), decreased placental weight (P = 0043), decreased placental cortisol (P = 007)

Carmichael, 2007;53 Casecontrol U.S.; Center for study Disease Control and Prevention Multistate, part of the National Birth Defects Prevention Study

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Chi, 2011;56 U.K.; British Skin Foundation, University of Oxford

Retrospective Population-based cohort study

Maternal interviews were Conrmed by clinical description No signicant association between cleft conducted with a or surgical or autopsy report. lip cleft palate and maternal use of standardized, computerEach case received an additional topical corticosteroids from 4 weeks before based telephone review by one clinical geneticist through 12 weeks after conception questionnaire in English to ensure that cases from each [OR 09 (95% CI 0243)] or Spanish, no earlier than study centre met standard 6 weeks and no later eligibility criteria than 24 months after the infants estimated date of delivery 35 503 pregnant women Prescription records Adjusted RR for orofacial cleft A signicant association of maternal prescribed topical (and its two categories, cleft exposure to potent very potent topical corticosteroids during the lip palate and isolated cleft corticosteroids with fetal growth restriction period from 85 days palate), fetal growth restriction, [adjusted RR 208 (95% CI 140310)]. before last menstrual preterm delivery and fetal death No signicant association of topical period to delivery or fetal corticosteroids of any potency with other death and 48 630 pregnancy outcomes unexposed women

2011 The Authors

Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al. 949 Table 5 Potency of topical corticosteroids (adapted from the British National Formulary61 and Chis thesis6) Potency Mild to moderate Topical corticosteroids (%)

A signicant association of topical corticosteroid use during rst trimester and cleft lip palate [adjusted OR 145 (95% CI 103205)]. However, exploratory analyses of the doseresponse and potencyresponse relations did not support a causal association. The observed association may arise from multiple comparisons

Adjusted OR with 95% CI of cleft lip palate and isolated cleft palate

Outcome measures

Alclometasone dipropionate 005 Betamethasone valerate 0025 Clobetasone butyrate 005 Fludroxycortide (urandrenolone) 00125 Fluocinolone acetonide 000625 Fluocortolone 025 Hydrocortisone 0125 Potent to very potent Betamethasone dipropionate 0050064 Betamethasone valerate 01012 Clobetasol propionate 005 Diucortolone valerate 0103 Fluocinolone acetonide 0025 Fluocinonide 005 Fluticasone propionate 0005005a Hydrocortisone butyrate 01a Mometasone furoate 01a Methylprednisolone aceponate 01a Triamcinolone acetonide 01
a The drugs have high potency based on efcacy but lower adverse effects39 (see Fig. 1).

Results

22 480 pregnant women Danish Prescription Drug who lled prescriptions Register for topical corticosteroids during the rst trimester and 810 156 controls receiving no prescriptions for topical corticosteroids

CA, congenital abnormality; CI, condence interval; LBW, low birth weight; OR, odds ratio; RR, risk ratio.

Using the Danish Prescription Drug Register, another recent retrospective nationwide cohort study included 22 480 pregnant women who lled prescriptions for topical corticosteroids during the rst trimester and 810 156 controls receiving no prescriptions for topical corticosteroids.58 The study observed that prescriptions for topical corticosteroid lled during the rst trimester were not associated with cleft palate alone [adjusted OR 145 (95% CI 085248)], but were marginally associated with cleft lip palate [adjusted OR 145 (95% CI 103205)]. However, exploratory analyses of the doseresponse and potencyresponse relations did not support a causal association. The observed association may arise from multiple statistical comparisons.58

Number of participants

Ascertainment of exposure

Conclusions
Current available data on the safety of topical corticosteroids during pregnancy suggest a lack of association between their use by the mother and oral clefts, preterm delivery and fetal death. The available evidence does suggest that use of potent very potent topical corticosteroids during pregnancy may be associated with placental insufciency and low birth weight. However, the ndings are from a single large cohort study56 and a small one.55 Further clinical studies are required to conrm this nding.

Study design Table 4 (Continued) First author, publication year, citation no.; country; funding source

Hviid, 2011;58 Denmark; Danish Medical Research Council and Lundbeck Foundation

Retrospective Nationwide cohort study

Setting

Recommendations
1 Mild moderate topical corticosteroids should be used in preference to more potent corticosteroids in pregnancy (grade of recommendation: B).

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950 Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al.

2 Potent very potent topical corticosteroids should be used as second-line therapy for as short a time as possible, and appropriate obstetric care should be provided as they increase the risk of fetal growth restriction (grade of recommendation: B). 3 The association between maternal exposure to potent very potent topical corticosteroids and fetal growth restriction needs to be considered when applying them during pregnancy. However, systemic corticosteroids have a greater bioavailability than that of topical corticosteroids, and thus have a greater potential for fetotoxicity than topical corticosteroids (systemic corticosteroids are associated with a reduction in fetal birth weight and an increase in preterm delivery59,60), and should not be used in preference (grade of recommendation: B). 4 On theoretical grounds the danger of adverse events is increased when areas with high absorption (e.g. genitals, eyelids, exures) are treated (grade of recommendation: D). 5 There are no data available to determine if newer lipophilic topical corticosteroids (mometasone furoate, uticasone propionate and methylprednisolone aceponate) with a good therapeutic index (Fig. 1) are associated with less risk of fetal growth restriction. On theoretical grounds a favourable side-effect prole for use in pregnancy is suggested; furthermore, they have the practical advantage of once daily application compared with older preparations (grade of recommendation: D).

What does this study add?


The best evidence suggests that mild moderate topical corticosteroids are preferred to potent very potent ones in pregnancy, because of the associated risk of fetal growth restriction with the latter. There are no associations of maternal exposure to topical corticosteroids with orofacial cleft, preterm delivery and fetal death.

Acknowledgments
The authors thank the Editorial Base of the Cochrane Skin Group for help with conducting the Cochrane Review. They also thank Dr Richard Mayon-White (Department of Primary Health Care, University of Oxford) for epidemiological advice.

References
1 Berth-Jones J. Topical therapy. In: Rooks Textbook of Dermatology (Burns T, Breathnach SM, Cox N, eds), 7th edn. Oxford: Blackwell Publishing, 2004; 75.152. 2 Jessop S, Whitelaw DA, Delamere FM. Drugs for discoid lupus erythematosus. Cochrane Database Syst Rev 2009; 4:CD002954. 3 Kirtschig G, Middleton P, Bennett C et al. Interventions for bullous pemphigoid. Cochrane Database Syst Rev 2010; 10:CD002292. 4 Marsland AM, Chalmers RJ, Hollis S et al. Interventions for chronic palmoplantar pustulosis. Cochrane Database Syst Rev 2006; 1: CD001433. 5 Al-Fares SI, Vaughan Jones S, Black MM. The specic dermatoses of pregnancy: a re-appraisal. J Eur Acad Dermatol Venereol 2001; 15:197206. 6 Chi CC. Evidence-based assessment of the safety of topical corticosteroids in pregnancy. DPhil thesis. Oxford: University of Oxford, 2009. 7 Hardy JR, Leaderer BP, Holford TR et al. Safety of medications prescribed before and during early pregnancy in a cohort of 81 975 mothers from the UK General Practice Research Database. Pharmacoepidemiol Drug Saf 2006; 15:55564. 8 Schirm E, Meijer WM, Tobi H et al. Drug use by pregnant women and comparable non-pregnant women in the Netherlands with reference to the Australian classication system. Eur J Obstet Gynecol Reprod Biol 2004; 114:1828. 9 Bakker MK, Jentink J, Vroom F et al. Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands. BJOG 2006; 113:55968. 10 Malm H, Martikainen J, Klaukka T et al. Prescription drugs during pregnancy and lactation a Finnish register-based study. Eur J Clin Pharmacol 2003; 59:12733. 11 Andrade SE, Gurwitz JH, Davis RL et al. Prescription drug use in pregnancy. Am J Obstet Gynecol 2004; 191:398407. 12 Olesen C, Sorensen HT, de Jong-van den Berg L et al. Prescribing during pregnancy and lactation with reference to the Swedish classication system. A population-based study among Danish women. The Euromap Group. Acta Obstet Gynecol Scand 1999; 78:68692. 13 Colvin L, Slack-Smith L, Stanley FJ et al. Pharmacovigilance in pregnancy using population-based linked datasets. Pharmacoepidemiol Drug Saf 2009; 18:21125.

Advice to women about using topical corticosteroids in pregnancy


1 Women can be reassured that there is no signicantly increased risk of orofacial cleft, preterm delivery and fetal death when using topical corticosteroids in pregnancy. There is also no increased risk of fetal growth restriction when using mild moderate topical corticosteroids in pregnancy. 2 Women should be informed that there is a small risk for fetal growth restriction when using potent very potent topical corticosteroids in pregnancy, but this risk is less than that of systemic corticosteroids, as an additional risk for preterm delivery has been found in pregnant women using systemic corticosteroids. 3 Depending on the severity of their skin conditions, women should use topical corticosteroids of the least potency required and limit the amount and time period of use. They should also be more cautious on areas of high absorption such as exures, armpits and genitals.

Whats already known about this topic?


Little is known about the safety of topical corticosteroids in pregnancy.

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Guideline on topical corticosteroids in pregnancy, C.-C. Chi et al. 951 14 Blume-Peytavi U, Blumeyer A, Tosti A et al. S1 guideline for diagnostic evaluation in androgenetic alopecia in men, women and adolescents. Br J Dermatol 2011; 164:515. 15 Phillips B, Ball C, Sackett D et al. Levels of Evidence. Oxford: Oxford Centre for Evidence-based Medicine, 2009, revised 2010. [WWW document]. Available at: http://www.cebm.net/index.aspx?o= 1025 (last accessed 8 September 2011). 16 Nanda R, van der Linden FP, Jansen HW. Production of cleft palate with dexamethasone and hypervitaminosis A in rat embryos. Experientia 1970; 26:111112. 17 Nasjleti CE, Avery JK, Spencer HH et al. Tritiated cortisone distribution and induced cleft palate in mice. J Oral Ther Pharmacol 1967; 4:7182. 18 Shah RM, Kilistoff A. Cleft palate induction in hamster fetuses by glucocorticoid hormones and their synthetic analogues. J Embryol Exp Morphol 1976; 36:1018. 19 Walker BE. 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