BJD

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

Evidence-based (S3) guideline on topical corticosteroids in pregnancy
´ ´ ˇ´ C.-C. Chi, G. Kirtschig,* W. Aberer,  J.-P. Gabbud,à J. Lipozencic,§ S. Karpati,– U.-F. Haustein,** T. Zuberbier   and F. Wojnarowskaàà
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 àDermatology 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 ààNuffield 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.

Conflicts of interest
T.Z.: consultant for Ansell, Bayer Schering, DST, Fujisawa, HAL, Henkel, Kryolan, Leti, MSD, Novartis, Procter and Gamble, Sanofi-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 first 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 significant 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 inflammatory dermatoses such as discoid lupus erythematosus,2 bullous pemphigoid3 and chronic palmoplantar pustulosis.4 Women with these chronic inflammatory dermatoses may continue to need topical corticosteroids during pregnancy. Moreover, women with specific 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
Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 165, pp943–952

corticosteroids on the fetus. Pharmacology references such as the British National Formulary do not give specific 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 benefit justifies 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 benefits and harms. Lack of information and clarity regarding the risk of

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We used the levels of evidence and grades of recommendation defined by the Oxford Centre for Evidence-Based Medicine (Tables 1 and 2).-C. Diflorasone diacetate cream induced cleft palate when applied topically to the chest skin of pregnant rats at a dose of 0Æ001 mg kg)1 daily. randomized controlled trial. the animal data show partially dose-dependent teratogenic effects in rodents depending on absorption and Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 165. or ‘first principles’ RCT. and post-stress concentrations in juvenile rhesus monkeys. so deviation from them should not be necessarily deemed negligent. poor-quality cohort or case–control studies 5 Expert opinion without explicit critical appraisal. Systemic corticosteroids have induced cleft palate in rabbits. Denmark. or some patients died prior to introduction of an intervention. U.22 It has been shown that considerable amounts of betamethasone 7.23 Topical corticosteroids were found to be teratogenic in animal studies.14 Two workshop meetings were held to establish a consensus for the development and implementation of the guideline. the treated rats had a higher stillbirth rate than the controls. which is only one-third of the comparable human topical dose. as well as evidence and recommendations to be used in their support. the Netherlands.6 On the other hand. euroderm. Finland. 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.15 . laboratory research.21-dipropionate appeared in the fetal blood of mice and rabbits after topical application to the mothers’ skin.16–19 The incidence of sex organ anomalies in mice was found to correlate with the dose of corticosteroids topically applied to the eyes. and U. mice.K. 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. cleft palate (22Æ2%) and visceral defects (45Æ5%). followed by weakened adherence to the regimen and compromised therapeutic effectiveness. Just as adherence to guidelines may not constitute defence against a claim of negligence. showed usage of topical corticosteroids by 2–8Æ6% of pregnant women.944 Guideline on topical corticosteroids in pregnancy. rats and hamsters. high plasma cortisol at the circadian baseline. are safe to be used during pregnancy. Despite the lack of sufficient safety information.25 In summary. At the first meeting it was established that no ‘best practices’ from national groups existed. Evidence for harm from animal studies Corticosteroids have been shown to be teratogenic in animals and have fetotoxic effects. A general assumption is that low-potency topical corticosteroids. and surveys from Australia.20 Prenatal administration of dexamethasone caused an irreversible deficiency of hippocampal neurons. The recommendations reflect the best data available at the time the report was prepared.21 After prenatal administration of one to four doses of betamethasone 0Æ5 mg kg)1 at 7-day intervals.pdf). < 80% follow-up) 2c Evidence obtained from outcomes research or ecological studies 3a Evidence obtained from systematic review (with homogeneity) of case–control studies 3b Evidence from individual case–control study 4 Evidence from case series. 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. topical corticosteroids leads to physicians’ uncertainty and often results in nonprescribing. however. Table 1 Levels of evidence defined 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 confidence interval 1c Evidence from all or none studies (all patients died prior to introduction of an intervention. 19% after two doses. 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. the results of future studies may require alteration of the conclusions or recommendations in this report. the birth weight of fetal lambs was found to be reduced (by 15% after one dose. but some now survive on it. It may be necessary or even desirable to depart from these recommendations in special circumstances. Caution should be exercised in interpreting the data.24 Rabbits given a topical dose of diflorasone diacetate 0Æ016 mg kg)1 daily had depressed fetal growth. external anomalies (31Æ9%).org/edf/images/stories/guidelines/EDF-Guideline-onSteroids-in-Pregnancy. this might be wrong.6–13 The uncertainty of the safety of topical corticosteroids in pregnancy highlights the need for an evidence-based guideline in making an informed clinical decision. pp943–952 Disclaimer This guideline was developed by the European Dermatology Forum (available in a more detailed form at http://www.S. or based on physiology. When the application dose was increased to 0Æ5 mg kg)1 daily. starting from 3 weeks before delivery. and causes pregnant women excessive concerns of possible fetal harm. C. there may be overprescribing of topical corticosteroids with adverse effects on the fetus. many women still use topical corticosteroids during pregnancy. and 27% after three and four doses). Chi et al. like hydrocortisone acetate.g. 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.

and thus the potential for systemic exposure. mometasone furoate. can result in adrenal insufficiency Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 165. for ethical reasons. mometasone furoate. hydrocortisone butyrate. the integrity of the epidermal barrier. Less than 0Æ5% of the applied methylprednisolone aceponate is percutaneously absorbed through intact skin. removal of the epidermal barrier by stripping increased the absorption to 15Æ4 ± 7Æ7%.-C. however.e. prednicarbate. no specific studies on topically applied corticosteroids in pregnant women have been conducted. Drug penetration is higher on the face. in intertriginous areas. alterations in the skin hydration and blood flow may change the systemic availability of topical corticosteroids. which have more favourable local and systemic side-effect profiles. and prolonged use are conditions which augment systemic absorption. triamcinolone acetonide. 1). In addition. the vehicle.35 However. The data on mometasone furoate and fluticasone propionate used by these routes are reassuring. there is evidence of fetal growth restriction and an increased rate of fetal death. or extrapolations from level 2 or 3 studies D Level 5 evidence.34 The vehicle may help to enhance penetration and promote systemic absorption. mometasone furoate.28 and also on systemic bioavailability (see Fig.27 This has also been described with newer topical lipophilic corticosteroids (i. which varies from < 0Æ5% to 7% when applied to intact skin27.40 but direct data supporting this are still awaited. PC. at doses as low as 2 g daily)1 for 1 week. During pregnancy. application on large surface areas. can suppress the adrenals after percutaneous absorption in patients with severe skin disease. HC. methylprednisolone acetate.30 Clobetasol propionate ointment.28 In addition. and pregnancy (there may be variation in different trimesters). the surface area and regional anatomical variation treated. MF.29 Hydrocortisone and other topical corticosteroids have different systemic bioavailability. Even hydrocortisone.39. CP. Therapeutic index of topical corticosteroids (modified from Luger et al. Data from nasal and inhaled corticosteroids may not be directly applicable. the least potent corticosteroid. whereas albumin has low affinity but . Pharmacology and pharmacokinetics in the mother Systemic effects of topical corticosteroids largely depend on the extent of percutaneous absorption. CBG is an a-globulin secreted by the liver with high affinity for corticosteroids but relatively low total binding capacity. On theoretical grounds. betamethasone valerate. should perhaps be preferred. 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. clobetasol propionate. BMV. Inflammation and ⁄or other disease processes in the skin may increase percutaneous absorption. fluticasone propionate and methylprednisolone aceponate). application frequency and prolonged use.26 Systemic effects of topical corticosteroids largely depend on the extent of percutaneous absorption. They bind to plasma proteins in varying degrees. is determined by many factors including: the chemical compound itself. pp943–952 Fig 1. 25 20 15 10 5 0 0 5 10 15 20 HC MPA/MF/ PC HCB BMV TRI Potential adverse effects systemic levels.Guideline on topical corticosteroids in pregnancy. the metabolism. a very potent topical corticosteroid. MPA. Only the unbound fraction can enter cells to mediate corticosteroid effects.32 but was not verified for mometasone furoate under more moderate conditions (10 g daily)1)33 nor in a study in psoriatic patients (15 g daily)1). the percutaneous absorption of 1% hydrocortisone cream during exacerbation of atopic dermatitis can be 11–31 times that in remission.31. fluticasone propionate and methylprednisolone aceponate) under extreme conditions. and especially in the perineum. hydrocortisone.36–38 but direct extrapolation to cutaneous application is not possible.62). HCB. degradability and other pharmacokinetic properties. The use of occlusive dressings. or extrapolations from level 1 studies C Level 4 studies. C. TRI. Chi et al. the use of occlusive dressings. depending on lipophilicity.e. wellhydrated skin. Metabolism of corticosteroids After absorption of corticosteroids. and subsequently on pharmacokinetic pathways for systemically administered corticosteroids. the newer lipophilic corticosteroids (i. 90% or more of cortisol in plasma is reversibly bound to two plasma proteins: corticosteroid-binding globulin (CBG or transcortin) and albumin. are metabolized primarily in the liver and excreted in the kidney and they cross the placenta in pregnant women. 945 Table 2 Grades of recommendation defined 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. Skin absorption and bioavailability of topical corticosteroids in pregnancy The extent of percutaneous absorption.

and Conference Proceedings Citation Index-Science using a search strategy incorporating generic names of topical corticosteroids and adverse pregnancy outcomes.45 By contrast.41 It is assumed that hydrocortisone is safe for use in pregnancy because of its low potency and high metabolism in the placenta. it is difficult to predict the effects of topically applied corticosteroid used by the mother on the unborn child. There are no studies available on the other corticosteroids. LILACS. Clinical trials are unethical and therefore have never been conducted. Maternal exposure to potent ⁄very potent topical corticosteroids was found to be significantly associated with fetal growth restriction {adjusted risk ratio (RR) 2Æ08 [95% confidence interval (CI) 1Æ40–3Æ10].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). were found. methylprednisolone and betamethasone are less metabolized by 11bHSD as about 67%. No associations of maternal exposure to topical corticosteroids of any potency with preterm delivery and fetal death was found. British Nursing Index.48 the authors systematically searched 12 databases including the Cochrane Skin Group Specialised Register.-C. SCI-EXPANDED.44 Only one-eighth to onetenth of prednisolone crosses the placenta to reach the fetus. and a greater fraction of the corticosteroid exists in the free state. They identified seven relevant studies. Evidence from human studies The data available as to possible fetal harm from maternal usage of topical corticosteroids were limited. A consumer (patient representative) assisted in the preparation of the Cochrane review to help ensure its relevance and readability. The key enzyme metabolizing corticosteroids in the placenta is the highly expressed 11b-hydroxysteroid dehydrogenase (11bHSD) which converts cortisol (hydrocortisone.K. but these studies all had drawbacks.56 The topical corticosteroids prescribed were stratified for potency as shown in Table 5. Conference Papers Index. EMBASE. CINAHL. cleft lip ± palate and isolated cleft palate. 45% and 30%. BIOSIS Previews. dexamethasone.47 and therefore high amounts of them may cross the placenta. relatively large binding capacity. Most of the studies found no significant associations between maternal use of topical corticosteroids and adverse pregnancy outcomes including mode of delivery.46 Fluticasone propionate and budesonide are not metabolized by placental 11bHSD. CENTRAL. 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. number needed to harm (NNH) 168} (level of evidence: 2b). including two cohort and five case–control studies which covered a total of almost 660 000 subjects (Table 4). and this leads to increased total plasma cortisone. no similar association between maternal exposure to mild ⁄moderate topical corticosteroids and fetal growth restriction was found. At higher corticosteroid concentrations. The elevated circulating oestrogen levels induce CBG production. General Practice Research Database (GPRD) which covers 5Æ5% of the U. The available data were inconclusive and primarily on orofacial cleft (level of evidence: 2a). the active form) to cortisone (biologically inactive). No significant associations of maternal exposure to topical corticosteroids with orofacial cleft and its two categories. the Cochrane Pregnancy and Childbirth Group Specialised Register. In a recent Cochrane review published in 2009. cross the placental barrier. a significant association between topical corticosteroids and orofacial cleft was found in one small case–control study. In contrast. . most of the hormone is bound.55 The limited available data identified by the Cochrane Review highlighted the need for further large-scale studies. C. At normal or low concentrations of corticosteroids.49–53 However.56 Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 165. The physiological significance of these changes with regard to exogenous corticosteroids remains to be established. A special state of physiological hypercorticism occurs during pregnancy. Chi et al. Table 3 Placental metabolism and transfer of various corticosteroids Metabolized by placental 11b-hydroxysteroid dehydrogenase Prednisolone Hydrocortisone Betamethasone Methylprednisolone Dexamethasone Fluticasone 85 Placental transfer 10–12% 15% 28–33% 44Æ6% 67% 0 In summary. Therefore. preterm delivery and stillbirth. but a study of the maternal–fetal cortisol transfer in the fetal–placental 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. MEDLINE.54 and a significant association between maternal use of very potent topical corticosteroids and low birth weight was found in another small cohort study.43. congenital abnormality. 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. as there are so many independent factors. the capacity of protein binding is exceeded.K. and a large population-based cohort study56 has been performed using the U. population.946 Guideline on topical corticosteroids in pregnancy. 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. respectively. pp943–952 Placental metabolism The fetal effects of corticosteroids depend on their efficiency of penetration through the placenta (Table 3).

country. 1997. publication year. respectively. The crude OR for stillbirth among women receiving prescription of topical corticosteroid during pregnancy was 2Æ6 (95% CI 0Æ83–8Æ05) A significant increase in the prevalence of Retrospective OR with 95% CI of topical maternal first-trimester use of topical interview corticosteroid use in the first corticosteroid among cases with syndromic trimester of pregnancy for cleft cleft [adjusted OR 18Æ6 (95% CI lip or palate. 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.. 0Æ56 (0Æ14–2Æ28) and 0Æ99 (0Æ54–1Æ84). Also. Chi et al. 0Æ93 (0Æ23–3Æ80) and 1Æ04 (0Æ56–1Æ92). not reported Case–control study . which are the critical periods for CAs (but the OR statistic was not reported). no significant association between maternal corticosteroid ointment use and other major or mild CAs was found No increased risk of LBW. and those of strong ⁄ very strong corticosteroids were 1Æ23 (0Æ45–3Æ37). singleton pregnant women exposed to topical corticosteroids within 30 days before conception and ⁄ or during pregnancy. preterm CI) for LBW. malformations. C. 2002. funding source Study design BJD Ó 2011 British Association of Dermatologists 2011 165. 2003. P = 0Æ032] Table 4 Studies on the safety of topical corticosteroids in pregnancy First author. using the dataset Hungarian Case–Control Surveillance of Congenital Abnormalities 20 830 cases of CAs. using Danish Medical Birth registry 363 primiparous.-C. PharmacoCrude and adjusted OR preterm delivery and stillbirth among the epidemiological with 95% CI for LBW.50 Denmark. exposure group. Western Danish Research Forum for Health Sciences. The adjusted OR (95% prescription database malformations. citation no. 9263 controls receiving no prescriptions Single teaching hospital 48 cases with nonsyndromic cleft lip or palate. respectively.49 Hungary. 947 Edwards. pp943–952 Czeizel.Ó 2011 The Authors Setting Population-based. 58 controls An association between cleft lip ± palate and maternal corticosteroid ointment treatment in the whole pregnancy [adjusted OR 2Æ21 (95% CI 1Æ11–4Æ39)] and in the first month of gestation [OR 4Æ19 (95% CI 1Æ47–11Æ97)] was revealed. not reported Case–control study Mygind. the adjusted OR was not significant in the second and third months of gestation.54 Australia. and Foundation of Hørslev Retrospective cohort study Guideline on topical corticosteroids in pregnancy. malformations and preterm delivery and stillbirth delivery among women receiving weak ⁄ medium strong corticosteroids were 0Æ7 (0Æ17–2Æ85). Danish Medical Research Council. using univariate and multiple regression analysis 1Æ29–270). However.

Swedish Medical Birth Registry Number of participants Ascertainment of exposure Outcome measures Results Study design ¨ ´ Kallen. publication year. 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). K. and cleft lip ± palate [OR 0Æ73 (95% CI 0Æ23–2Æ37)] Increased frequency of mild vaginal bleeding (P = 0Æ031). 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 0Æ9 (95% CI 0Æ2–4Æ3)] or Spanish. local area only Cohort study Single maternity hospital Plasma cortisol. decreased placental weight (P = 0Æ043). gestational age. not reported Multicentric database. lip ± cleft palate and maternal use of standardized. University of Oxford Retrospective Population-based cohort study Maternal interviews were Confirmed by clinical description No significant association between cleft conducted with a or surgical or autopsy report. status of newborn and mother. pregnancy outcome: mode of delivery. 2003. placental weight.52 multinational.55 Senegal. birth weight. compared with observed number as RR (observed ⁄ expected) with 95% CI based on exact Poisson distribution Mantel–Haenszel OR with 95% CI after stratification by registry 948 Guideline on topical corticosteroids in pregnancy.S. funding source Setting Population-based. no earlier than study centre met standard 6 weeks and no later eligibility criteria than 24 months after the infant’s estimated date of delivery 35 503 pregnant women Prescription records Adjusted RR for orofacial cleft A significant association of maternal prescribed topical (and its two categories. antenatal care visit containing 1094 (usually week exposed to topical 10–12) 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.K. Wallenberg Foundation 51 Register analysis No significant association between topical corticosteroid use in the first trimester of pregnancy and orofacial clefts [RR 2Æ01 (95% CI 0Æ55–5Æ15)] Pradat.-C. country. Compared with nonusers of very potent topical corticosteroids 1110 infants with cleft lip ± cleft palate and 4079 control infants Interviewed at 6–9 months pregnancy. decreased placental cortisol (P = 0Æ07) Carmichael.. Kruskall–Wallis H test No correlations of first-trimester exposure to topical corticosteroids with cleft palate or lip [OR 0Æ52 (95% CI 0Æ16–1Æ64)]. Chi et al. 2007. [adjusted RR 2Æ08 (95% CI 1Æ40–3Æ10)]. fetal growth restriction. 2003. citation no. Sweden. ´ Mahe. 2007. before last menstrual preterm delivery and fetal death No significant association of topical period to delivery or fetal corticosteroids of any potency with other death and 48 630 pregnancy outcomes unexposed women Ó 2011 The Authors . C. Malformation Drug Exposure Surveillance (MADRE) Case–control study 149 932 women Prospective with first-trimester interview at the first drug exposure.53 Case–control U. not reported 34 of 99 women with exposure to potent topical corticosteroids (28 clobetasol propionate. British Skin Foundation..Table 4 (Continued) First author.56 U.A. Center for study Disease Control and Prevention Multistate. part of the National Birth Defects Prevention Study BJD Ó 2011 British Association of Dermatologists 2011 165. cleft palate [OR 0 (95% CI 0–3Æ41)]. 60 g monthly). decreased birthweight (P = 0Æ046). v2 and Fisher’s two-tailed exact test. pp943–952 Chi. 2011.

Results 22 480 pregnant women Danish Prescription Drug who filled prescriptions Register for topical corticosteroids during the first trimester and 810 156 controls receiving no prescriptions for topical corticosteroids CA. The available evidence does suggest that use of potent ⁄very potent topical corticosteroids during pregnancy may be associated with placental insufficiency and low birth weight. preterm delivery and fetal death. the findings are from a single large cohort study56 and a small one. 1). country.55 Further clinical studies are required to confirm this finding. The observed association may arise from multiple statistical comparisons. Using the Danish Prescription Drug Register. Study design Table 4 (Continued) First author. but were marginally associated with cleft lip ± palate [adjusted OR 1Æ45 (95% CI 1Æ03–2Æ05)]. However. However. CI. OR. Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 165. risk ratio. citation no. publication year. C. low birth weight. 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 0Æ05 Betamethasone valerate 0Æ025 Clobetasone butyrate 0Æ05 Fludroxycortide (flurandrenolone) 0Æ0125 Fluocinolone acetonide 0Æ00625 Fluocortolone 0Æ25 Hydrocortisone 0Æ1–2Æ5 Potent to very potent Betamethasone dipropionate 0Æ05–0Æ064 Betamethasone valerate 0Æ1–0Æ12 Clobetasol propionate 0Æ05 Diflucortolone valerate 0Æ1–0Æ3 Fluocinolone acetonide 0Æ025 Fluocinonide 0Æ05 Fluticasone propionate 0Æ005–0Æ05a Hydrocortisone butyrate 0Æ1a Mometasone furoate 0Æ1a Methylprednisolone aceponate 0Æ1a Triamcinolone acetonide 0Æ1 a The drugs have high potency based on efficacy but lower adverse effects39 (see Fig. congenital abnormality. RR. pp943–952 .. 949 Table 5 Potency of topical corticosteroids (adapted from the British National Formulary61 and Chi’s thesis6) Potency Mild to moderate Topical corticosteroids (%) A significant association of topical corticosteroid use during first trimester and cleft lip ± palate [adjusted OR 1Æ45 (95% CI 1Æ03–2Æ05)]. However. confidence interval.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).Guideline on topical corticosteroids in pregnancy.-C. 2011.58 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.58 The study observed that prescriptions for topical corticosteroid filled during the first trimester were not associated with cleft palate alone [adjusted OR 1Æ45 (95% CI 0Æ85–2Æ48)]. LBW. another recent retrospective nationwide cohort study included 22 480 pregnant women who filled prescriptions for topical corticosteroids during the first trimester and 810 156 controls receiving no prescriptions for topical corticosteroids. funding source Hviid. exploratory analyses of the dose–response and potency–response relations did not support a causal association. exploratory analyses of the dose–response and potency–response relations did not support a causal association. Chi et al. odds ratio.

The specific dermatoses of pregnancy: a re-appraisal. 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. Pharmacovigilance in pregnancy using population-based linked datasets. they have the practical advantage of once daily application compared with older preparations (grade of recommendation: D). eds). Pharmacoepidemiol Drug Saf 2009. preterm delivery and fetal death when using topical corticosteroids in pregnancy. de Jong-van den Berg L et al. 3 Kirtschig G. Pharmacoepidemiol Drug Saf 2006. Prescription drugs during pregnancy and lactation – a Finnish register-based study. but this risk is less than that of systemic corticosteroids. 114:182–8. However. • There are no associations of maternal exposure to topical corticosteroids with orofacial cleft. 1: CD001433. 113:559–68. Cochrane Database Syst Rev 2009. because of the associated risk of fetal growth restriction with the latter.950 Guideline on topical corticosteroids in pregnancy. Safety of medications prescribed before and during early pregnancy in a cohort of 81 975 mothers from the UK General Practice Research Database. Breathnach SM. women should use topical corticosteroids of the least potency required and limit the amount and time period of use. 1) are associated with less risk of fetal growth restriction. Davis RL et al. pp943–952 . armpits and genitals. Holford TR et al. BJOG 2006.g. They should also be more cautious on areas of high absorption such as flexures. Eur J Obstet Gynecol Reprod Biol 2004. Chi et al. Slack-Smith L. Hollis S et al. flexures) are treated (grade of recommendation: D). DPhil thesis. Oxford: University of Oxford. 15:555–64. occasional and pregnancy-related drugs in the Netherlands. 4 On theoretical grounds the danger of adverse events is increased when areas with high absorption (e.1–52. Middleton P. 2009. 6 Chi CC. Oxford: Blackwell Publishing. during and after pregnancy for chronic. fluticasone propionate and methylprednisolone aceponate) with a good therapeutic index (Fig. 2 Jessop S. 5 Al-Fares SI. 4 Marsland AM. Acknowledgments The authors thank the Editorial Base of the Cochrane Skin Group for help with conducting the Cochrane Review. Evidence-based assessment of the safety of topical corticosteroids in pregnancy. The Euromap Group. A population-based study among Danish women. systemic corticosteroids have a greater bioavailability than that of topical corticosteroids. Chalmers RJ. They also thank Dr Richard Mayon-White (Department of Primary Health Care. Meijer WM. Sorensen HT. Prescription drug use in pregnancy. 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. 12 Olesen C. Cochrane Database Syst Rev 2010. Eur J Clin Pharmacol 2003. Cox N. 59:127–33. Prescribing during pregnancy and lactation with reference to the Swedish classification system. 11 Andrade SE. Martikainen J. 5 There are no data available to determine if newer lipophilic topical corticosteroids (mometasone furoate. and appropriate obstetric care should be provided as they increase the risk of fetal growth restriction (grade of recommendation: B). Delamere FM. 13 Colvin L. Vroom F et al. Cochrane Database Syst Rev 2006. 10:CD002292. as an additional risk for preterm delivery has been found in pregnant women using systemic corticosteroids. J Eur Acad Dermatol Venereol 2001.-C. Whitelaw DA. What’s already known about this topic? • Little is known about the safety of topical corticosteroids in pregnancy. Klaukka T et al. 3 Depending on the severity of their skin conditions. Jentink J. 191:398–407. Stanley FJ et al. Interventions for bullous pemphigoid. Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 165. 2 Women should be informed that there is a small risk for fetal growth restriction when using potent ⁄very potent topical corticosteroids in pregnancy. Vaughan Jones S. C. Bennett C et al. Advice to women about using topical corticosteroids in pregnancy 1 Women can be reassured that there is no significantly increased risk of orofacial cleft. In: Rook’s Textbook of Dermatology (Burns T. Black MM. 7th edn. Am J Obstet Gynecol 2004. 8 Schirm E. There is also no increased risk of fetal growth restriction when using mild ⁄moderate topical corticosteroids in pregnancy. References 1 Berth-Jones J. 10 Malm H. eyelids. On theoretical grounds a favourable side-effect profile for use in pregnancy is suggested. 7 Hardy JR. 4:CD002954. 15:197–206. Leaderer BP. and should not be used in preference (grade of recommendation: B). genitals. Gurwitz JH.60). What does this study add? • The best evidence suggests that mild ⁄moderate topical corticosteroids are preferred to potent ⁄very potent ones in pregnancy. Tobi H et al. Drug use by pregnant women and comparable non-pregnant women in the Netherlands with reference to the Australian classification system. Drugs for discoid lupus erythematosus. Drug prescription patterns before. Acta Obstet Gynecol Scand 1999. 9 Bakker MK. 75. 2 Potent ⁄very potent topical corticosteroids should be used as second-line therapy for as short a time as possible. Interventions for chronic palmoplantar pustulosis. University of Oxford) for epidemiological advice. 78:686–92. Topical therapy. 18:211–25. furthermore. preterm delivery and fetal death. 2004.

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