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Summary
Correspondence
Ching-Chi Chi. E-mail: chingchi@cgmh.org.tw
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
943
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.
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.
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
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
systemic levels. In addition, there is evidence of fetal growth restriction and an increased rate of fetal death.
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
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.
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
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]
Study design
Casecontrol study
Mygind, 2002;50 Denmark; Western Danish Research Forum for Health Sciences, Danish Medical Research Council, and Foundation of Hrslev
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
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
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
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
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
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
Setting
Recommendations
1 Mild moderate topical corticosteroids should be used in preference to more potent corticosteroids in pregnancy (grade of recommendation: B).
2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp943952
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).
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
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