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Using corticosteroids during pregnancy: Are topical, inhaled, or systemic agents associated with risk?
D. Oren, MSC, I. Nulman, MD, M. Makhija, MSC, S. Ito, MD, Gideon Koren, MD, FRCPC
I am concerned about use of corticosteroids during pregnancy. Some of my women patients of reproductive age are using topical, inhaled, or oral preparations, and I am not sure what to advise.
Both topical and systemic corticosteroids are used for a variety of autoimmune and inflammatory conditions. Results of first-trimester studies were inconclusive and underpowered. Recent meta-analyses suggest a small but significant association between use of systemic corticosteroids during the first trimester and oral clefts. This is consistent with results of animal studies. No similar evidence exists for topical or inhaled corticosteroids, probably because of much lower systemic exposure.
Je m'inquiète à propos du recours aux corticostéroïdes pendant la grossesse. Certaines de mes patientes en âge de procréer utilisent des préparations topiques, inhalées ou par voie orale et je ne suis pas sûr des conseils à leur donner.
Les corticostéroïdes, sous forme tant topique que systémique, sont utilisés pour une variété de problèmes inflammatoires et immunitaires. Les résultats d'études pendant le premier trimestre de la grossesse ne se prêtaient pas à des conclusions convaincantes ou concluantes. De récentes méta-analyses font valoir une association faible mais significative entre l'utilisation des corticostéroïdes systémiques durant le premier trimestre et les fissures orales. Ceci corrobore les études chez l'animal. Aucune donnée probante n'existe pour les corticostéroïdes sous forme topique ou inhalée, probablement en raison de la plus faible exposition systémique.
Corticosteroids are used to treat a variety of conditions; discontinuing them during pregnancy sometime exacerbates these conditions. Corticosteroids are available alone or in combination with other drugs for systemic, inhaled, and topical use. Systemic corticosteroids are used for autoimmune and inflammatory conditions. Inhaled steroids are now first-line treatment for asthma. Topical corticosteroids are frequently used to treat allergic and inflammatory dermatologic diseases, such as atopic dermatitis and psoriasis. Existing data on the safety of corticosteroids during pregnancy, particularly during the first trimester, are often conflicting and difficult to interpret.
Commonly used systemic corticosteroids include prednisone, cortisone, and the active metabolites of prednisone and dexamethasone. Corticosteroids cross human placenta1; fluorinated corticosteroids penetrate the placenta more rapidly.2 The increased incidence of low birth weight and stillbirths reported in fetuses exposed to corticosteroids can often be linked to the conditions for which the mothers were given the drugs.3
Several studies have suggested an association between oral clefts and use of systemic corticosteroids,4-6 but one case-control and several prospective cohort studies failed to show such an association.7-12 A meta-analysis conducted by the Motherisk program of 123 175 women who received oral corticosteroids during the first trimester showed a slightly increased risk of oral clefts. Pooled results of odds ratios (ORs) in case-control studies showed a threefold increase in oral clefts among offspring of women who received oral corticosteroids during pregnancy. When results of six cohort studies were pooled, no significant increase in oral clefts was seen. When the largest study (50 282 patients) was excluded because it did not distinguish between major and minor malformations, however, the OR increased to 3.03 (95% confidence interval 1.08 to 8.54) for major malformations in children whose mothers received corticosteroids during the first trimester of pregnancy.3
A recent prospective, controlled study followed 311 women who used various corticosteroids during the first trimester. Both corticosteroid-exposed women and controls had malformation rates within the expected baseline risk for the general population. The authors also recalculated a cumulative OR from seven controlled studies, including their own study, and found no significant increase in risk of major anomalies.13
Because most human studies of systemic corticosteroid use during pregnancy have looked at the drugs in combination with other medications, it is difficult to assess the risk of individual corticosteroids. While systemic corticosteroids do not seem to pose a major teratogenic risk for humans, there is a small but significantly increased risk of oral clefts with first-trimester exposure. These results are consistent with results of extensive studies in animals.14,15
Inhaled corticosteroids used to treat asthma or other respiratory symptoms include beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone.16
It is estimated that up to 4% of all pregnancies are complicated by maternal asthma,17 making asthma one of the most common respiratory complications seen in pregnancy. Poor control of chronic asthma and exacerbation of acute asthma during pregnancy can result in adverse maternal and fetal outcomes, such as hypoxia, low birth weight, and intrauterine growth restriction.18-20 A randomized controlled study has shown that long-term use of low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild, persistent asthma of recent onset.19 Inhaled steroids have also been shown to reduce risk of hospitalization due to asthma.21,22
Epidemiologic data on inhaled corticosteroids have shown no increase in rates of congenital malformations. A retrospective study of women treated with triamcinolone, beclomethasone, and oral theophylline for asthma during pregnancy found no congenital abnormalities in any treatment groups.23 In addition, START (Inhaled Steroid Treatment As Regular Therapy), the first long-term, multicentre, prospective, double-blind study, reported that treating asthmatic pregnant women with 400 microgram of budesonide is safe.24
These results corroborate data from the Swedish Registry Study25 of about 3000 pregnancies, which showed a normal rate of malformations in newborns exposed to budesonide during the first trimester.
Inhaled corticosteroids are currently recommended as part of routine management of moderate-to-severe chronic asthma during pregnancy.26
Commonly used topical corticosteroids include hydrocortisone and betamethasone. The systemic effects of topical corticosteroids are generally limited because only about 3% of the medication in topical preparations is absorbed systemically following 8 hours of contact with normal skin.27 Absorption varies with different types and doses of preparations and the nature and extent of underlying skin conditions. When corticosteroids are used long term or on large areas of skin, they might have systemic effects.28-34
Epidemiologic fetal safety data on topical corticosteroids are sparse. Two population-based studies found that treatment with topical corticosteroids during pregnancy did not increase risk of congenital abnormalities in humans.35,36
The apparent increased risk of oral clefts associated with systemic corticosteroid use has to be balanced against potentially serious implications for mothers (and indirectly fetuses) if needed steroid therapy is discontinued or not initiated for underlying maternal conditions. Since oral clefts occur at about one per thousand births, this increased risk will have a minimal absolute effect on the overall malformation rate of 3%. Since palate formation is completed by 12 weeks? gestation, no risk of oral clefts exists thereafter.
When exposure has already occurred, a level II ultrasound scan might be able to detect clefting. More studies are needed to determine which cleft phenotype is associated with corticosteroids and whether it is cleft lip (with or without palate) or cleft palate alone, or both.
- Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2002. p. 662-70.
- Mok CC, Wong RW. Pregnancy in systemic lupus erythematosus. Postgrad Med J 2001;77:157-65.
- Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62:385-92.
- Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts: a case-control study. Teratology 1998;58:2-5.
- Robert E, Vollset SE, Botto L, Lancaster PAL, Merlob P, Cocchi G, et al. Malformation surveillance and maternal drug exposure: the MADRE project. Int J Risk Safety Med 1994;6:78-118.
- Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242-4.
- Vickers CF. Double-blind trial of betamethasone. BMJ 1962;20:156-7.
- Warrell DW, Taylor R. Outcome for the foetus of mothers receiving prednisolone during pregnancy. Lancet 1968;1:117?8.
- Heinonen OP, Slone D, Shapiro S. Antimicrobial and antiparasitic agents. Birth defects and drugs in pregnancy. Littleton, Mass: Publishing Sciences Group; 1977. p. 296-313.
- Mogadam M, Dobbins WO, Korelitz BI, Ahmed SW. Pregnancy in inflamatory bowel disease: effect of sulfasalazine and corticosteroid on fetal outcome. Gastroenterology 1981;80:72-6.
- Mintz G, Niz J, Gutierrez G, Garcia-Alonso A, Karchmer S. Prospective study of pregnancy in systemic lupus erythematosus. Results of a multidisciplinary approach. J Rheumatol 1986;13:732-9.
- Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology 1997;56:355-40.
- Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after first trimeter exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;18:93-101.
- Walker BE. Induction of cleft palate in rats with antiinflammatory drugs. Teratology 1971;4(1):39-42.
- Pinsky L, Digeorge AM. Cleft palate in the mouse: a teratogenic index of glucocorticoid potency. Science 1965;147:402-3.
- Passalacqua G, Albasno M, Canonica GW, Bachert C, Van Cauwenberge P, Davies RJ, et al. Inhaled and nasal corticosteroids: safety aspects. Allergy 2000;55:16-33.
- Venkataraman MT, Shanies HM. Pregnancy and asthma. J Asthma 1997;34:265-71.
- Witlin AG. Asthma in pregnancy. Semin Perinatol 1997;21:284-97.
- Dombrowski MP. Pharmacologic therapy of asthma during pregnancy. Obstet Gynecol Clin North Am 1997;24:559-74.
- Jana N, Vasishta K, Saha SC, Khunnu B. Effect of bronchial asthma on the course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol 1995;21:227-32.
- Pauwels RA, Pedersen S, Busse WW, O?Byrne PM, START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-6.
- Donahue JG, Weiss ST, Livingston JM, Goetsch MA, Greineder DK, Platt R. Inhaled steroids and the risk of hospitalization for asthma. JAMA 1997;227:887-91.
- Blais L, Suissa S, Boivin JF, Ernst P. First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma. Thorax 1998;53:1025-9.
- Silverman M, Sheffer A, Diaz Amor P, Woolcock AJ, Lindmark B, Fladner F, et al. Prospective pregnancy outcome data from the START study. On behalf of the safety committee. Eur Respir J 2002;20(Suppl 38):53S.
- Norjavaara E, De Verdier MG. Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;111:736-42.
- Sheffer AL, Taggart VS, National Asthma Education Program. Expert panel report guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. Med Care 1993;31(Suppl 3):S20-8.
- Tauscher AE, Fleischer AB Jr, Phelps KC, Feldman SR. Psoriasis and pregnancy. J Cutan Med Surg 2002;6:561?70.
- Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman?s the pharmacologic basis of therapeutics. 7th ed. New York, NY: McGraw-Hill Medical Publishing Division; 1985. p. 1473.
- Mizuchi A, Miyachi Y, Tamaki K, Kukita A. Percutaneous absorption of betamethasone 17-benzoate measured by radioimmunoassay. J Invest Dermatol 1976;67:279-82.
- Schaefer H, Zesch A, Stuttgen G. Penetration, permeation, and absorption of triamcinolone acetonide in normal and psoriatic skin. Arch Dermatol Res 1977;258:241-9.
- Wester RC, Noonan PK, Maibach HI. Percutaneous absorption of hydrocortisone increases with long-term administration. In vivo studies in the rhesus monkey. Arch Dermatol 1980;116:186-8.
- Turpeinen M. Absorption of hydrocortisone from the skin reservoir in atopic dermatitis. Br J Dermatol 1991;124:358-60.
- Barnetson RS, White AD. The use of corticosteroids in dermatological practice. Med J Aust 1992;156:428-31.
- Melendres JL, Bucks DA, Camel E, Wester RC, Maibach HI. In vivo percutaneous absorption of hydrocortisone: multiple-application dosing in man. Pharm Res 1992;9:1164-7.
- Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology 1997;56:335-40.
- Mygind H, Thulstrup AM, Pedersen L, Larsen H. Risk of intrauterine growth retardation, malformations and other birth outcomes in children after topical use of corticosteroid in pregnancy. Acta Obstet Gynecol Scand 2002;81(3):234-9.