Basic & Clinical Pharmacology & Toxicology, 2015, 116, 308–314
Doi: 10.1111/bcpt.12367
MiniReview
Use of Inhaled and Oral Corticosteroids in Pregnancy and the Risk of Malformations or Miscarriage Anne-Mette Bay Bjørn1, Vera Ehrenstein2, Ellen Aagaard Nohr3 and Mette Nørgaard2 Department of Gynecology and Obstetrics, Aarhus University Hospital Skejby, Aarhus N, Denmark, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark and 3Research Unit for Gynecology and Obstetrics, Institute for Clinical Research, University of Southern Denmark, Odense, Denmark 1
(Received 23 January 2014; Accepted 8 December 2014) Abstract: Corticosteroids are potent anti-inflammatory and immunosuppressive drugs, which sometimes must be given to pregnant women. Corticosteroids have been suspected to be teratogenic for many years; however, there is conflicting evidence regarding the association. Based on a literature review of three databases, this MiniReview provides an overview of inhaled and oral corticosteroid use in pregnancy with specific emphasis on the association between use of corticosteroids during pregnancy and risk of miscarriage and congenital malformations in offspring. The use of corticosteroids among pregnant women ranged from 0.2% to 10% and increased nearly two times in recent years. Taken together, the evidence suggests that the use of corticosteroids in early pregnancy is not associated with an increased risk of congenital malformations overall or oral clefts in offspring; at the same time, published estimates are inconsistent. The use of inhaled corticosteroids was associated with a slightly increased risk of miscarriage, whereas the use of oral corticosteroids was not; however, confounding by indication could not be ruled out.
Because of their anti-inflammatory and immunosuppressive properties, corticosteroids are widely used to treat many medical conditions, including asthma, rheumatoid arthritis, eczema and inflammatory bowel disease [1]. Cortisol, the naturally occurring corticosteroid, exerts a range of physiological effects, including regulation of pathways in fat, protein and carbohydrate metabolism, cardiovascular function, growth and immunity [2]. Synthetic corticosteroids act similarly to cortisol: they bind to the same intracellular receptor proteins, although most of the synthetic corticosteroids have stronger affinity (e.g. prednisolone’s potency is 5:1 as compared to cortisol; for dexamethasone, the potency is 30:1) [2]. Speculations about teratogenicity of corticosteroids arose in 1951 because of the finding that treatment of pregnant mice with corticosteroids caused cleft palate in the offspring [3]. Concerns arose that corticosteroids could lead to more severe adverse pregnancy outcome, mainly because corticosteroids affect almost every cell in the body [4] and because of the higher potency of the synthetic corticosteroids [5]. Miscarriage is the most common adverse event of early pregnancy, affecting approximately 20% of pregnancies [6,7]. Studies of congenital malformations often focus on the prevalence of malformations at birth, whereby pregnancies ending in a miscarriage are excluded [8,9].
Author for correspondence: Anne-Mette Bay Bjørn, Department of Gynecology and Obstetrics, Aarhus University Hospital, Skejby, Bredstrupgaardsvej, 8200 Aarhus N, Denmark (e-mail [email protected]).
In this MiniReview, we provide an overview of the use of inhaled and oral corticosteroids in pregnancy, with specific emphasis on the association between use of corticosteroids during pregnancy and risk of miscarriage and congenital malformations in offspring. Methods To identify relevant studies, we searched the PubMed, EMBASE and CINAHL databases with the following limitations: studies in human beings, English language and published from January 1995 to December 2013. In addition, we identified studies through communication with other researchers and by reviewing the reference lists of relevant articles. For the identification of studies of corticosteroid use during pregnancy, we used the following search terms: ‘drug utilization’, ‘glucocorticoids’ or ‘anti-asthmatics’ and ‘pregnancy’. To identify studies on congenital malformations in the offspring and use of corticosteroids, we used the following search terms: ‘congenital abnormalities’ or ‘cleft palate’, ‘glucocorticoids’ or ‘anti-asthmatics’ and ‘pregnancy’. Finally, we used the following search terms ‘spontaneous abortion’ and ‘glucocorticoids’ or ‘anti-asthmatics’ to identify studies that addressed the association between miscarriage and use of corticosteroids. We used the following criteria to restrict the literature: (1) for the drug utilization studies, we required that they include corticosteroid use in pregnancy; (2) for studies that addressed congenital malformations and miscarriage, we selected only studies that specifically addressed inhaled or oral corticosteroid use in early pregnancy defined as the first trimester (until gestational week 12); and (3) if more than one study was conducted based on the same data sources and with overlapping study periods, we only included the most comprehensive study. We included seven drug utilization studies [10–16], eleven
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1999+2000 20
2008+2009 15 10
≤30 days before pregnancy
first trimester
second trimester
CS oral
CS inhaled
CS total
CS oral
CS inhaled
CS total
CS oral
CS inhaled
CS total
CS oral
0
CS inhaled
5
CS total
Prevalence of prescribed drug use/1,000 women
25
third trimester
Fig. 1. Prevalence (per 1000 women) of corticosteroid (CS) drug use across pregnancy among primiparous women in 1999–2000 and 2008–2009 [12]. prevalence studies [17–25] and six case–control studies [26–31] that met our criteria.
Results Use of corticosteroids in pregnancy. Prevalence of corticosteroid use in early pregnancy varied from 0.5% [13] to 10% [14]. The studies classified the use of corticosteroids differently; most studies reported the corticosteroid use classified as systemic [10,11,13–16] and one study reported the use of inhaled and oral corticosteroids separately [12]. Differences over time of corticosteroid use during pregnancy were described in one study [12], showing increases in first-trimester use from 1.1% to 1.8% and in second-trimester use from 1.0% to 1.9% over the period of 1999–2000 to 2008–2009 (fig. 1). Corticosteroid use and risk of congenital malformations in offspring. Published estimates of the association between corticosteroid use and risk of congenital malformations in offspring were inconsistent. Prevalence odds ratios (POR) ranged from 0.8 (95% confidence interval (CI), 0.4–1.7) [17] to 2.1 (95% CI, 0.5–9.6) [22] (table 1). The largest study, which included 892,362 pregnant women, of whom 12,478 used corticosteroids during pregnancy, reported a POR for congenital malformations overall of 1.1 (95% CI, 1.0–1.2) comparing users and non-users of inhaled corticosteroids during pregnancy [21]. The association of corticosteroid use in early pregnancy and oral clefts in offspring was evaluated in four prevalence studies [18,20,21,32] and five case–control studies [27–31], with reported POR ranging from 0.5 (95% CI, 0.1–3.3) [18] to 1.4 (1.0–1.9) [21], whereas the odds ratios (OR) ranged from 0.6 (95% CI, 0.2–1.7) [30] to 5.2 (95% CI, 1.5–17.1) [31] (table 1). Studies on corticosteroid use and risk of miscarriage. Most published studies found an association between the use of corticosteroids and the risk of miscarriage [19,24–26], with
relative risk estimates ranging from 1.2 [25,26] to 1.7 [19], while one small study showed no association but had wide confidence intervals (OR, 1.0; 95% CI, 0.5–2.1) [22] (table 2). The largest prevalence study included almost 300,000 pregnancies from the Health Improvement Network in England and Wales of whom 8849 used inhaled corticosteroids; they reported an OR for miscarriage of 1.2 (95% CI, 1.2–1.3) [25]. In a Danish registry-based case–control study (10,974 cases and 109,740 controls), the adjusted OR for miscarriage associated with the current use of inhaled corticosteroids within 60 days before the miscarriage was also 1.2 (95% CI, 1.0–1.4) [26].
Discussion The use of inhaled and oral corticosteroids in pregnancy is common, and the use seems to have increased nearly two times in recent years. Taken together, the evidence suggests that the use of corticosteroids in early pregnancy is not associated with an increased risk of congenital malformations overall or oral clefts in offspring. It seems that inhaled corticosteroid use increases slightly the risk of miscarriage, whereas the use of oral corticosteroids does not. To interpret the results from drug utilization studies, it is important to consider the possibility of low compliance, which could lead to over-estimation of drug use. Among non-pregnant women in Denmark, there was a strong agreement between self-reported drug intake and dispensation record [33]; however, this result may not be generalizable to pregnant women, who may be more likely to be non-compliant for fear of teratogenicity [8]. At the same time, a series of Hungarian validation studies on drug use in pregnancy showed that only a small group of pregnant women (2.4%) abstained from using prescribed drugs due to fear of teratogenic effects [34]. A recent Danish study of adherence to medical treatment among women with ulcerative colitis (n = 115) before and/or during pregnancy estimated a positive predictive value of selfreported drug use of 86.2% (95% CI 74.6–93.9) [35], suggesting high compliance with therapy among pregnant women
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K€allen [21] Sweden 1995–2004 Bjørn [18] Denmark 1998–2009 Hviid [20] Denmark 1996–2008 Vasilakis–Scaramozza [32] United Kingdom January 1991–April 2002 Alexander [17] Canada 1991–1993 Blais [45] Canada 1990–2000 Gur [19] Israel 1988–2001 Park–Wyllie [22] Canada 1985–1995 Schatz [23] USA Jun 1978–Dec 1989 Carmichael [28] USA Oct. 1997–Dec. 2002
Author, country, study period
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Inhaled Oral Inhaled Oral Inhaled
Inhaled
Systemicb
Systemicc
Inhaled, intranasal, and oral Inhaled
Prevalence studyf
Prevalence study
Prevalence studye
Prevalence studye
Prevalence studye
Prevalence studyg
Prevalence studyh
Prevalence studyi
Danish Medical Birth Registry 83,043 primiparous women
Danish Medical Birth Registry 832,636 live births
The United Kingdom’s General Practice Research Database 23,751 pregnancies Nova Scotia Atlee Perinatal Database, Halifax County, Canada, Grace Maternity Hospital 14,526 pregnancies RAMQ, MED-ECHO, and ISQ databases, Quebec 4561 pregnancies from women with asthma
The Israeli Teratogen Information Service 1101 pregnancies
Canadian Motherisk cohort 372 pregnancies
Kaiser-Permanente Prospective Study of Asthma During Pregnancy 1502 pregnancies American National Birth Defects Prevention Study 1769 infants with oral clefts 4143 control infants
Systemicc
Inhaled Oral
Prevalence studye
Swedish Medical Birth Registry 892,362 pregnanciesa
Case–control
Inhaled
Study design
Data sources, study population
Type of corticosteroid exposure
Table 1. Studies of corticosteroid use in early pregnancy and risk of congenital malformations and oral clefts in offspring
14
4
10
7
8
150 24
53 10
627
N of exposed infants with a malformation
1.4 (0.9–2.5)
2.1 (0.5–9.6)
2.0 (0.9–4.4)
0.9 (0.4 –2.0)
0.8 (0.4–1.7)
1.1 (0.9–1.4) 1.2 (0.8–1.9)
1.0 (0.8–1.3) 1.0 (0.6–2.0)
1.1 (1.0–1.2)
Relative risk estimates* (95% confidence interval)
19 5 9 2
6 3 No data 5 1
1 No data
48
N of exposed infants with oral clefts
Outcome of interest Congenital malformations overall
CLP: CP: CLP: CP:
1.5 0.7 2.1 0.8
(0.9–2.5) (0.3–1.8) (0.9–4.7) (0.2–3.6)
CLP: 0.7 (0.2–0.6) CLP: 1.3 (0.1–14)
CLP: 0.8 (0.3–1.7) CP: 0.9 (0.3–2.9)
All: 0.5 (0.1–3.3)
All: 1.4 (1.0–1.9)
Relative risk estimates* (95% confidence interval)
Oral clefts
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Oral
Oral
Case–control
Case–control
Case–control
The California Birth Defects Monitoring Program 1299 malformed infants. 734 control infants
Spanish Collaborative Study of Congenital Malformations – ECEMC 24,038 malformed infants. 23,517 control infants The Hungarian Congenital Abnormality Registry – HCCSCA 20,830 malformed infants. 35,727 control infants
Oral
Systemicd
Inhaled
Case–control
Study design
Malformation Drug Exposure Surveillance Project – MADRE 11,150 malformed infants. 23,517 control infants
Data sources, study population
1
All: 1.3 (0.8–2.0)
All: 5.2 (1.5–17.1)
All: 0.6 (0.2–1.7) CLP: 0.7 (0.2–2.2) CP: 0.6 (0.1–5.1) All: 1.3 (0.7–2.2) CLP: 1.8 (1.0–3.1) CP: 0.3 (0.04–1.5) CLP: 4.3 (1.1–17.2) CP: 5.3 (1.1; 26.5)
4 3 1 15 13 1 6 3 5
Relative risk estimates* (95% confidence interval)
N of exposed infants with oral clefts
N of exposed infants with a malformation
Relative risk estimates* (95% confidence interval)
Oral clefts
Congenital malformations overall
Outcome of interest
Abbreviations: All, all clefts; CLP, cleft lip with or without cleft palate; CP, cleft palate. Study population definition: athe study population defined in K€allen et al. [57]. Exposure definitions regarding systemic use: boral, intramuscular and intravenous preparations; coral and intravenous preparations; doral and injection according to the ATC-classification H02A. Outcome definition regarding congenital malformations overall: enot categorized; fdiagnoses of dislocation of the hip, undescended testes and chromosomal disorders excluded; gson-genetic major congenital malformations; hmajor and minor malformations according to Heinonen et al. [58]; imajor malformations. *the risk estimates are given as prevalence odds ratios for the prevalence studies and odds ratio for the case–control studies. For references 18 and 22, the risk estimates are calculated using the Episheet software (version 2011, by Kenneth J. Rothman).
Pradat [30] Australia, France, Italy, Israel, Japan, the Netherlands, South America 1990–2002 Carmichael [27] USA 1987–1988 Rodriguez–Pinilla [31] Spain Apr. 1976–Dec. 1995 Czeizel [28] Hungary 1980–1994
Author, country, study period
Type of corticosteroid exposure
Table 1. (continued)
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ANNE-METTE BAY BJØRN ET AL. Table 2.
Studies of corticosteroid use and risk of miscarriage.
Author, country, study period Tata [25] England and Wales Jan. 1988–Nov. 2004 Gur [19] Israel 1988–2001 Silverman [24] Trial including 32 countries Oct. 1996–Jan. 1998 Park–Wyllie [22] Canada 1985–1995 Bjørn [26] Denmark 1997–2009
Data sources, study population
Study design
Exposure c
Relative risk estimates* (95% confidence interval); N of exposed cases
The Health Improvement Network 281,019 pregnancies
Prevalence study
Inhaled
1.2 (1.2–1.3)
The Israeli Teratogen Information Service 1101 pregnancies
Prevalence studyc
Systemica
1.7 (1.1–2.5); 36
START (inhaled Steroid Treatment As Regular Therapy) trial 313 pregnancies Canadian Motherisk cohort 372 pregnancies
Prevalence studyc
Inhaled
1.3 (0.6–2.5); 23
Prevalence studyd
Systemicb
1.0 (0.5–2.1); 13
Case–control studye
Inhaled Oral
1.2 (1.0–1.4); 140 0.8 (0.5–1.2); 28
The Danish National Registry of Patients 10,974 cases of miscarriage, 109,740 controls
Exposure definitions regarding systemic use: aoral, intramuscular and intravenous preparations; boral and intravenous preparations. Outcome definition regarding miscarriage: cnot defined; dmiscarriage before 26 gestational weeks; emiscarriage before 22 gestational weeks. *the risk estimates are given as prevalence odds ratios for the prevalence studies and odds ratio for the case–control studies. For references 19, 22 and 24, the risk estimates are calculated using the Episheet software (version 2011, by Kenneth J. Rothman).
with chronic diseases. Geographical differences in drug utilization patterns may stem from differences in reporting policies for over-the-counter or reimbursed drugs. Furthermore, differences in socio-economic or health characteristics of the underlying populations may influence the use of prescribed drugs during pregnancy [36]. Regarding the studies of congenital malformations, factors such as the route of administration of corticosteroids and the classification of malformations differed among the existing studies, which complicated comparisons. Furthermore, to detect even a common congenital malformation, a population of at least half a million pregnant women is needed and as many as 5 million are required to detect rare events [37]. Even with large databases available, only very few women who used corticosteroids in early pregnancy and who gave birth to an infant with oral cleft were identified [20,26]. Multinational studies could enable sample sizes large enough to provide a better precision of the estimates [38]. Large population-based studies performed with medical databases from Sweden and Denmark found no association between the use of corticosteroids in early pregnancy and malformations in offspring [18,20,21]. The Nordic medical databases are considered a valid tool for epidemiological research of congenital malformations [38], with positive predictive value of 88.2% (range 85.9–90.5%) for diagnoses recorded in the Danish National Registry of Patients compared against medical records [39]. In the case–control studies that reported an increased risk of oral clefts with the use of oral corticosteroids, early pregnancy exposure information was based on retrospective data collected by means of interviews or questionnaires [27,28,30,31], with the risk of differential recall of drug use [40]. The Hungarian Case-Control Surveillance System of Congenital
Abnormalities (HCCSSCA), which was established in 1980, contains information on 22,843 cases of congenital malformations captured in 1980–1996 [41]. Data on exposure during pregnancy were collected by women’s self-report after having given birth, potentially inducing spurious associations due to differential recall, which could result in observed odds ratios biased nearly two times [42]. Furthermore, two studies reviewed here were based on teratogenic information system reporting [19,22], in which self-referral bias cannot be ruled out. Self-referral bias could create an apparent association where none exists [40], because reasons for contacting a teratogenic information system may themselves be associated with the outcome under study [43]. Taking the evidence all together, the use of corticosteroids in early pregnancy does not seem to be associated with congenital malformations in offspring. Asthma is a common indication for inhaled corticosteroids, and it may be difficult to separate the effect of corticosteroids from the effect of the underlying asthma. A recent metaanalysis indicated that infants of pregnant women with asthma were 11% more likely to have congenital malformations diagnosed compared with infants of women with asthma [RR 1.1 (95% CI 1.0–1.2)], although discussion has been raised that this risk could be driven by minor malformations [44]. A Canadian prevalence study using data from the RAMQ (the Regie de l’assurance-maladie du Quebec) database included a total of 41,637 pregnancies, divided into 13,280 pregnancies in women with asthma and 28,357 pregnancies in women without asthma, showed that maternal asthma was associated with a 30% increased risk of any congenital malformation (OR: 1.3; 95%CI, 1.2–1.4) [45]. However, this study could not distinctly separate asthma effects from drug effects [45], and although discussed thoroughly in several studies [45–50],
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the isolated effect of the underlying asthma is difficult to estimate. A large Swedish prevalence study of 2,205 infants with cleft palate found a RR of 2.0 (95%CI, 1.1–3.8) among pregnant users of corticosteroids [51] which also was the association found in the mouse experiments [3]. Some studies did not describe the oral clefts separately [18,21,29,31] or reported the effects on cleft lip in retrospective studies with risk of recall bias [27,28,30]. Agreement that inhaled corticosteroids was associated with a slightly increased risk of miscarriage was reported in two large population-based studies [25,26], while no association was identified for oral use [19,22,26]. Presence of an association with miscarriage for inhaled but not oral corticosteroids is counter-intuitive. Oral corticosteroids reach higher concentrations in the maternal circulation [2] and therefore could be expected to lead to higher levels of foetal exposure. One explanation for the association observed for inhaled corticosteroids could be confounding by asthma [52]. Asthma may also be a risk factor for miscarriage [23,25]. Biologically explained, hypoxia is induced during asthma exacerbations causing abnormal smooth muscle activity in the uterus, similar to airway smooth muscle contractions in the lungs [53,54]. An increased risk of miscarriage of 1.57 (95% CI 1.02–2.41) among 1,044 pregnant women with asthma compared with 860 pregnant women without asthma is reported [23]. Also a higher risk of miscarriage (OR, 1.28; 95% CI, 1.15–1.43) among women with asthma who experienced one or more exacerbations in the year before pregnancy compared with women with asthma has been reported [25]. Lack of an apparent association with miscarriage for oral corticosteroids could also be a reflection of their protective effect. Miscarriage may occur as a result of an abnormal immune response [54], which anti-inflammatory properties of corticosteroids might inhibit in high doses. In fact, high doses of corticosteroids are used to prevent recurrent miscarriages [53], although the effectiveness of this treatment is still controversial [53,55,56]. Only one study included information about gestational age at miscarriage [26]. Data on gestational age allow differentiation between early and late miscarriage, which may have different aetiologies. Bjørn et al. found that current use of inhaled corticosteroids within 60 days before miscarriage was associated with a slightly increased risk of early miscarriage but not with late miscarriage [26]. This could reflect that exposure in early pregnancy influences the foetus’ environment and therefore increases the risk of early pregnancy loss. Conclusion Around 2% of all pregnant women use corticosteroids in early pregnancy, and the prevalence of corticosteroid use has increased in recent years. The use of corticosteroids did not seem to increase the risk of congenital malformations, but the use of inhaled corticosteroids was associated with a slightly increased risk of miscarriage. However, confounding by indication cannot be ruled out.
313 References
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21 K€allen B, Olausson PO. Use of anti-asthmatic drugs during pregnancy. 3. Congenital malformations in the infants. Eur J Clin Pharmacol 2007;63:383–8. 22 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. 23 Schatz M, Zeiger RS, Harden K, Huffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;100:301–6. 24 Silverman M, Sheffer A, Diaz PV, Lindmark B, Radner F, Broddene M et al. Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide. Ann Allergy Asthma Immunol 2005;95:566–70. 25 Tata LJ, Lewis SA, McKeever TM, Smith CJP, Doyle P, Smeeth L et al. A comprehensive analysis of adverse obstetric and pediatric complications in women with asthma. Am J Respir Crit Care Med 2007;175:991–7. 26 Bjørn AMB, Nielsen RB, Nørgaard M, Nohr EA, Sørensen HT, Ehrenstein V. Risk of miscarriage among users of corticosteroid hormones: a population-based nested case-control study. Clin Epidemiol 2013;5:287–94. 27 Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86: 242–4. 28 Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ. Maternal corticosteroid use and orofacial clefts. Am J Obstet Gynecol 2007;197:585.e1–7. 29 Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology 1997;56:335– 40. 30 Pradat P, Robert-Gnansia E, Di Tanna GL, Rosano A, Lisi A, Mastroiacovo P et al. First trimester exposure to corticosteroids and oral clefts. Birth Defects Res A Clin Mol Teratol 2003;67:968–70. 31 Rodrıguez-Pinilla E, Martınez-Frıas M. Corticosteroids during pregnancy and oral clefts: a case-control study. Teratology 1998;58:2–5. 32 Vasilakis-Scaramozza C, Aschengrau A, Cabral HJ, Jick SS. Asthma drugs and the risk of congenital anomalies. Pharmacotherapy 2013;33:363–8. 33 Løkkegaard EL, Johnsen SP, Heitmann BL, Stahlberg C, Pedersen AT, Obel EB et al. The validity of self-reported use of hormone replacement therapy among Danish nurses. Acta Obstet Gynecol Scand 2004;83:476–81. 34 Czeizel AF, Petik D, Vargha P. Validation studies of drug exposures in pregnant women. Pharmacoepidemiol Drug Saf 2003;12:409–16. 35 Julsgaard M, Nørgaard M, Hvas CL, Buck D, Christensen LA. Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis. Inflamm Bowel Dis 2011;17:1573–80. 36 Lee D, Bergman U. Studies of drug utilization. In: Storm B, (ed). Pharmacoepidemiology, 4th edn. John Whiley & Sons Ltd, West Sussex, 2005; 401–8. 37 Skegg DCG, Doll R. Record linkage for drug monitoring. J Epidemiol Community Health 1981;35:25–31. 38 Furu K, Wettermark B, Andersen M, Martikainen J, Almarsdottir AB, Sørensen HT. The Nordic countries as a cohort for pharmacoepidemiological research. Basic Clin Pharmacol Toxicol 2010; 106:86–94.
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39 Larsen H, Nielsen GL, Bendsen J, Flint C, Olsen J, Sørensen HT. Predictive value and completeness of the registration of congenital abnormalities in three Danish population-based registries. Scand J Public Health 2003;31:12–6. 40 Ehrenstein V, Sørensen HT, Bakketeig LS, Pedersen L. Medical databases in studies of drug teratogenicity: methodological issues. Clin Epidemiol 2010;2:37–43. 41 Czeizel AE, Rockenbauer M, Siffel C, Varga E. Description and mission evaluation of the Hungarian case-control surveillance of congenital abnormalities, 1980-1996. Teratology 2001;63:176–85. 42 Rockenbauer M, Olsen J, Czeizel AE, Pedersen L, Sørensen HT. Recall bias in a case-control surveillance system on the use of medicine during pregnancy. Epidemiology 2001;12:461–6. 43 Rothman KJ, Greenland S, Lash T. Validity in epidemiologic studies. In: Rothman KJ, Greenland S, Lash T, (eds). Modern epidemiology, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, 2008; 128–47. 44 Murphy VE, Wang G, Namazy JA, Powel H, Gibson PG, Chambers C et al. The risk of congenital malformations, perinatal mortality and neonatal hospitalization among pregnant women with asthma: A systematic review and meta-analysis. BJOG 2013;120:812–22. 45 Blais L, Kettani FZ, Elftouh N, Forget A. Effect of maternal asthma on the risk of specific congenital malformations: A population-based cohort study. Birth Defects Res A Clin Mol Teratol 2012;88:216–22. 46 Dombrowski MP. Asthma and pregnancy. Obstet Gynecol 2006;108:667–81. 47 Namazy JA, Schatz M. Treatment of asthma during pregnancy and perinatal outcomes. Curr Opin Allergy Clin Immunol 2005;5:229– 33. 48 Rey E, Boulet LP. Pregnancy plus: asthma in pregnancy. BMJ 2007;334:582–5. 49 Schatz M. Asthma and pregnancy. Lancet 1999;353:1202–4. 50 Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W et al. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol 2004;113:1040–5. 51 K€allen B. Oral Clefts. In: K€allen B, (ed). Epidemiology of Human Congenital Malformations, 1st edn. Springer Verlag, Springer International Publishing Switzerland, 2014; 73–7. 52 Csizmadi I, Collet JP, Boivin JF. Bias and confounding in pharmacoepidemiology. In: Storm B, (ed). Pharmacoepidemiology, 4th edn. John Wiley&Sons Ltd, West Sussex, 2011; 791–809. 53 Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JW, Farwell V et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997;337:148–54. 54 Mellor A, Munn D. Immunology at the maternal-fetal interface: lessons for T cell tolerance and suppression. Annu Rev Immunol 2000;18:367–91. 55 Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2006;19:CD000112. 56 Salmon JE. A noninflammatory pathway for pregnancy loss: Innate immune activation? J Clin Invest 2004;114:15–7. 57 K€allen B, Otterblad Olausson P. Use of anti-asthmatic drugs during pregnancy. 1. Maternal characteristics, pregnancy and delivery complications. Eur J Clin Pharmacol 2007;63:363–73. 58 Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy, 1st edn. Publishing Sciences Group, Inc., Littleton, 1977.
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Use of Inhaled and Oral Corticosteroids in Pregnancy and the Risk of Malformations or Miscarriage Anne-Mette Bay Bjørn1, Vera Ehrenstein2, Ellen Aagaard Nohr3 and Mette Nørgaard2 Department of Gynecology and Obstetrics, Aarhus University Hospital Skejby, Aarhus N, Denmark, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark and 3Research Unit for Gynecology and Obstetrics, Institute for Clinical Research, University of Southern Denmark, Odense, Denmark 1
(Received 23 January 2014; Accepted 8 December 2014) Abstract: Corticosteroids are potent anti-inflammatory and immunosuppressive drugs, which sometimes must be given to pregnant women. Corticosteroids have been suspected to be teratogenic for many years; however, there is conflicting evidence regarding the association. Based on a literature review of three databases, this MiniReview provides an overview of inhaled and oral corticosteroid use in pregnancy with specific emphasis on the association between use of corticosteroids during pregnancy and risk of miscarriage and congenital malformations in offspring. The use of corticosteroids among pregnant women ranged from 0.2% to 10% and increased nearly two times in recent years. Taken together, the evidence suggests that the use of corticosteroids in early pregnancy is not associated with an increased risk of congenital malformations overall or oral clefts in offspring; at the same time, published estimates are inconsistent. The use of inhaled corticosteroids was associated with a slightly increased risk of miscarriage, whereas the use of oral corticosteroids was not; however, confounding by indication could not be ruled out.
Because of their anti-inflammatory and immunosuppressive properties, corticosteroids are widely used to treat many medical conditions, including asthma, rheumatoid arthritis, eczema and inflammatory bowel disease [1]. Cortisol, the naturally occurring corticosteroid, exerts a range of physiological effects, including regulation of pathways in fat, protein and carbohydrate metabolism, cardiovascular function, growth and immunity [2]. Synthetic corticosteroids act similarly to cortisol: they bind to the same intracellular receptor proteins, although most of the synthetic corticosteroids have stronger affinity (e.g. prednisolone’s potency is 5:1 as compared to cortisol; for dexamethasone, the potency is 30:1) [2]. Speculations about teratogenicity of corticosteroids arose in 1951 because of the finding that treatment of pregnant mice with corticosteroids caused cleft palate in the offspring [3]. Concerns arose that corticosteroids could lead to more severe adverse pregnancy outcome, mainly because corticosteroids affect almost every cell in the body [4] and because of the higher potency of the synthetic corticosteroids [5]. Miscarriage is the most common adverse event of early pregnancy, affecting approximately 20% of pregnancies [6,7]. Studies of congenital malformations often focus on the prevalence of malformations at birth, whereby pregnancies ending in a miscarriage are excluded [8,9].
Author for correspondence: Anne-Mette Bay Bjørn, Department of Gynecology and Obstetrics, Aarhus University Hospital, Skejby, Bredstrupgaardsvej, 8200 Aarhus N, Denmark (e-mail [email protected]).
In this MiniReview, we provide an overview of the use of inhaled and oral corticosteroids in pregnancy, with specific emphasis on the association between use of corticosteroids during pregnancy and risk of miscarriage and congenital malformations in offspring. Methods To identify relevant studies, we searched the PubMed, EMBASE and CINAHL databases with the following limitations: studies in human beings, English language and published from January 1995 to December 2013. In addition, we identified studies through communication with other researchers and by reviewing the reference lists of relevant articles. For the identification of studies of corticosteroid use during pregnancy, we used the following search terms: ‘drug utilization’, ‘glucocorticoids’ or ‘anti-asthmatics’ and ‘pregnancy’. To identify studies on congenital malformations in the offspring and use of corticosteroids, we used the following search terms: ‘congenital abnormalities’ or ‘cleft palate’, ‘glucocorticoids’ or ‘anti-asthmatics’ and ‘pregnancy’. Finally, we used the following search terms ‘spontaneous abortion’ and ‘glucocorticoids’ or ‘anti-asthmatics’ to identify studies that addressed the association between miscarriage and use of corticosteroids. We used the following criteria to restrict the literature: (1) for the drug utilization studies, we required that they include corticosteroid use in pregnancy; (2) for studies that addressed congenital malformations and miscarriage, we selected only studies that specifically addressed inhaled or oral corticosteroid use in early pregnancy defined as the first trimester (until gestational week 12); and (3) if more than one study was conducted based on the same data sources and with overlapping study periods, we only included the most comprehensive study. We included seven drug utilization studies [10–16], eleven
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1999+2000 20
2008+2009 15 10
≤30 days before pregnancy
first trimester
second trimester
CS oral
CS inhaled
CS total
CS oral
CS inhaled
CS total
CS oral
CS inhaled
CS total
CS oral
0
CS inhaled
5
CS total
Prevalence of prescribed drug use/1,000 women
25
third trimester
Fig. 1. Prevalence (per 1000 women) of corticosteroid (CS) drug use across pregnancy among primiparous women in 1999–2000 and 2008–2009 [12]. prevalence studies [17–25] and six case–control studies [26–31] that met our criteria.
Results Use of corticosteroids in pregnancy. Prevalence of corticosteroid use in early pregnancy varied from 0.5% [13] to 10% [14]. The studies classified the use of corticosteroids differently; most studies reported the corticosteroid use classified as systemic [10,11,13–16] and one study reported the use of inhaled and oral corticosteroids separately [12]. Differences over time of corticosteroid use during pregnancy were described in one study [12], showing increases in first-trimester use from 1.1% to 1.8% and in second-trimester use from 1.0% to 1.9% over the period of 1999–2000 to 2008–2009 (fig. 1). Corticosteroid use and risk of congenital malformations in offspring. Published estimates of the association between corticosteroid use and risk of congenital malformations in offspring were inconsistent. Prevalence odds ratios (POR) ranged from 0.8 (95% confidence interval (CI), 0.4–1.7) [17] to 2.1 (95% CI, 0.5–9.6) [22] (table 1). The largest study, which included 892,362 pregnant women, of whom 12,478 used corticosteroids during pregnancy, reported a POR for congenital malformations overall of 1.1 (95% CI, 1.0–1.2) comparing users and non-users of inhaled corticosteroids during pregnancy [21]. The association of corticosteroid use in early pregnancy and oral clefts in offspring was evaluated in four prevalence studies [18,20,21,32] and five case–control studies [27–31], with reported POR ranging from 0.5 (95% CI, 0.1–3.3) [18] to 1.4 (1.0–1.9) [21], whereas the odds ratios (OR) ranged from 0.6 (95% CI, 0.2–1.7) [30] to 5.2 (95% CI, 1.5–17.1) [31] (table 1). Studies on corticosteroid use and risk of miscarriage. Most published studies found an association between the use of corticosteroids and the risk of miscarriage [19,24–26], with
relative risk estimates ranging from 1.2 [25,26] to 1.7 [19], while one small study showed no association but had wide confidence intervals (OR, 1.0; 95% CI, 0.5–2.1) [22] (table 2). The largest prevalence study included almost 300,000 pregnancies from the Health Improvement Network in England and Wales of whom 8849 used inhaled corticosteroids; they reported an OR for miscarriage of 1.2 (95% CI, 1.2–1.3) [25]. In a Danish registry-based case–control study (10,974 cases and 109,740 controls), the adjusted OR for miscarriage associated with the current use of inhaled corticosteroids within 60 days before the miscarriage was also 1.2 (95% CI, 1.0–1.4) [26].
Discussion The use of inhaled and oral corticosteroids in pregnancy is common, and the use seems to have increased nearly two times in recent years. Taken together, the evidence suggests that the use of corticosteroids in early pregnancy is not associated with an increased risk of congenital malformations overall or oral clefts in offspring. It seems that inhaled corticosteroid use increases slightly the risk of miscarriage, whereas the use of oral corticosteroids does not. To interpret the results from drug utilization studies, it is important to consider the possibility of low compliance, which could lead to over-estimation of drug use. Among non-pregnant women in Denmark, there was a strong agreement between self-reported drug intake and dispensation record [33]; however, this result may not be generalizable to pregnant women, who may be more likely to be non-compliant for fear of teratogenicity [8]. At the same time, a series of Hungarian validation studies on drug use in pregnancy showed that only a small group of pregnant women (2.4%) abstained from using prescribed drugs due to fear of teratogenic effects [34]. A recent Danish study of adherence to medical treatment among women with ulcerative colitis (n = 115) before and/or during pregnancy estimated a positive predictive value of selfreported drug use of 86.2% (95% CI 74.6–93.9) [35], suggesting high compliance with therapy among pregnant women
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
K€allen [21] Sweden 1995–2004 Bjørn [18] Denmark 1998–2009 Hviid [20] Denmark 1996–2008 Vasilakis–Scaramozza [32] United Kingdom January 1991–April 2002 Alexander [17] Canada 1991–1993 Blais [45] Canada 1990–2000 Gur [19] Israel 1988–2001 Park–Wyllie [22] Canada 1985–1995 Schatz [23] USA Jun 1978–Dec 1989 Carmichael [28] USA Oct. 1997–Dec. 2002
Author, country, study period
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
Inhaled Oral Inhaled Oral Inhaled
Inhaled
Systemicb
Systemicc
Inhaled, intranasal, and oral Inhaled
Prevalence studyf
Prevalence study
Prevalence studye
Prevalence studye
Prevalence studye
Prevalence studyg
Prevalence studyh
Prevalence studyi
Danish Medical Birth Registry 83,043 primiparous women
Danish Medical Birth Registry 832,636 live births
The United Kingdom’s General Practice Research Database 23,751 pregnancies Nova Scotia Atlee Perinatal Database, Halifax County, Canada, Grace Maternity Hospital 14,526 pregnancies RAMQ, MED-ECHO, and ISQ databases, Quebec 4561 pregnancies from women with asthma
The Israeli Teratogen Information Service 1101 pregnancies
Canadian Motherisk cohort 372 pregnancies
Kaiser-Permanente Prospective Study of Asthma During Pregnancy 1502 pregnancies American National Birth Defects Prevention Study 1769 infants with oral clefts 4143 control infants
Systemicc
Inhaled Oral
Prevalence studye
Swedish Medical Birth Registry 892,362 pregnanciesa
Case–control
Inhaled
Study design
Data sources, study population
Type of corticosteroid exposure
Table 1. Studies of corticosteroid use in early pregnancy and risk of congenital malformations and oral clefts in offspring
14
4
10
7
8
150 24
53 10
627
N of exposed infants with a malformation
1.4 (0.9–2.5)
2.1 (0.5–9.6)
2.0 (0.9–4.4)
0.9 (0.4 –2.0)
0.8 (0.4–1.7)
1.1 (0.9–1.4) 1.2 (0.8–1.9)
1.0 (0.8–1.3) 1.0 (0.6–2.0)
1.1 (1.0–1.2)
Relative risk estimates* (95% confidence interval)
19 5 9 2
6 3 No data 5 1
1 No data
48
N of exposed infants with oral clefts
Outcome of interest Congenital malformations overall
CLP: CP: CLP: CP:
1.5 0.7 2.1 0.8
(0.9–2.5) (0.3–1.8) (0.9–4.7) (0.2–3.6)
CLP: 0.7 (0.2–0.6) CLP: 1.3 (0.1–14)
CLP: 0.8 (0.3–1.7) CP: 0.9 (0.3–2.9)
All: 0.5 (0.1–3.3)
All: 1.4 (1.0–1.9)
Relative risk estimates* (95% confidence interval)
Oral clefts
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Oral
Oral
Case–control
Case–control
Case–control
The California Birth Defects Monitoring Program 1299 malformed infants. 734 control infants
Spanish Collaborative Study of Congenital Malformations – ECEMC 24,038 malformed infants. 23,517 control infants The Hungarian Congenital Abnormality Registry – HCCSCA 20,830 malformed infants. 35,727 control infants
Oral
Systemicd
Inhaled
Case–control
Study design
Malformation Drug Exposure Surveillance Project – MADRE 11,150 malformed infants. 23,517 control infants
Data sources, study population
1
All: 1.3 (0.8–2.0)
All: 5.2 (1.5–17.1)
All: 0.6 (0.2–1.7) CLP: 0.7 (0.2–2.2) CP: 0.6 (0.1–5.1) All: 1.3 (0.7–2.2) CLP: 1.8 (1.0–3.1) CP: 0.3 (0.04–1.5) CLP: 4.3 (1.1–17.2) CP: 5.3 (1.1; 26.5)
4 3 1 15 13 1 6 3 5
Relative risk estimates* (95% confidence interval)
N of exposed infants with oral clefts
N of exposed infants with a malformation
Relative risk estimates* (95% confidence interval)
Oral clefts
Congenital malformations overall
Outcome of interest
Abbreviations: All, all clefts; CLP, cleft lip with or without cleft palate; CP, cleft palate. Study population definition: athe study population defined in K€allen et al. [57]. Exposure definitions regarding systemic use: boral, intramuscular and intravenous preparations; coral and intravenous preparations; doral and injection according to the ATC-classification H02A. Outcome definition regarding congenital malformations overall: enot categorized; fdiagnoses of dislocation of the hip, undescended testes and chromosomal disorders excluded; gson-genetic major congenital malformations; hmajor and minor malformations according to Heinonen et al. [58]; imajor malformations. *the risk estimates are given as prevalence odds ratios for the prevalence studies and odds ratio for the case–control studies. For references 18 and 22, the risk estimates are calculated using the Episheet software (version 2011, by Kenneth J. Rothman).
Pradat [30] Australia, France, Italy, Israel, Japan, the Netherlands, South America 1990–2002 Carmichael [27] USA 1987–1988 Rodriguez–Pinilla [31] Spain Apr. 1976–Dec. 1995 Czeizel [28] Hungary 1980–1994
Author, country, study period
Type of corticosteroid exposure
Table 1. (continued)
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Studies of corticosteroid use and risk of miscarriage.
Author, country, study period Tata [25] England and Wales Jan. 1988–Nov. 2004 Gur [19] Israel 1988–2001 Silverman [24] Trial including 32 countries Oct. 1996–Jan. 1998 Park–Wyllie [22] Canada 1985–1995 Bjørn [26] Denmark 1997–2009
Data sources, study population
Study design
Exposure c
Relative risk estimates* (95% confidence interval); N of exposed cases
The Health Improvement Network 281,019 pregnancies
Prevalence study
Inhaled
1.2 (1.2–1.3)
The Israeli Teratogen Information Service 1101 pregnancies
Prevalence studyc
Systemica
1.7 (1.1–2.5); 36
START (inhaled Steroid Treatment As Regular Therapy) trial 313 pregnancies Canadian Motherisk cohort 372 pregnancies
Prevalence studyc
Inhaled
1.3 (0.6–2.5); 23
Prevalence studyd
Systemicb
1.0 (0.5–2.1); 13
Case–control studye
Inhaled Oral
1.2 (1.0–1.4); 140 0.8 (0.5–1.2); 28
The Danish National Registry of Patients 10,974 cases of miscarriage, 109,740 controls
Exposure definitions regarding systemic use: aoral, intramuscular and intravenous preparations; boral and intravenous preparations. Outcome definition regarding miscarriage: cnot defined; dmiscarriage before 26 gestational weeks; emiscarriage before 22 gestational weeks. *the risk estimates are given as prevalence odds ratios for the prevalence studies and odds ratio for the case–control studies. For references 19, 22 and 24, the risk estimates are calculated using the Episheet software (version 2011, by Kenneth J. Rothman).
with chronic diseases. Geographical differences in drug utilization patterns may stem from differences in reporting policies for over-the-counter or reimbursed drugs. Furthermore, differences in socio-economic or health characteristics of the underlying populations may influence the use of prescribed drugs during pregnancy [36]. Regarding the studies of congenital malformations, factors such as the route of administration of corticosteroids and the classification of malformations differed among the existing studies, which complicated comparisons. Furthermore, to detect even a common congenital malformation, a population of at least half a million pregnant women is needed and as many as 5 million are required to detect rare events [37]. Even with large databases available, only very few women who used corticosteroids in early pregnancy and who gave birth to an infant with oral cleft were identified [20,26]. Multinational studies could enable sample sizes large enough to provide a better precision of the estimates [38]. Large population-based studies performed with medical databases from Sweden and Denmark found no association between the use of corticosteroids in early pregnancy and malformations in offspring [18,20,21]. The Nordic medical databases are considered a valid tool for epidemiological research of congenital malformations [38], with positive predictive value of 88.2% (range 85.9–90.5%) for diagnoses recorded in the Danish National Registry of Patients compared against medical records [39]. In the case–control studies that reported an increased risk of oral clefts with the use of oral corticosteroids, early pregnancy exposure information was based on retrospective data collected by means of interviews or questionnaires [27,28,30,31], with the risk of differential recall of drug use [40]. The Hungarian Case-Control Surveillance System of Congenital
Abnormalities (HCCSSCA), which was established in 1980, contains information on 22,843 cases of congenital malformations captured in 1980–1996 [41]. Data on exposure during pregnancy were collected by women’s self-report after having given birth, potentially inducing spurious associations due to differential recall, which could result in observed odds ratios biased nearly two times [42]. Furthermore, two studies reviewed here were based on teratogenic information system reporting [19,22], in which self-referral bias cannot be ruled out. Self-referral bias could create an apparent association where none exists [40], because reasons for contacting a teratogenic information system may themselves be associated with the outcome under study [43]. Taking the evidence all together, the use of corticosteroids in early pregnancy does not seem to be associated with congenital malformations in offspring. Asthma is a common indication for inhaled corticosteroids, and it may be difficult to separate the effect of corticosteroids from the effect of the underlying asthma. A recent metaanalysis indicated that infants of pregnant women with asthma were 11% more likely to have congenital malformations diagnosed compared with infants of women with asthma [RR 1.1 (95% CI 1.0–1.2)], although discussion has been raised that this risk could be driven by minor malformations [44]. A Canadian prevalence study using data from the RAMQ (the Regie de l’assurance-maladie du Quebec) database included a total of 41,637 pregnancies, divided into 13,280 pregnancies in women with asthma and 28,357 pregnancies in women without asthma, showed that maternal asthma was associated with a 30% increased risk of any congenital malformation (OR: 1.3; 95%CI, 1.2–1.4) [45]. However, this study could not distinctly separate asthma effects from drug effects [45], and although discussed thoroughly in several studies [45–50],
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the isolated effect of the underlying asthma is difficult to estimate. A large Swedish prevalence study of 2,205 infants with cleft palate found a RR of 2.0 (95%CI, 1.1–3.8) among pregnant users of corticosteroids [51] which also was the association found in the mouse experiments [3]. Some studies did not describe the oral clefts separately [18,21,29,31] or reported the effects on cleft lip in retrospective studies with risk of recall bias [27,28,30]. Agreement that inhaled corticosteroids was associated with a slightly increased risk of miscarriage was reported in two large population-based studies [25,26], while no association was identified for oral use [19,22,26]. Presence of an association with miscarriage for inhaled but not oral corticosteroids is counter-intuitive. Oral corticosteroids reach higher concentrations in the maternal circulation [2] and therefore could be expected to lead to higher levels of foetal exposure. One explanation for the association observed for inhaled corticosteroids could be confounding by asthma [52]. Asthma may also be a risk factor for miscarriage [23,25]. Biologically explained, hypoxia is induced during asthma exacerbations causing abnormal smooth muscle activity in the uterus, similar to airway smooth muscle contractions in the lungs [53,54]. An increased risk of miscarriage of 1.57 (95% CI 1.02–2.41) among 1,044 pregnant women with asthma compared with 860 pregnant women without asthma is reported [23]. Also a higher risk of miscarriage (OR, 1.28; 95% CI, 1.15–1.43) among women with asthma who experienced one or more exacerbations in the year before pregnancy compared with women with asthma has been reported [25]. Lack of an apparent association with miscarriage for oral corticosteroids could also be a reflection of their protective effect. Miscarriage may occur as a result of an abnormal immune response [54], which anti-inflammatory properties of corticosteroids might inhibit in high doses. In fact, high doses of corticosteroids are used to prevent recurrent miscarriages [53], although the effectiveness of this treatment is still controversial [53,55,56]. Only one study included information about gestational age at miscarriage [26]. Data on gestational age allow differentiation between early and late miscarriage, which may have different aetiologies. Bjørn et al. found that current use of inhaled corticosteroids within 60 days before miscarriage was associated with a slightly increased risk of early miscarriage but not with late miscarriage [26]. This could reflect that exposure in early pregnancy influences the foetus’ environment and therefore increases the risk of early pregnancy loss. Conclusion Around 2% of all pregnant women use corticosteroids in early pregnancy, and the prevalence of corticosteroid use has increased in recent years. The use of corticosteroids did not seem to increase the risk of congenital malformations, but the use of inhaled corticosteroids was associated with a slightly increased risk of miscarriage. However, confounding by indication cannot be ruled out.
313 References
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