inhalan kortikosteroid

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MiniReview

Use of Inhaled and Oral Corticosteroids in Pregnancy andthe Risk of Malformations or Miscarriage

Anne-Mette Bay Bjørn1, Vera Ehrenstein2, Ellen Aagaard Nohr3 and Mette Nørgaard2

1Department 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

(Received 23 January 2014; Accepted 8 December 2014)

Abstract: Corticosteroids are potent anti-inflammatory and immunosuppressive drugs, which sometimes must be given to preg-nant women. Corticosteroids have been suspected to be teratogenic for many years; however, there is conflicting evidenceregarding the association. Based on a literature review of three databases, this MiniReview provides an overview of inhaled andoral 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 rangedfrom 0.2% to 10% and increased nearly two times in recent years. Taken together, the evidence suggests that the use of corticos-teroids 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 increasedrisk 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 medi-

cal conditions, including asthma, rheumatoid arthritis, eczema

and inflammatory bowel disease [1]. Cortisol, the naturally

occurring corticosteroid, exerts a range of physiologicaleffects, including regulation of pathways in fat, protein and

carbohydrate metabolism, cardiovascular function, growth and

immunity [2]. Synthetic corticosteroids act similarly to corti-

sol: 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 cor-

tisol; 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, affect-

ing approximately 20% of pregnancies [6,7]. Studies of con-

genital malformations often focus on the prevalence of

malformations at birth, whereby pregnancies ending in a mis-

carriage are excluded [8,9].

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 mal-

formations 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 ‘sponta-

neous 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 malforma-

tions 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

Author for correspondence: Anne-Mette Bay Bjørn, Department of Gynecology and Obstetrics, Aarhus University Hospital, Skejby, Breds-trupgaardsvej, 8200 Aarhus N, Denmark (e-mail [email protected]).

© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)

Basic & Clinical Pharmacology & Toxicology, 2015, 116, 308–314 Doi: 10.1111/bcpt.12367


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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 corticoste-

roid 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 preg-

nancy 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 corticoster-

oids during pregnancy, reported a POR for congenital malfor-

mations 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 stud-

ies [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 preg-

nancies 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 associ-

ated 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 associ-

ated 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-preg-

nant 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 self-

reported drug use of 86.2% (95% CI 74.6 – 93.9) [35], suggest-

ing high compliance with therapy among pregnant women

0

5

10

15

20

25

C S

t o t a l

C S

i n h a l e d

C S

o r a l

C S

t o t a l

C S

i n h a l e d

C S

o r a l

C S

t o t a l

C S

i n h a l e d

C S

o r a l

C S

t o t a l

C S

i n h a l e d

C S

o r a l

≤30 days before

pregnancy

first trimester second trimester third trimester P r e v a l e n c e o f p r e s c r i

b e d d r u g u s e / 1 , 0

0 0

w o m e

n

1999+2000

2008+2009

Fig. 1. Prevalence (per 1000 women) of corticosteroid (CS) drug use across pregnancy among primiparous women in 1999 – 2000 and 2008 – 2009

[12].


MiniReview USE OF CORTICOSTEROIDS IN PREGNANCY 309


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T a b l e 1 .

( c o n t i n u e d )

A u t h o r , c o u n t r y ,

s t u d y p e r i o d

D a t a s o u r c e s , s t u d y p o p u l a t i o n

S t u d y d e s i g n

T y p e o f

c o r t i c o s t e r o i d

e x p o s u r e

O u t c o m e o f i n t e r e s t

C o n g e n i t a l m a l f o r m a t i o n s o v e r a l l

O

r a l c l e f t s

N o f

e x p o s e d

i n f a n t s w

i t h

a m a l f o r m a t i o n

R e l a t i v e r i s k

e s t i m a t e s * ( 9 5 %

c o n f i d e n c e

i n t e r v a l )

N o f

e x p o s e d

i n f a n t s w i t h

o r a l c l e f t s

R e l a t i v e r i s k e s t i m a t e s *

( 9 5 % c o n f i d e n c e i n t e r v a l )

P r a d a t [ 3 0 ]

A u s t r a l i a

, F r a n c e ,

I t a l y , I s r a e l ,

J a p a n , t h e N e t h e r l a n d s

,

S o u t h A m e r i c a

1 9 9 0 –

2 0 0 2

M a l f o r m a t i o n D r u g E x p o s u r e

S u r v e i l l a n c e P r o j e c t –

M A D R E

1 1 , 1

5 0

m a l f o r m e d i n f a n t s . 2 3

, 5 1 7 c o n t r o l i n f a n t s

C a s e – c o n t r o l

I n h a l e d

S y s t e m i c d

4 3 1 1 5 1 3 1

A l l : 0 . 6 ( 0

. 2 –

1 . 7 )

C L P : 0 . 7 ( 0

. 2 –

2 . 2 )

C P : 0

. 6 ( 0

. 1 –

5 . 1 )

A l l : 1 . 3 ( 0

. 7 –

2 . 2 )

C L P : 1 . 8 ( 1

. 0 –

3 . 1 )

C P : 0 . 3 ( 0

. 0 4 – 1 . 5 )

C a r m i c h a e l [ 2 7 ]

U S A

1 9 8 7 –

1 9 8 8

T h e C a l i f o r n i a B i r t h D e f e c t s M o n i t o r i n g P r o g r a m

1 2 9 9 m

a l f o r m e d i n f a n t s . 7 3 4 c o n t r o l i n f a n t s


O r a l

6 3

C L P : 4 . 3 ( 1

. 1 –

1 7 . 2

)

C P : 5 . 3 ( 1

. 1 ; 2 6

. 5 )

R o d r i g u e z –

P i n i l l a [ 3 1 ]

S p a i n

A p r .

1 9 7 6 –

D e c .

1 9 9 5

S p a n i s h C o l l a b o r a t i v e S t u d y o f C o n g e n i t a l

M a l f o r m a t i o n s –

E C E M C

2 4 , 0

3 8




O r a l

5

A l l : 5 . 2 ( 1

. 5 –

1 7 . 1

)

C z e i z e l [ 2 8 ]

H u n g a r y

1 9 8 0 –

1 9 9 4

T h e H u n

g a r i a n C o n g e n i t a l A b n o r m a l i t y

R e g i s t r y –

H C C S C A

2 0 , 8

3 0




O r a l

1

A l l : 1 . 3 ( 0

. 8 –

2 . 0 )

A b b r e v i a t i o n s : A l l

, a l l c l e f t s ; C L P

, c l e f t l i p w i t h o r w i t h o u t c l e f t p a l a t e ; C P

, c l e f t p a l a t e

.

S t u d y p o p u l a t i o n d e f i n i t i o n : a t h e s t u d y p o

p u l a t i o n d e f i n e d i n K € a l l e n e t a l . [ 5 7 ]

.

E x p o s u r e d e f i n i t i o n s r e g a r d i n g s y s t e m i c u

s e :

b o r a l , i n t r a m u s c u l a r a n d i n t r a v e n o u s p r e p a r a t i o n s ; c o r a l a n d i n t r a v e n o u s p r e p a r a t i o n s ;

d o r a l a n d i n j e c t i o n a c c o r d i n g t o t h e A T C - c

l a s s i f i c a t i o n H 0 2 A

.

O u t c o m e d e f i n i t i o n r e g a r d i n g c o n g e n i t a l m

a l f o r m a t i o n s o v e r a l l : e n o t c a t e g o r i z e d ;

f d i

a g n

o s e s o f d i s l o c a t i o n o f t h e h i p ,

u n d e s c e n d e d t e s t e s a n d c h r o m o s o m a l d i s o r d e r s e x c l u d e d ; g s o n - g e n e t i c m a j o r c o n g e n i -

t a l m a l f o r m a t i o n s ;

h m a j o r a n d m i n o r m a l f o r m a t i o n s a c c o r d i n g t o H e i n o n e n e t a l . [ 5 8 ] ; i

m a j o r m a l f o r m a t i o n s .

* t h e r i s k e s t i m a t e s a r e g i v e n a s p r e v a l e n c e o d d s r a t i o s f o r t h e p r e v a l e n c e s t u d i e s a n d o d

d s r a t i o f o r t h e c a s e –

c o n t r o l s t u d i e s .

F o r r e f e r e n c e s 1 8 a n d 2 2

, t h e r i s k e s t i m a t e s a r e c a l c u l a t e d u s i n g t h e E p i s h e e t s o f t w a r e ( v e r s i o n 2 0 1 1 , b y K e n n e t h J . R o t h m a n ) .




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with chronic diseases. Geographical differences in drug utili-

zation patterns may stem from differences in reporting poli-

cies 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 admin-

istration of corticosteroids and the classification of malforma-

tions differed among the existing studies, which complicatedcomparisons. Furthermore, to detect even a common congeni-

tal malformation, a population of at least half a million preg-

nant women is needed and as many as 5 million are required

to detect rare events [37]. Even with large databases avail-

able, 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 da-

tabases from Sweden and Denmark found no association

between the use of corticosteroids in early pregnancy and mal-

formations in offspring [18,20,21]. The Nordic medical data-bases 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 col-

lected 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 malforma-

tions 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 ruledout. Self-referral bias could create an apparent association

where none exists [40], because reasons for contacting a tera-

togenic 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 con-

genital 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 meta-

analysis indicated that infants of pregnant women with asthma

were 11% more likely to have congenital malformations diag-

nosed 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],

Table 2.

Studies of corticosteroid use and risk of miscarriage.

Author, country, study period Data sources, s tudy population Study design Exposure

Relative risk estimates*

(95% confidence interval);

N of exposed cases

Tata [25]

England and Wales

Jan. 1988 –

Nov. 2004

The Health Improvement Network

281,019 pregnancies

Prevalence studyc Inhaled 1.2 (1.2 – 1.3)

Gur [19]

Israel

1988 – 2001

The Israeli Teratogen Information Service

1101 pregnancies

Prevalence studyc Systemica 1.7 (1.1 – 2.5); 36

Silverman [24]

Trial including 32 countries

Oct. 1996 – Jan. 1998

START (inhaled Steroid Treatment

As Regular Therapy) trial

313 pregnancies

Prevalence studyc Inhaled 1.3 (0.6 – 2.5); 23

Park – Wyllie [22]

Canada

1985 – 1995

Canadian Motherisk cohort

372 pregnancies

Prevalence studyd Systemicb 1.0 (0.5 – 2.1); 13

Bjørn [26]

Denmark

1997 – 2009

The Danish National Registry of Patients

10,974 cases of miscarriage, 109,740 controls

Case – control studye Inhaled

Oral

1.2 (1.0 – 1.4); 140

0.8 (0.5 – 1.2); 28

Exposure definitions regarding systemic use: a

oral, intramuscular and intravenous preparations; b

oral 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).


312 ANNE-METTE BAY BJØRN ET AL. MiniReview


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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 preg-

nant users of corticosteroids [51] which also was the associa-

tion 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 recallbias [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 associa-

tion with miscarriage for inhaled but not oral corticosteroids is

counter-intuitive. Oral corticosteroids reach higher concentra-

tions 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 corticos-

teroids 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 abnormalimmune 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 contro-

versial [53,55,56].

Only one study included information about gestational age

at miscarriage [26]. Data on gestational age allow differentia-

tion between early and late miscarriage, which may have dif-

ferent 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’ environ-ment 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 indi-

cation cannot be ruled out.

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