Australasian Journal of Dermatology

(2006)

47

, 3436 doi: 10.1111/j.1440-0960.2006.00219.x

2006 The Australasian College of Dermatologists

Blackwell Science, LtdOxford, UKAJDAustralasian Journal of Dermatology0004-83802005 Blackwell Publishing Asia Pty Ltd20064713436Personal Review

Systemic corticosteroid use in pregnancyGJ Rennick

Correspondence: Dr Gordon Rennick, Skin and Cancer Founda-tion, 95 Rathdowne St, Carlton, Vic. 3053, Australia. Email:gordon.rennick@bigpond.com

Gordon J Rennick, FRACP.

Abbreviations:

SGCS systemic glucocorticosteroids

RCT randomized controlled trialSubmitted 2 March 2005; accepted 18 August 2005.

PERSONAL REVIEW

Use of systemic glucocorticosteroids in pregnancy: Be alert but not alarmed

Gordon J Rennick

Department of Dermatology, Royal Childrens Hospital, Parkville, Victoria, Australia

does raise some concerns regarding the use of SGCS inpregnancy. The author aims to summarize this literature toassist dermatologists to understand the issues.

HISTORICAL OVERVIEW

In 1972, a RCT was published showing that antenatal SGCSgiven to pregnant women early in premature labour mark-edly reduced the risk of respiratory distress syndromein their newborns.

2

Respiratory distress syndrome (alsoknown as hyaline membrane disease) is the major causedirectly or indirectly of neonatal morbidity and mortality inpremature infants.

During the very same year, Archie Cochrane, a UK phy-sician and the name behind the Cochrane collaboration,published his influential work.

3

In 1979, he wrote It issurely a great criticism of our profession that we have notorganised a critical summary, by specialty or subspecialty,adapted periodically, of all relevant randomized controlledtrials.

4

Despite repeated randomized trials throughout the 1970sand 1980s and a systematic review of randomized trials in1990 providing incontrovertible evidence in favour of ante-natal SGCS therapy,

5

obstetricians all over the world wereslow to adopt this treatment. The causes of this tardinessare unclear although a possible explanation mooted in arecent Cochrane review was that the use of antenatal SGCSwas not promoted by any pharmaceutical company.

6

The consequence of the failure of obstetricians to adoptantenatal SGCS was that tens of thousands of prematurebabies probably suffered and possibly died, and neededmore expensive treatment than was necessary along theway. The Cochrane collaboration has long utilized the dia-grammatic representation of the RCT of antenatal SGCS astheir logo.

7

The diagram summarizes the evidence thatwould have been revealed had the available RCT of ante-natal SGCS been reviewed systematically in 1982.

By the mid-1990s, the message had got through regardingthe use of antenatal SGCS, and this was in widespread use

SUMMARY

Concerns have been raised regarding the use ofrepeated courses of systemic glucocorticosteroidsgiven to pregnant women with threatened prematurelabour to improve fetal lung maturity. Most worryingare animal studies showing detrimental effects on thedeveloping brain, though human data to date are con-flicting. Additional concerns relate to the fetal originsof adult diseases, particularly vascular diseases suchas hypertension and atherosclerosis. It is currentlyrecommended that obstetricians give only a singlecourse of antenatal corticosteroids to pregnantwomen to enhance lung maturity instead of givingrepeated doses, which was previously a commonpractice. Other clinicians including dermatologists,gastroenterologists and rheumatologists may havereason to provide systemic glucocorticosteroids topregnant women. Although systemic glucocorticos-teroids all cross the placenta to some degree, theextent to which they do so depends on the druginvolved. The choice of systemic glucocorticosteroidfor the pregnant women in light of this evolvingliterature is discussed.

Key words: brain, central nervous system, foetus,newborn, prenatal exposure delayed effect.

INTRODUCTION

Systemic glucocorticosteroids have been used for manyyears in pregnant women and are generally believed to besafe for the unborn child. They are considered Category Amedications in pregnancy by the Australian Drug Evalua-tion Committee.

1

Despite this, emerging evidence drawnpredominantly from the paediatric and obstetric literature

Systemic corticosteroid use in pregnancy 35

2006 The Australasian College of Dermatologists

for women in premature labour. Despite a paucity of RCTof multiple courses of antenatal SGCS, it became common-place for obstetricians to give multiple courses of SGCS towomen who remained at risk for preterm birth. A survey ofSGCS prescribing practices by Australian obstetricians

8

showed 85% prescribed repeat courses of SGCS for womenin which the risk of preterm birth persists or recurs, andsimilarly high rates were found in the USA

9

and UK.

10

EVOLVING CONCERNS

At the turn of the new millennium, concerns were raisedregarding the repeated use of SGCS and fetal brain growthand development.

11

There is considerable evidence fromexperimental animals that corticosteroids can have anadverse effect on the growth and development of the imma-ture brain.

12

Animal models tell us what can happen, notnecessarily what does happen, and while a lot of the liter-ature pertains to small mammals (rodents, rabbits), sheep

13

and monkeys

14

have also been studied. A recent review

12

concluded that the effects of repeated maternal glucocorti-coids on fetal development are a concern. For example, inpregnant sheep single and repeated doses of betametha-sone resulted in retarded brain growth in the foetuses, withrepeated doses having more profound effects, particularlyat term.

13

In pregnant sheep, repeated (but not single) dosesof betamethasone resulted in reduced myelination in bothpremature and term foetuses as measured by thickness ofthe retinae.

15

Some human data support a transientlysmaller head circumference,

16

although other studies havenot shown this.

17,18

Postnatal SGCS given to exprematureinfants with chronic lung disease have also been associatedwith an increased risk of neurological impairment.

19

Another difficult to resolve concern with use of repeatedcourses of SGCS relates to their longer-term potential topredispose to adult disease. It is hypothesized that by influ-encing fetal programming, antenatal SGCS may predisposeto adult hypertension, type 2 maturity onset diabetes, coro-nary artery disease and cerebrovascular accidents.

2022

An Australian study showed that teenage children whoreceived any antenatal SGCS

in utero

have higher bloodpressure (both systolic and diastolic) in comparison withthose children who did not.

23

The current consensus is to give a single course of ante-natal SGCS only (as per the published evidence from RCT),and to await further trials of benefits and risks as there isinsufficient evidence to support the previously widespreadpractice of repeated doses of antenatal SGCS.

24

The stan-dard single course for women in threatened prematurelabour consists of a total of 24 mg of either betamethasoneor dexamethasone in divided dosage over 48 hours. This isapproximately equivalent to 125 mg of prednisolone.

THE ROLE OF THE PLACENTA IN HANDLING ANTENATAL SYSTEMIC

GLUCOCORTICOSTEROIDS

All exogenously administered SGCS given to pregnantwomen to some extent cross the placenta. The amount of

a given SGCS administered to the mother that ends up inthe fetal circulation depends upon a number of variables,including the type of SGCS given, the dose, the route ofadministration, the binding affinity of carrier proteins andthe extent of placental metabolism. These processes arecomplex.

25

Essentially, the placenta functions to limitmaternally derived exogenous or endogenous glucocorti-costeroid access to the foetus. Specifically, the placentalenzyme 11

hydroxysteroid hydroxylase converts activehydroxylated corticosteroids to inactive 11 ketone com-pounds. The degree of conversion depends on the structureof the particular substrate. Designed to deal with endoge-nous maternal corticosteroids, this enzyme does less wellin performing its function as a physiological barrier to someexogenous maternal corticosteroids, particularly dexam-ethasone and betamethasone. In a study unlikely to berepeated today,

26

10 pregnant women were given a radiola-belled infusion of prednisolone or prednisone close to thetime of elective Caesarean section. Fetal plasma levels ofexogenous prednisolone were 810-fold less than simulta-neous maternal plasma levels, whereas maternal and fetalplasma levels of exogenous prednisone were similar. Thissuggests that for prednisolone the placenta does functionas a relatively effective though incomplete barrier. Methyl-prednisolone crosses the placenta poorly, while hydrocorti-sone crosses well.

27

Little information could be found on the transfer ofintralesional or topical glucocorticosteroids across the pla-centa. Although it is known that topical glucocorticosteroidscan be absorbed in amounts large enough to cause systemicadverse effects identical in type to systemically adminis-tered glucocorticosteroids, the number of reports of suchadverse effects is small and seems to involve gross misuseof a topical glucocorticosteroid preparation.

28

CONCLUSION

Dermatologists may have occasion to use SGCS in severalinstances in pregnant women, including specific pregnancydermatoses and other conditions coincident with pregnancy.Dermatologists are unlikely to use multiple courses of SGCSin pregnancy as has been used previously by many obstetri-cians, but are more likely to use a single long course (e.g.pemphigoid gestationis), or a single short course (e.g. flareof atopic dermatitis). Dermatologists should be aware that:

1. There have been recent changes in the prescribing pat-terns of SGCS to pregnant women with threatened pre-mature labour by obstetricians as detailed above. Thereasons for these recent changes predominantly relateto the absence of RCT showing benefit for multiplecourses and the concerns of potential neurologicaleffects on the developing brain (smaller head size, lessmyelinization). Although there is strong evidence foreffects on the developing brain from animal studies,human studies to date have shown conflicting results.

2. The placenta functions as a barrier to protect the foetusfrom maternal corticosteroids, both endogenous andexogenous.

36 GJ Rennick

2006 The Australasian College of Dermatologists

3. Some glucocorticosteroids are better than others atovercoming the placental barrier, but to some extent allexogenous glucocorticosteroids do cross this barrier.Prednisolone appears to cross the placenta only to asmall extent in comparison with prednisone, and mayfor this reason be preferred. In the pregnant woman whocannot tolerate oral glucocorticosteroids (e.g. hyper-emesis gravidarum), a parenteral glucocorticosteroidthat crosses the placenta poorly may be preferred.Betamethasone and dexamethasone have been tradi-tionally used by obstetricians because they cross theplacenta well, as does hydrocortisone; whereas methyl-prednisolone crosses the placenta poorly.

4. Any decision by dermatologists regarding SGCS use inpregnancy also needs to consider the possible adverseeffects on both mother and foetus of not treating the skincondition.

5. There is little information regarding the transfer ofintralesional glucocorticosteroids or topical glucocorti-costeroids across the placenta, though it is assumed anyamounts transferred would likely be small and not clin-ically significant in the vast majority of cases of reason-able usage.

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