Blackwell Science, LtdOxford, UKAJDAustralasian Journal of Dermatology0004-83802005 Blackwell Publishing Asia Pty Ltd20064713436Personal ReviewSystemic corticosteroid use in pregnancyGJ

Rennick

Australasian Journal of Dermatology (2006) 47, 3436

doi: 10.1111/j.1440-0960.2006.00219.x

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

SUMMARY
Concerns have been raised regarding the use of
repeated courses of systemic glucocorticosteroids
given to pregnant women with threatened premature
labour to improve fetal lung maturity. Most worrying
are animal studies showing detrimental effects on the
developing brain, though human data to date are conflicting. Additional concerns relate to the fetal origins
of adult diseases, particularly vascular diseases such
as hypertension and atherosclerosis. It is currently
recommended that obstetricians give only a single
course of antenatal corticosteroids to pregnant
women to enhance lung maturity instead of giving
repeated doses, which was previously a common
practice. Other clinicians including dermatologists,
gastroenterologists and rheumatologists may have
reason to provide systemic glucocorticosteroids to
pregnant women. Although systemic glucocorticosteroids all cross the placenta to some degree, the
extent to which they do so depends on the drug
involved. The choice of systemic glucocorticosteroid
for the pregnant women in light of this evolving
literature is discussed.
Key words: brain, central nervous system, foetus,
newborn, prenatal exposure delayed effect.

INTRODUCTION
Systemic glucocorticosteroids have been used for many
years in pregnant women and are generally believed to be
safe for the unborn child. They are considered Category A
medications in pregnancy by the Australian Drug Evaluation Committee.1 Despite this, emerging evidence drawn
predominantly from the paediatric and obstetric literature

Correspondence: Dr Gordon Rennick, Skin and Cancer Foundation, 95 Rathdowne St, Carlton, Vic. 3053, Australia. Email:
gordon.rennick@bigpond.com
Gordon J Rennick, FRACP.
Submitted 2 March 2005; accepted 18 August 2005.
2006 The Australasian College of Dermatologists

does raise some concerns regarding the use of SGCS in

pregnancy. The author aims to summarize this literature to
assist dermatologists to understand the issues.

HISTORICAL OVERVIEW
In 1972, a RCT was published showing that antenatal SGCS
given to pregnant women early in premature labour markedly reduced the risk of respiratory distress syndrome
in their newborns.2 Respiratory distress syndrome (also
known as hyaline membrane disease) is the major cause
directly or indirectly of neonatal morbidity and mortality in
premature infants.
During the very same year, Archie Cochrane, a UK physician and the name behind the Cochrane collaboration,
published his influential work.3 In 1979, he wrote It is
surely a great criticism of our profession that we have not
organised a critical summary, by specialty or subspecialty,
adapted periodically, of all relevant randomized controlled
trials.4
Despite repeated randomized trials throughout the 1970s
and 1980s and a systematic review of randomized trials in
1990 providing incontrovertible evidence in favour of antenatal SGCS therapy,5 obstetricians all over the world were
slow to adopt this treatment. The causes of this tardiness
are unclear although a possible explanation mooted in a
recent Cochrane review was that the use of antenatal SGCS
was not promoted by any pharmaceutical company.6
The consequence of the failure of obstetricians to adopt
antenatal SGCS was that tens of thousands of premature
babies probably suffered and possibly died, and needed
more expensive treatment than was necessary along the
way. The Cochrane collaboration has long utilized the diagrammatic representation of the RCT of antenatal SGCS as
their logo.7 The diagram summarizes the evidence that
would have been revealed had the available RCT of antenatal SGCS been reviewed systematically in 1982.
By the mid-1990s, the message had got through regarding
the use of antenatal SGCS, and this was in widespread use

Abbreviations:
SGCS
RCT

systemic glucocorticosteroids
randomized controlled trial

Systemic corticosteroid use in pregnancy

for women in premature labour. Despite a paucity of RCT
of multiple courses of antenatal SGCS, it became commonplace for obstetricians to give multiple courses of SGCS to
women who remained at risk for preterm birth. A survey of
SGCS prescribing practices by Australian obstetricians 8
showed 85% prescribed repeat courses of SGCS for women
in which the risk of preterm birth persists or recurs, and
similarly high rates were found in the USA 9 and UK.10

EVOLVING CONCERNS
At the turn of the new millennium, concerns were raised
regarding the repeated use of SGCS and fetal brain growth
and development.11 There is considerable evidence from
experimental animals that corticosteroids can have an
adverse effect on the growth and development of the immature brain.12 Animal models tell us what can happen, not
necessarily what does happen, and while a lot of the literature pertains to small mammals (rodents, rabbits), sheep 13
and monkeys14 have also been studied. A recent review 12
concluded that the effects of repeated maternal glucocorticoids on fetal development are a concern. For example, in
pregnant sheep single and repeated doses of betamethasone resulted in retarded brain growth in the foetuses, with
repeated doses having more profound effects, particularly
at term.13 In pregnant sheep, repeated (but not single) doses
of betamethasone resulted in reduced myelination in both
premature and term foetuses as measured by thickness of
the retinae.15 Some human data support a transiently
smaller head circumference,16 although other studies have
not shown this.17,18 Postnatal SGCS given to expremature
infants with chronic lung disease have also been associated
with an increased risk of neurological impairment. 19
Another difficult to resolve concern with use of repeated
courses of SGCS relates to their longer-term potential to
predispose to adult disease. It is hypothesized that by influencing fetal programming, antenatal SGCS may predispose
to adult hypertension, type 2 maturity onset diabetes, coronary artery disease and cerebrovascular accidents. 2022
An Australian study showed that teenage children who
received any antenatal SGCS in utero have higher blood
pressure (both systolic and diastolic) in comparison with
those children who did not.23
The current consensus is to give a single course of antenatal SGCS only (as per the published evidence from RCT),
and to await further trials of benefits and risks as there is
insufficient evidence to support the previously widespread
practice of repeated doses of antenatal SGCS. 24 The standard single course for women in threatened premature
labour consists of a total of 24 mg of either betamethasone
or dexamethasone in divided dosage over 48 hours. This is
approximately equivalent to 125 mg of prednisolone.

THE ROLE OF THE PLACENTA IN HANDLING

ANTENATAL SYSTEMIC
GLUCOCORTICOSTEROIDS
All exogenously administered SGCS given to pregnant
women to some extent cross the placenta. The amount of

35

a given SGCS administered to the mother that ends up in

the fetal circulation depends upon a number of variables,
including the type of SGCS given, the dose, the route of
administration, the binding affinity of carrier proteins and
the extent of placental metabolism. These processes are
complex.25 Essentially, the placenta functions to limit
maternally derived exogenous or endogenous glucocorticosteroid access to the foetus. Specifically, the placental
enzyme 11 hydroxysteroid hydroxylase converts active
hydroxylated corticosteroids to inactive 11 ketone compounds. The degree of conversion depends on the structure
of the particular substrate. Designed to deal with endogenous maternal corticosteroids, this enzyme does less well
in performing its function as a physiological barrier to some
exogenous maternal corticosteroids, particularly dexamethasone and betamethasone. In a study unlikely to be
repeated today,26 10 pregnant women were given a radiolabelled infusion of prednisolone or prednisone close to the
time of elective Caesarean section. Fetal plasma levels of
exogenous prednisolone were 810-fold less than simultaneous maternal plasma levels, whereas maternal and fetal
plasma levels of exogenous prednisone were similar. This
suggests that for prednisolone the placenta does function
as a relatively effective though incomplete barrier. Methylprednisolone crosses the placenta poorly, while hydrocortisone crosses well.27
Little information could be found on the transfer of
intralesional or topical glucocorticosteroids across the placenta. Although it is known that topical glucocorticosteroids
can be absorbed in amounts large enough to cause systemic
adverse effects identical in type to systemically administered glucocorticosteroids, the number of reports of such
adverse effects is small and seems to involve gross misuse
of a topical glucocorticosteroid preparation. 28

CONCLUSION
Dermatologists may have occasion to use SGCS in several
instances in pregnant women, including specific pregnancy
dermatoses and other conditions coincident with pregnancy.
Dermatologists are unlikely to use multiple courses of SGCS
in pregnancy as has been used previously by many obstetricians, but are more likely to use a single long course (e.g.
pemphigoid gestationis), or a single short course (e.g. flare
of atopic dermatitis). Dermatologists should be aware that:
1. There have been recent changes in the prescribing patterns of SGCS to pregnant women with threatened premature labour by obstetricians as detailed above. The
reasons for these recent changes predominantly relate
to the absence of RCT showing benefit for multiple
courses and the concerns of potential neurological
effects on the developing brain (smaller head size, less
myelinization). Although there is strong evidence for
effects 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 foetus
from maternal corticosteroids, both endogenous and
exogenous.
2006 The Australasian College of Dermatologists

36

GJ Rennick

3. Some glucocorticosteroids are better than others at

overcoming the placental barrier, but to some extent all
exogenous glucocorticosteroids do cross this barrier.
Prednisolone appears to cross the placenta only to a
small extent in comparison with prednisone, and may
for this reason be preferred. In the pregnant woman who
cannot tolerate oral glucocorticosteroids (e.g. hyperemesis gravidarum), a parenteral glucocorticosteroid
that crosses the placenta poorly may be preferred.
Betamethasone and dexamethasone have been traditionally used by obstetricians because they cross the
placenta well, as does hydrocortisone; whereas methylprednisolone crosses the placenta poorly.
4. Any decision by dermatologists regarding SGCS use in
pregnancy also needs to consider the possible adverse
effects on both mother and foetus of not treating the skin
condition.
5. There is little information regarding the transfer of
intralesional glucocorticosteroids or topical glucocorticosteroids across the placenta, though it is assumed any
amounts transferred would likely be small and not clinically significant in the vast majority of cases of reasonable usage.

10.

11.
12.
13.

14.

15.

16.

17.

18.

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