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J. Perinat. Med. 36 (2008) 191–196 • Copyright  by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2008.032

Recommendations and guidelines for perinatal practice

Guideline for the use of antenatal corticosteroids for fetal


maturation*

Xavier Miracle1,**, Gian Carlo Di Renzo2, Ann Introduction


Stark3, Avroy Fanaroff4, Xavier Carbonell-
Estrany1 and Erich Saling5 (Coordinators of
• Women at risk of preterm birth before 34 weeks’ ges-
WAPM Prematurity working group)
tation are routinely given a course of antenatal corti-
1
Neonatology Service, Hospital Clinic, Institut Clinic de costeroids (ACS) because there is good evidence that
Ginecologia, Obstetricia I Neonatologia, Universitat de treatment reduces neonatal death, respiratory distress
Barcelona, Barcelona, Spain syndrome (RDS) and intraventricular hemorrhage
2
Department of Obstetrics and Gynecology and Center (IVH).
for Perinatal and Reproductive Medicine, University of • The origin of this practice comes from Liggins and
Perurgia, Italy Howie’s first randomized trial in 1972 w26x which dem-
3
Baylor College of Medicine, Texas Children’s Hospital, onstrated a reduction in the incidence of RDS and
Houston, Texas, USA mortality.
4
Rainbow Babies and Children’s Hospital, Cleveland, • Subsequent randomized controlled trials have com-
Ohio and Case Western Reserve University School of pared single courses of corticosteroids with either pla-
Medicine, USA cebo or no intervention, confirming the efficacy of this
treatment w37x.
5
Institute of Perinatal Medicine, Berlin, Neukoelln
• Three major institutions have been elaborating and
updating recommendations and guidelines on the use
Abstract of antenatal corticosteroids:
The aim is to present a document, which is based on
1. The National Institutes of Health (NIH) published
current evidence and serves as a guideline for use in clin-
a Consensus Development Conference State-
ical practice. The following questions are addressed:
ment in 1994 on the use of ACS w36x and in 2000
• Is the use of antenatal corticosteroids (ACS) an effec- on the use of repeated courses of ACS w34x.
tive therapy? 2. In May 2002, The American College of Obstetri-
• Who are the candidates for antenatal corticosteroid cians and Gynecologists’ Committee on Obstetric
therapy? Practice (ACOG) w5x supported the conclusions of
• Is there benefit after 34 weeks’ gestation? the NIH consensus conference.
• When is the optimal time to treat? 3. The Royal College of Obstetricians and Gynecol-
• Which are the optimal steroids; what is the ideal dose ogists (RCOG) w35x published the third edition of
and route of administration? their guideline in February 2004 (previously pub-
• Are there any contraindications to the administration of lished in April 1996 and December 1999).
ACS?
• Are antenatal corticosteroids indicated in women with • In the last few years new relevant information has
premature rupture of membranes (PROM)? been published: The Cochrane Review on ACS (2006)
• Is the use of ACS recommended in pregnancies com- w37x has been updated, aiming to assess the effects
plicated by maternal diabetes mellitus? of ACS on fetal, neonatal and maternal morbidity and
• Should the treatment with corticosteroids be repeated? mortality and on child development.
Regarding the controversial issue of single versus
*This paper was worked out under the auspices of the WAPM to
achieve consensus on issues in perinatal practice. Coordinator multiple courses of ACS therapy, two large random-
of the working group: Xavier Miracle. ized clinical trials have been recently published (Wap-
**Corresponding author: ner et al. w43x, and Crowther et al. w7x) and included in
Dr. Xavier Miracle
Neonatal Department an updated Cochrane review on repeat doses of pre-
Hospital Clı́nic de Barcelona (Seu Maternitat) natal corticosteroids (2007) w9x. The larger study on
Carrer Sabino Arana 1 multiple doses, the Canadian MACS trial w27x (Multiple
08028 Barcelona Courses of Antenatal Corticosteroids for preterm birth
Tel: q3493 2275600 Ext: 7443-7503
Fax: q3493 2275605 Study) has finished recruitment and should probably
E-mail: xmiracle@ya.com be ready this year.
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192 Miracle et al., Guideline for the use of antenatal corticosteroids for fetal maturation

For the first time, data regarding long-term effects Other studies show a decrease in the incidence of IVH
on the use of multiple steroid treatments have been and mortality between 24 and 28 weeks’ gestation with
released. Outcomes at 2–3 years from the studies of a reduction in the severity of RDS but not the incidence
Wapner et al. and Crowther et al. have been published at this interval w2x.
in The New England Journal of Medicine (September, After 34 weeks’ gestation the use of ACS is still effec-
2007) w8, 44x. tive but the reduction in RDS, IVH and neonatal death is
We would like to incorporate this new information in not significant. The number of women who will need to
order to develop a practical clinical protocol for the be treated to prevent one case of RDS would be much
use of antenatal corticosteroids. higher. In 2005, Stutchfield et al. w41x showed that ACS
• In the last Cochrane Review (2006) Roberts & Dalziel are still effective after 37 weeks’ gestation in infants born
w37x included twenty-one randomized trials (3885 by elective cesarean section. There was a significant
women and 4269 infants). Six new studies have been reduction in RDS and transient tachypnea of the newborn
added since the previous review. Main results showed (TTN).
that ‘‘ACS does not increase risk to the mother of Previous guidelines recommended considering the use
death, chorioamnionitis or puerperal sepsis. Treatment of ACS after 34 weeks’ gestation if there was evidence
with ACS is associated with an overall reduction in of pulmonary immaturity w5, 23, 35, 36x. We would
neonatal death, RDS, IVH, necrotizing enterocolitis concur with that recommendation.
(NEC), respiratory support, intensive care admissions
and systemic infections in the first 48 h of life’’. They
also indicated that ACS is effective in women with pre- 2. When to treat?
mature rupture of membranes (PROM) and pregnancy
related hypertension syndromes. ‘‘There is evidence to
suggest benefit across a wide range of gestational • All women at high risk of preterm delivery should start
ages from 26 to 34q6 weeks and in the current era a course of ACS unless delivery is imminent (less than
of neonatal practice. ’’The authors concluded that the one hour) even if only one dose is anticipated.
‘‘evidence from this new review supports the contin- • Tocolytic drugs should be considered by the obstetri-
ued use of a single course of antenatal corticosteroids cians in order to gain time to administer the preferred
to accelerate fetal lung maturation in women at risk of complete course of ACS.
preterm birth. A single course of antenatal corticoste- • Accurate and standardized diagnosis of high-risk pre-
roids should be considered routine for preterm delivery term labor is essential to avoid over-diagnosing and
with few exceptions. Further information is required treating patients with unnecessary doses of
concerning optimal dose to delivery interval, optimal corticosteroids and tocolytics.
corticosteroid to use, effects in multiple pregnancies,
and to monitor the long-term effects into adulthood’’. The 2006 Cochrane Review w37x has shown that ‘‘ACS
use reduces neonatal death even when infants are born
-24 h after the first dose has been given’’. Another study
has confirmed that incomplete courses of ACS are
beneficial w13x.
1. Who are candidates for antenatal
The exact time interval for ACS to become beneficial
corticosteroid therapy?
is unknown. There is a potential benefit commencing
within hours of the first dose.
• Antenatal administration of corticosteroid therapy There is considerable variation in the way that spon-
would be indicated to all women at high risk of pre- taneous preterm labor is diagnosed, managed and treat-
term delivery between 24 and 34 weeks of gestation. ed internationally. Accurate and standardized diagnosis
• Antenatal steroids could also be indicated over of high-risk preterm labor is essential to avoid overdiag-
34 weeks of gestation when there is evidence of pul- nosing and overtreating patients with tocolytics and cor-
monary immaturity. ticosteroids and unnecessary hospitalizations.
The European Association of Perinatal Medicine has
The 2006 Cochrane Review w37x stated in their conclu- published an international clinical guideline for the man-
sions that there is evidence to suggest benefit of ACS agement of spontaneous preterm labor which states that
administration to a wide range of gestational ages from contractions and cervical changes are not enough to
26 to 34q6 weeks. Benefit under 28 weeks was the sub- define the risk of preterm labor. Oncofetal fibronectin
ject of debate in a previous analysis. This review shows (fFN) and ultrasonography to determine cervical length
that RDS is reduced in all age subgroups above may be considered to complement the clinical assess-
26 weeks, and there is also a significant reduction in IVH ment. With the use of biochemical markers and sonogra-
and neonatal death in the subgroup from 26 to 29q6 phic evaluation of the cervix, it is possible to identify the
weeks. majority of women who are not in preterm labor w10, 11x.
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Miracle et al., Guideline for the use of antenatal corticosteroids for fetal maturation 193

3. Which are the optimal steroids; what is the group of patients with premature rupture of membranes
ideal dose and route of administration? (PROM) w37x. However, delaying delivery with established
clinical chorioamnionitis could be detrimental for both
mother and fetus.
• We recommend betamethasone as the steroid of
choice, when available, to be given in a course of two
doses of 12 mg administered intramuscularly 24 h
5. Are antenatal corticosteroids indicated in
apart.
women with premature rupture of membranes
An alternative regimen would be four doses of 6 mg (PROM)?
dexamethasone intramuscularly every 12 h.
These are the two most extensively studied steroid
• ACS therapy is indicated in women with PROM from
regimens, although there are no randomized trials directly
24 to 32 weeks’ gestation not presenting clinical signs
comparing these two drugs. Both regimens were found
of chorioamnionitis.
to be equally effective for the prevention of RDS w6x.
There is no absolute evidence to recommend beta- This scenario includes considerable risk of infection for
methasone over dexamethasone and previous guidelines the mother and the fetus. The evidence justifying the use
did not find enough evidence to recommend one above of ACS in PROM is based on two major meta-analyses:
the other w5, 36x. However, in one recent study, Lee et al. In the 2006 Cochrane Review w37x ‘‘ACS are shown to
w23x found that betamethasone was associated with a be beneficial in the subgroup of infants whose mothers
greater reduction in risk of death than dexamethasone, have PROM. Neonatal death, RDS, IVH, NEC, and dura-
corroborating Jobe’s results in 2004 w22x. tion of respiratory support are all reduced, without an
Two other studies have indicated a decreased risk of increase in either maternal or neonatal infection’’. Similar
cystic periventricular leukomalacia (PVL) in premature results were obtained from Harding et al.’s meta-analysis
infants exposed to betamethasone, this association was in 2001 w17x. Beyond 32 weeks of gestation, the risk of
not found with dexamethasone, particularly when using chorioamnionitis is higher than the risks derived from
multiple doses w3, 40x. These results were not confirmed prematurity w15, 24x.
in Lee’s study w23x. Because of this new evidence we
recommend betamethasone as the steroid of choice. A
course of betamethasone is still indicated in patients 6. Is the use of ACS recommended in
receiving treatment with hydrocortisone for other causes, pregnancies complicated by maternal
because very little hydrocortisone crosses the placenta. diabetes mellitus?
There is little data available on other routes of admin-
istration or dosage in humans, although extensive animal
• A course of ACS is indicated in pregnant women with
studies have been done: fetal intravascular hydrocorti-
pregestational or gestational diabetes at risk of pre-
sone, given by cordocentesis, was shown to be ineffec-
term delivery.
tive in maturing the lungs w21x. Intra-amniotic beta-
• Close monitoring and treatment by an experienced
methasone matures the lungs but the persisting pres-
obstetrical team is essential to guarantee diabetic
ence of the drug is associated with increased fetal
control and avoid the possibility of severe transient
mortality and morbidity w32x. Some studies have been
hyperglycemia.
published on the possibility of giving steroids directly to
the fetus intramuscularly rather than to the mother, show- Infants of diabetic mothers delivered early might have
ing that the lung maturing effects are similar to maternal pulmonary immaturity at a more advanced gestation than
injection, the negative effect on fetal growth is not seen infants of nondiabetic mothers. Elective and spontane-
and the effects on the brain are less than with maternal ous preterm delivery is more likely to occur in women
dosing w20, 33x. This effect seems to result from different with pregestational diabetes than in healthy controls, with
pharmacokinetics of the drug w30x. preeclampsia, polyhydramnios and infections being com-
mon complications w38x.
Close maternal glycemic control before and during
4. Are there any contraindications to the pregnancy is essential, and has been demonstrated to
administration of ACS? reduce the incidence of hyaline membrane disease (RDS)
in this group of infants w45x.
Administration of a course of betamethasone at the
• ACS therapy would be contraindicated in maternal
usual dose and interval is recommended in diabetic preg-
systemic infections including tuberculosis. In women
nant women although there is little evidence of efficacy
with chorioamnionitis caution is advised.
and safety of this practice. Women with gestational or
Administration of ACS is not related to an increase in pregestational diabetes were excluded from the majority
either maternal or neonatal infection, even in the sub- of early randomized trials w37x.
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194 Miracle et al., Guideline for the use of antenatal corticosteroids for fetal maturation

Caution is advised during ACS administration with pleted and are included in a Cochrane review on repeat
close glycemic control during three days after the first doses of prenatal corticosteroids, recently published in
dose. The steroid effect begins approximately 12 h after 2007 w9x. In this review, five trials met the inclusion cri-
the first dose and lasts for five days w28x. teria recruiting a total of 2028 women.
Obstetricians should consider the use of ACS in dia- The first trial was published in 2001 by Guinn et al.
betic pregnant women above 34 weeks’ gestation if there w15x. No significant difference in composite neonatal
is evidence of pulmonary immaturity by amniotic fluid morbidity was found between the single and the weekly
analysis. The fluorescence polarization test is the most course of ACS. However, a subgroup analyses showed
common test used for assessing fetal lung maturation. a significant decrease in composite morbidity among
infants born at -28 weeks’ gestation, with a lower rate
of severe RDS. Differences in head circumference and
7. Should courses of corticoids be repeated? birth weight were not found in the multiple courses
group.
Wapner et al.’s trial w43x was published in 2006. Like
• Despite the new evidence from the recently completed the previous study, no significant difference in the pri-
randomized trials comparing single versus multiple mary outcome was found between the two groups, a
doses of steroids, we are not able at this time to mod- composite of severe RDS, CLD, grade III or IV IVH, or
ify the recommendations of The NIH Consensus PVL. However, in the subgroup of infants delivered before
Development Panel on the use of repeated courses of 32 weeks of gestation, better neonatal lung function
antenatal corticoids. On the basis of current evidence results were found in the repeat doses group. Some indi-
we are not able to provide a final answer on the num- vidual morbidities were significantly lower in the multiple
ber of doses or the interval between them that are safe course therapy group, including less need for mechanical
for the fetus. ventilation, continuous positive airway pressure, use of
surfactant and a reduction in the incidence of pneumo-
Early trials w26, 29, 37x on the use of ACS did not show
thorax. Mean birth weight and head circumference were
any benefit in primary outcomes for infants born more
similar in both groups although a reduction in birth weight
than 7 days after steroid administration. Especially, no
was found in infants exposed to repeat courses after
reduction in the incidence of RDS or neonatal mortality
adjustment for gestational age. The safety monitoring
was demonstrated. This lack of benefit led to a common
committee recommended stopping the trial early
practice of repeating courses or doses of ACS in a non-
because of the lack of reduction in composite morbidity
standardized way w4x.
and concerns regarding the tendency toward decreased
Animal and non-randomized studies in humans sug-
birth weight in the repeat courses group.
gested that multiple courses of steroids could lead to
In the larger trial, published by Crowther et al. w7x in
harmful effects on myelination of the brain w12, 18x,
reduction in birthweight w19x or effects on brain growth 2006, women received a single weekly dose of steroids
through to adulthood w31x, neurodevelopmental problems rather than the standard weekly course given in the pre-
in childhood behavior w1, 14x, or effects on the hypotha- vious studies. Despite the lower global dose received,
lamo-pituitary-adrenal axis with a spectrum from hyper- significant lower rates of RDS were found, with a reduc-
activity in young life to hypoactivity in adult life w39x. tion in severe lung disease, use of oxygen, surfactant
Approximately 50% of women given antenatal cortico- administration and peak inspired oxygen concentration
steroids remained undelivered 7–14 days after an initial in the multiple dose group. There were no differences in
course. Large randomized trials on this field were the incidences of chorioamnionitis in the mother or IVH,
needed. PVL, NEC, ROP or infection in the newborn. However, z
The NIH Consensus Statement on the use of repeated scores for weight and head circumference were lower at
courses of antenatal corticoids concluded in the year birth in the repeat doses group, although there were no
2000 w34x, that ‘‘because of insufficient scientific data significant differences by the time of hospital discharge.
from randomized clinical trials regarding efficacy and The authors of the Cochrane review on repeat doses
safety, repeat courses of corticosteroids should not be of prenatal corticosteroids concluded that: ‘‘Repeat
used routinely. In general it should be reserved for dose(s) of prenatal corticosteroids reduce the occurrence
patients enrolled in randomized controlled trials.’’ and severity of neonatal lung disease and the risk of seri-
Several large trials w7, 15, 27, 42, 43x have been devel- ous health problems in the first few weeks of life. These
oped in recent years comparing single versus multiple short-term benefits for babies support the use of repeat
courses. The TEAMS w42x trial did not progress from the dose(s) of prenatal corticosteroids for women at risk of
pilot phase due to lack of funding. The MACS w27x trial preterm birth. However, these benefits are associated
completed recruitment and results are expected this year. with a reduction in some measures of weight, and head
One more trial from the US is in progress (Obstetrix circumference at birth, and there is still insufficient
2003). Three other major trials have already been com- evidence on the longer-term benefits and risks’’.
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Miracle et al., Guideline for the use of antenatal corticosteroids for fetal maturation 195

For the first time, data regarding long-term effects on doses would be preferably contemplated in patients
the use of repeat doses of antenatal corticosteroids have enrolled in randomized controlled trials and patients
been published: Ronald Wapner w44x and Caroline Crow- should be followed up for long-term neurodevelopmental
ther w8x reported follow-up data on neurodevelopmental outcomes.
and growth outcomes at 24–36 months of age. Both
studies show no significant differences in physical meas-
ures or growth, blood pressure, use of health services or References
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