Antenatal Use of Corticosteroids in Women at Risk for Preterm Delivery

06/06/12 Antenatal use of corticosteroids in women at risk for preterm delivery

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©2012 UpToDate®

AuthorsMen-Jean Lee, MDDebra Guinn, MD

Section EditorCharles J Lockwood, MD

Deputy EditorVanessa A Barss, MD

Antenatal use of corticosteroids in women at risk for preterm delivery

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2012. | This topic last updated: may 11, 2012.

INTRODUCTION — In a landmark paper, Liggins and Howie demonstrated that antenatal corticosteroid therapy

administered to women at risk for preterm delivery (PTD) reduced the incidence of respiratory distress syndrome

(RDS) and mortality in their offspring [1]. The efficacy of antenatal corticosteroid therapy has been confirmed

subsequently by over a dozen randomized placebo-controlled trials [2-16]. The reduction in the severity and

incidence of RDS has resulted in decreased requirements for surfactant therapy, lower concentrations of

supplemental oxygen, and decreased need for prolonged mechanical ventilation in the neonatal period [17].

Premature infants exposed to antenatal corticosteroid therapy also have more circulatory stability and are less

likely to experience an intraventricular hemorrhage (IVH) or necrotizing enterocolitis than unexposed preterm

infants.

The National Institutes of Health (NIH) [17], American College of Obstetricians and Gynecologists (ACOG) [18],

Royal College of Medicine [19], and other major organizations have recommended antenatal corticosteroid

treatment for women at risk for preterm delivery prior to 34 weeks of gestation. The specific recommendations made

by the NIH are listed in the table (table 1).

This topic will review scientific evidence supporting the use of antenatal corticosteroids to improve neonatal

outcomes in women at risk for preterm delivery, pharmacological issues associated with this therapy, and other

clinical concerns from administration of antenatal corticosteroids.

MECHANISM OF ACTION — Antenatal corticosteroid therapy leads to improvement in neonatal lung function via

two mechanisms: by enhancing maturational changes in lung architecture, and by inducing lung enzymes that play

a role in biochemical maturation [20,21].

Alveoli are lined with two types of cells, the type 1 and type 2 pneumocytes. The type 1 pneumocyte is responsible

for gas exchange in the alveoli, while the type 2 pneumocyte is responsible for the production and secretion of

surfactant. Antenatal corticosteroid therapy accelerates morphologic development of both types of alveolar cells.

This is observed histologically as: flattening of epithelial cells, thinning of alveolar septa, and increased

cytodifferentiation. These changes, and others, increase maximal lung volume and compliance.

Antenatal corticosteroids also regulate enzymes in type II pneumocytes that stimulate phospholipid synthesis and

subsequent release of surfactant (figure 1). The sequence of events is as follows [22-24]: (1) free corticosteroid

enters the fetal type II pneumocyte and binds to specific intracellular corticosteroid receptors, (2) the steroid-

receptor complex then binds with corticosteroid response elements (GREs) located along the genome, (3) there is

increased transcription of certain genes and the resulting messenger ribonucleic acid (mRNA) is translated into

specific enzymatic proteins, and (4) the enzymatic proteins stimulate phospholipid synthesis.

In addition, antenatal corticosteroids alter production of surfactant binding proteins and enhance fetal lung

antioxidant enzymes. Cumulatively, the architectural and biochemical changes induced by antenatal corticosteroid

therapy improve both lung mechanics and gas exchange. For these changes to occur, however, the lungs need to



have reached a stage that is biologically ready to respond to corticosteroids (see 'Gestational age at

administration' below).

EVIDENCE OF CLINICAL EFFICACY

Reduction of RDS — In the original study by Liggins and Howie, 282 gravida at high risk for preterm delivery before

37 weeks of gestation were randomly assigned to receive betamethasone (two doses of 12 mg given

intramuscularly 24 hours apart) or placebo (cortisone acetate 6 mg) [1]. Administration of betamethasone was

associated with a lower incidence of RDS in offspring (9.0 versus 25.8 percent in controls) [1]. The maximum benefit

of antenatal corticosteroid therapy was in the subgroup of infants delivered more than 48 hours but less than seven

days after treatment (incidence of RDS: 3.6 versus 33.3 percent in controls), and when the drug was given between

26 and 32 weeks of gestation (incidence of RDS: 11.8 versus 69.6 percent in controls) (see 'Repeated courses of

therapy' below).

Subsequent trials performed worldwide have consistently confirmed a significant reduction in the frequency of RDS

among infants who received antenatal corticosteroid therapy. A systematic review reported treatment with antenatal

corticosteroids was associated with an overall reduction in respiratory distress syndrome (RR 0.66, 95% CI 0.59-

0.73, 21 studies, 4038 infants) and moderate to severe RDS (RR 0.55, 95% CI 0.43-0.71, six studies, 1686 infants)

[25]. As a result, treated infants had less need for respiratory support (mechanical ventilation, oxygen

supplementation).

A significant benefit was observed among infants born between one and seven days after the first treatment dose

(RR 0.46; 95% CI 0.35-0.60, nine trials, 1110 infants), but not for those born less than 24 hours or more than seven

days after the first dose [25]. However, these conclusions were based on analysis of subgroups defined after

randomization and intervention, which may have biased the results [26].

Reduction of IVH, NEC, NNM, infection — Other benefits of antenatal corticosteroid therapy demonstrated by

systematic review include reductions in the risk of IVH (RR 0.54, 95% CI 0.43-0.69; 13 studies, 2872 infants),

necrotizing enterocolitis (NEC) (RR 0.46, 95% CI 0.29-0.74; eight studies, 1675 infants), neonatal mortality (NNM)

(RR 0.69, 95% CI 0.58-0.81; 18 studies 3956 infants), and systemic infection in the first 48 hours of life (RR 0.56,

95% CI 0.38-0.85; five studies, 1319 infants) [25].

Some of these benefits derive from the beneficial effect on respiratory morbidity; however, maturational effects in

numerous tissues due to corticosteroid stimulation of developmentally regulated genes and physiological function

suggest an independent effect, as well [17,27].

Gender and race — The effects of corticosteroids do not appear to be limited by gender or race [28].

Multiple gestation — The small number of multiple gestations included in trials precludes a definite conclusion

about the effectiveness of this therapy or optimum dose in these pregnancies (multiple gestation RR RDS 0.85,

95% CI 0.60-1.20) [25]. In theory, multiple gestations may require higher doses of antenatal corticosteroids to

maximize fetal exposure. However, a randomized trial found that maternal and cord blood betamethasone levels

were similar in singleton and multiple gestations [29]. This trial did not compare clinical outcomes. A prospective

pharmacokinetic study also found pharmacokinetics were the same in singleton and multiple gestations [30].

We suggest prescribing the standard dosing schedule for both singleton and multiple gestations. The NIH

consensus statement on the effect of corticosteroids for fetal maturation on perinatal outcomes also stated it was

reasonable to treat women with multiple gestation as one would treat women with threatened premature delivery

carrying a singleton. (See "Twin pregnancy: Prenatal issues", section on 'Antenatal corticosteroids'.)

CHOICE OF AGENT

Drug and dose — Two regimens of antenatal corticosteroid treatment have evolved and are effective for

accelerating fetal lung maturity. Each regimen is considered a single course of therapy:



Betamethasone (two doses of 12 mg given intramuscularly 24 hours apart)

Dexamethasone (four doses of 6 mg given intramuscularly 12 hours apart).

These doses were selected arbitrarily, but subsequently were shown to deliver corticosteroid concentrations to the

fetus that are comparable to the physiologic stress levels of cortisol that occur after birth in untreated premature

infants who develop RDS [31]. Both regimens result in occupancy of an estimated 75 to 80 percent of available

corticosteroid receptors, which should provide near-maximal induction of antenatal corticosteroid receptor-mediated

response in fetal target tissues [32].

The beneficial fetal effects of standard doses of antenatal corticosteroids are not significantly reduced in women of

high body mass index (BMI), but further study of this issue is needed [33]. A randomized trial found that maternal

and cord blood betamethasone levels were similar in obese (BMI ≥30 kg/m2) and multiple gestations; this trial did

not compare clinical outcomes [29] Non-human primate studies are underway to determine if lower, weight-based

dosing regimens are as efficacious for lung maturation, while minimizing undesirable side effects.

Alternative dosing regimens are unproven, and discussed below. (See 'Alternative dosing regimens' below.).

Betamethasone — One milliliter of the betamethasone suspension used in clinical practice (Celestone

Soluspan) is actually a combination of 3 mg of betamethasone sodium phosphate and 3 mg of betamethasone

acetate. Betamethasone sodium phosphate is a soluble ester that is rapidly absorbed and pharmacologically

active, while betamethasone acetate is only slightly soluble and, therefore, provides sustained activity. The onset

and duration of action of intramuscularly administered betamethasone suspension is affected by the vascularity at

the injection site.

Betamethasone binds weakly to plasma proteins; only the unbound portion of the circulating dose is active. The

biological half-life of intramuscularly injected betamethasone is 35 to 54 hours [17]. Drug concentrations in cord

blood are approximately 20 percent of maternal levels one hour following maternal injection (approximately a 3:1

gradient crossing the placenta) [32].

Dexamethasone — Dexamethasone is available as dexamethasone sodium phosphate, which has a rapid

onset and relatively short duration of action. Therefore, the dosage frequency of dexamethasone is shorter than that

of betamethasone. Although dexamethasone is well absorbed from the gastrointestinal tract, there are concerns

regarding efficacy and complications after oral administration (see 'Oral administration' below).

Hydrocortisone — If both betamethasone and dexamethasone are unavailable, hydrocortisone 500 mg

intravenously every 12 hours for four doses has been proposed as an alternative therapy [34]. A systematic review

suggested this drug may not be effective, but data were limited to a few small trials [16]. Since hydrocortisone is

extensively metabolized in the placenta, relatively little crosses into the fetal compartment and adequate fetal

therapy cannot be assured.

In women incidentally receiving high dose hydrocortisone for treatment of a medical disorder, a standard course of

betamethasone or dexamethasone, when indicated for fetal lung maturation, is still recommended.

Comparative studies — The effects of betamethasone and dexamethasone have mostly been studied in

comparison with various controls, rather than in trials comparing the two drugs to each other [35,36]. This indirect

evidence suggested that betamethasone was associated with a greater reduction in the risk of adverse outcome

than dexamethasone (table 2A-B); in particular, betamethasone was associated with a greater reduction in risk of

neonatal death [36].

In contrast, the only randomized trial directly comparing the two drugs (Betacode trial) found no significant

differences between the drugs in the rate of RDS, need for vasopressor therapy, NEC, retinopathy of prematurity,

patent ductus arteriosus, neonatal sepsis, or NNM [37]. However, neonates exposed to betamethasone had a

significantly higher rate of IVH (17 versus 6 percent, RR 2.97, 95% CI 1.22-7.24) and brain lesions (18 versus 7



percent, RR 2.7, 95%CI 1.18-6.19). Long-term outcome data were not available.

The findings of the small Betacode trial are in conflict with several larger cohort and case control studies that

suggested use of dexamethasone was neurotoxic and associated with adverse neurologic outcomes compared to

use of betamethasone or no antenatal corticosteroid [36,38-44]. In addition, studies in neonates showed that

postnatal use of dexamethasone in premature infants was associated with shorter stature, smaller head

circumference, poorer motor skills and coordination, lower IQ scores, and an increased frequency of clinically

significant disabilities in survivors [45].

Investigators have hypothesized that the effects of dexamethasone on the developing brain may be gestational age

dependent or related to the length of the exposure (prenatal and postnatal). Alternatively, the presence of sulfating

agents in commonly available dexamethasone preparations may be neurotoxic, thereby mitigating the potential

benefits of the corticosteroid [46,47].

In summary, studies have consistently shown that both betamethasone and dexamethasone are effective in

reducing most morbidities and mortality related to prematurity. Dexamethasone has the advantage of having a lower

cost and wider availability, but there are concerns over risk of neurotoxicity. Currently, there is insufficient high

quality evidence on possible adverse effects on which to base a strong recommendation for use of one drug over the

other [48].

GESTATIONAL AGE AT ADMINISTRATION — We recommend administration of antenatal corticosteroids to

pregnant woman at 23 to 34 weeks who are at increased risk of preterm delivery within the next seven days.

23 to 34 weeks — A meta-analysis of randomized trials of antenatal corticosteroids in women at risk of preterm

birth provides strong evidence that RDS, IVH, and neonatal death are significantly reduced when corticosteroids are

given at 26 to 34 weeks of gestation [25]. Meta-analyses of trials of corticosteroid administration prior to 26 weeks

of gestation have not demonstrated a significant benefit [25,49]; however, data from this gestational age group were

limited before publication of the following trial.

The benefit of administering antenatal corticosteroids earlier in gestation was demonstrated in a prospective cohort

study including almost 5000 infants born at 22 to 25 weeks of gestation at 23 academic perinatal centers in the

United States [50]. Compared to no exposure to antenatal steroids, the composite outcome ‘death or

neurodevelopmental impairment at 18 to 22 months of age’ was significantly lower for exposed fetuses who were

born at 23 weeks of gestation (83.4 versus 90.5 percent; AOR 0.58 (95% CI 0.42-0.80)), at 24 weeks of gestation

(68.4 versus 80.3 percent; AOR 0.62 (95% CI 0.49-0.78)), and at 25 weeks of gestation (52.7 versus 67.9 percent;

AOR 0.61 (95% CI 0.50-0.74)), but not for those infants born at 22 weeks of gestation (90.2 versus 93.1; AOR 0.80

(95% CI 0.29-2.21)). Corticosteroid exposed infants born at 23, 24, and 25 weeks of gestation also had significant

reductions in the following outcomes: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage,

or periventricular leukomalacia; and death or necrotizing enterocolitis.

It is unlikely that administration of antenatal corticosteroids at ≤22 weeks of gestation could significantly improve

lung function, as there are only a few primitive alveoli at this gestational age on which the drug can exert an effect

[51].

Some parents may choose to have aggressive neonatal intervention if they deliver prior to 23 weeks of gestation,

even though survivors have high rates of long-term handicap. If well-counseled parents elect to pursue active

resuscitation of neonates that deliver prior to 23 weeks, then it is reasonable to administer a course of antenatal

corticosteroids prior to delivery. Parents should be informed that this intervention may provide a survival benefit while

increasing the risk of survival with severe impairment. Also, if the pregnancy is not delivered, then "salvage" or

repeat courses of antenatal corticosteroids may need to be considered later in gestation (see below).

After 34 weeks — Whether there is a significant improvement in outcome following antenatal corticosteroid use

after 34 weeks of gestation is unclear since the baseline risks of RDS, IVH, and neonatal mortality are already low

at that time. Given the lack of high-quality data in this population, the NIH Consensus Development Conference on



the Effect of Glucocorticoids for Fetal Maturation on Perinatal Outcomes stated that administration of antenatal

corticosteroids after 34 weeks can be considered if there is evidence of pulmonary immaturity [17]. There is

evidence from a randomized trial that administration of antenatal corticosteroids at 34 to 37 weeks in pregnancies

with documented fetal lung immaturity significantly increased the level of at least one test of fetal lung maturity

(increase in TDx- FLM-II: 28.4 versus 9.8 without treatment) [52].

Subsequent to the NIH statement, two randomized trials assessing clinical outcomes were published:

The ASTECS trial (Antenatal Steroids For Term Caesarean Section) supported the continued effectiveness of

antenatal corticosteroids in reducing respiratory distress after 37 weeks of gestation [53]. This trial

randomized 998 women to antenatal corticosteroids or no antenatal corticosteroids at the time of their

decision to deliver by elective cesarean delivery at 37 weeks of gestation or greater. Two

betamethasone injections were administered in the 48 hours before planned delivery.

The overall incidence of respiratory problems (composite of transient tachypnea of the newborn (TTN)

and RDS) was lower in neonates who were treated antenatally (2.4 versus 5.1 percent; RR 0.46, 95% CI

0.23-0.93).

A Brazilian trial that randomly assigned 320 women at 34 to 36 weeks of gestation at risk of imminent

premature delivery to receive a course of betamethasone or placebo did not find a benefit to antenatal

corticosteroid treatment [54]. Thirteen percent of infants were lost to follow-up and 27 of the remaining 273

infants delivered after 36 weeks.

The rate of RDS was low (2/143 in the corticosteroid group and 1/130 in the placebo group), while the

rate of TTN was similar and high in both groups (34/143 (24 percent) versus 29/130 (22 percent)). The

study was not powered to detect differences in the rate of RDS.

There was no reduction in the risk of composite respiratory morbidity with corticosteroid use: adjusted

risk of respiratory morbidity 1.12 (95% CI 0.74-1.70; 36/143 (25 percent) versus 30/130 (23 percent)),

even after adjustment for subgroups by week of gestation (34th, 35th, 36th).

There was no significant difference between groups in neonatal morbidity (88/143 (62 percent) versus

93/130 (72 percent) or in the duration of hospital stay (5.12 versus 5.22 days)).

Phototherapy for jaundice was required less often in babies whose mothers received corticosteroids (risk

ratio 0.63, 95% CI 0.44-0.91).

Long-term neurologic outcome data were not evaluated as part of either trial. In animal models, exposure to

antenatal corticosteroids increases cell death in mitotically active portions of the brain at the time of exposure [55].

In humans, neuronal division is generally completed before the 24 weeks of gestation, except for the cerebellum and

dentate gyrus. Subsequently, most cell division involves glial, especially oligodendroglial cells, which are

responsible for laying down myelin. As humans approach term, the peak brain growth spurt occurs. This

developmental process may make the term brain more vulnerable to steroid-induced apoptosis and cell death

compared to earlier gestations.

Given the low risk of severe respiratory morbidity after 34 weeks of gestation, the lack of consistent evidence of

corticosteroid efficacy, and the potential for long-term CNS maldevelopment following exposure, we suggest

avoiding use of antenatal corticosteroids after 34 weeks of gestation. Pregnancies over 34 weeks in which fetal risks

exceed neonatal risks should be delivered expeditiously. In those in which the fetal and neonatal risks are

comparable, we suggest demonstrating pulmonary maturity, when possible, prior to performing late preterm

deliveries; or, for those patients in which a planned late preterm or early term cesarean is being considered, two

betamethasone injections may be given in the 48 hours before planned delivery. Further randomized clinical trials

are underway to determine if antenatal corticosteroids improve neonatal outcomes in late preterm births, regardless

of route of delivery.



TIMING BEFORE DELIVERY — Antenatal corticosteroid therapy should be administered to all women at high risk

for preterm delivery unless "impending" delivery (eg, birth expected within an hour or two) is anticipated [17]. Liberal

use of a single course of antenatal therapy is recommended because the minimal time interval between drug

administration and delivery required to observe a benefit has not been clearly defined, and the hour of delivery

cannot be predicted accurately.

Several observations suggest neonatal benefits begin to accrue within a few hours of corticosteroid administration.

Cell cultures have shown that choline begins to be incorporated into phospholipids at six hours and peaks at 48

hours postinjection of antenatal corticosteroids [56]. Decreased lung albumin is detectable as early as eight hours

following antenatal corticosteroid exposure in the fetal lamb model [57]. By 15 hours following antenatal

corticosteroid administration, decreases in both lung albumin and ventilatory pressure and increases in maximum

lung volume are observed. In addition, infants who received one dose of betamethasone in utero, but delivered before

the second dose could be given, had better outcomes than infants who did not receive any antenatal corticosteroids

[58]. Therefore, antenatal corticosteroids should not be withheld if delivery is anticipated prior to the completion of

the full dose of medication.

SAFETY OF SINGLE COURSE THERAPY — Administration of a single course of antenatal corticosteroid therapy

(ie, two doses of betamethasone or four doses of dexamethasone) appears to be safe for the fetus/infant, but has

risks for some pregnant women.

Fetus and infant — There is no association between a single course of antenatal corticosteroids and adverse

neonatal events, such as reduced lung volume, poor neurologic outcome, impaired growth, neonatal sepsis, or

clinically significant adrenal suppression [17,25].

Administration of antenatal corticosteroids can be associated with transient fetal heart rate (FHR) and behavioral

changes that typically return to baseline by four to seven days after treatment. The most consistent FHR finding is

a decrease in variability on Days 2 and 3 [59-63]. Fetal breathing and body movements are also commonly reduced,

which may result in a lower biophysical profile (BPP) score or nonreactive nonstress test (NR-NST) [63-66].

However, a placebo controlled randomized trial in humans did not report a decrease in maternal perception of fetal

movements in patients who received antenatal corticosteroids [36].

These behavioral changes may reflect a physiologic response of the brain to corticosteroids. Alternatively, they may

be a consequence of a transient increase in fetal vascular resistance and blood pressure, which has been

demonstrated in some animal studies [67-71], although other studies have not shown effects on fetal blood flow

velocity waveform patterns in the umbilical artery, middle cerebral artery, and ductus venosus [65,72]. Three human

studies have demonstrated a transient improvement in umbilical artery end-diastolic flow in 63 to 71 percent of their

study populations [73-75]. The improvement began about eight hours after the first dose of betamethasone and

lasted a median of three days (range 1 to 10 days).

Preterm fetuses with severe early-onset growth restriction and absent or reversed end-diastolic umbilical artery flow

(EDF) do not have a consistent cardiovascular response to maternal betamethasone administration. Some fetuses

exhibit transient improvement of EDF, while others do not. The latter group appears to be at higher risk of severe

intrauterine acidosis or death. However, these observations are based on a small number of events in two studies

and need to be confirmed before a change in management of this subgroup of fetuses is considered [75,76].

Given these observations, the possibility of transient fetal changes associated with antenatal corticosteroids should

be considered within the total clinical picture when assessing a fetus for possible delivery because of a

nonreassuring fetal evaluation (NR-NST or low BPP score) within a few days of corticosteroid administration.

Follow-up of children and adults — Long-term studies of exposed fetuses have also been generally reassuring.

Follow-up studies at 3 to 6, 12, 22, and 30 years of age have not found adverse effects on growth, lung function, and

psychosexual, motor, cognitive, neurologic, and ophthalmologic outcomes compared with controls [20,77-82].

In the largest and longest study, the Auckland Steroid Trial followed 253 fetuses exposed to betamethasone and



281 placebo-exposed controls to a mean age of 30 years [81]. Antenatal corticosteroid-exposed adults displayed

small, although statistically significant, increases in insulin resistance, but no difference in cardiovascular risk

factors compared to unexposed controls. There were no differences between groups in cognitive functioning,

working memory and attention, psychiatric morbidity, handedness, or health related quality of life [82]. However,

another long-term outcome study in a British cohort of young adults reported antenatal corticosteroid exposure is

associated with increased aortic arch stiffness and altered glucose metabolism in adulthood, which suggests that

the effect of these drugs on the cardiovascular system requires further study [83].

Maternal effects — Most pregnant women tolerate a single course of antenatal corticosteroids without difficulty.

Treatment does not increase the risk of maternal death, chorioamnionitis, or puerperal sepsis [25]. Case reports

have described pulmonary edema, primarily associated with combination treatment with tocolytics, especially in the

setting of chorioamnionitis, fluid overload, or multiple gestation [84-86]. Betamethasone itself has low

mineralocorticoid activity compared to other corticosteroids. Hypertension is not a contraindication to therapy [87].

Transient hyperglycemia occurs in many women; the steroid effect begins approximately 12 hours after the first

dose and may last for five days. Hyperglycemia can be severe in the diabetic gravida if not closely monitored and

treated [88,89]. Screening for gestational diabetes, if indicated, should be performed either before corticosteroid

administration or at least five days after the first dose [90,91]. (See "Obstetrical management of pregnancy

complicated by pregestational diabetes mellitus", section on 'Antenatal glucocorticoids'.)

The total leukocyte count increases by about 30 percent within 24 hours after betamethasone injection, and the

lymphocyte count significantly decreases [92,93]. These changes return to baseline values within three days.

ALTERNATIVE DOSING REGIMENS — Clinical concern over the prompt completion of steroid injections prior to

delivery has prompted some practitioners to accelerate the dosing interval, increase the quantity of drug

administered, or change the route of administration. There is limited evidence supporting the safety and efficacy of

these modifications.

Higher dose — Maternal treatment with 12 mg betamethasone results in a four-fold, essentially maximal, increase

in unbound fetal plasma corticosteroid activity and near saturation (75 to 80 percent) nuclear occupancy of receptor-

steroid complexes in the fetal lung [94]. Thus, any excess steroid administered would only result in, at most, a

negligible increase in fetal lung maturation and excretion of any remaining unbound steroid. This hypothesis was

supported by a study in which doubling the dose of betamethasone to 24 mg per day in the clinical setting was not

associated with increased efficacy [95].

There are limited data on optimal dosing of antenatal corticosteroids in multiple gestations. The standard singleton

dosage should not be increased for multiple gestations unless data showing a benefit become available (see

'Gender and race' above).

Shorter dosing interval — Pharmacokinetic studies by Ballard and Ballard demonstrated that the standard dosing

intervals of two 12 mg doses of betamethasone administered 24 hours apart provide maximum glucocorticoid

receptor occupancy and near-maximal stimulation of glucocorticoid receptor target genes in fetal tissues [21,96]. If

receptors are not available for activation, then a higher daily dose of glucocorticoid probably should not be effective

and the excess drug would likely be excreted. In addition, supraphysiological doses of glucocorticoids are known to

induce suppression of glucocorticoid receptor levels by a process known as “homologous downregulation” [97]. The

duration of exposure of unbound glucocorticoid receptors to the glucocorticoid ligand appears to play a role in

activation of the requisite target genes, so administration of more steroids faster may not necessarily result in

increased stimulation of the molecular machinery to induce the desired physiological response in the target tissue.

In a non-inferiority trial that tested this hypothesis, the incidence of RDS was equivalent (approximately 37 percent

in each group) in offspring of patients treated with a 12- or 24-hour dosing interval [98]. There were no statistically

significant differences between groups in any neonatal outcome, although all 10 cases of necrotizing enterocolitis

among the 260 infants in the trial occurred in the 12-hour dosing group. In view of these data, shorter dosing

intervals should not be used routinely. However, the benefits and risks of this approach should be evaluated further



in a multicenter randomized trial as a shorter dosing interval would increase the number of women who complete

the full two-dose course of therapy before delivery.

Intravenous administration — The clinical efficacy of intravenous antenatal corticosteroids has not been studied

in human pregnancy. Intravenous administration results in rapid peaks and troughs in the maternal and fetal steroid

concentrations and, therefore, produces less sustained fetal exposure to corticosteroid stimulation.

Oral administration — Outpatient oral administration of dexamethasone has also been used to facilitate

completion of full courses of corticosteroids in ambulatory women at increased risk of preterm delivery. In one trial,

170 women between 24 and 33 weeks of gestation at high risk of preterm delivery were randomly assigned to

receive either 6 mg intramuscular dexamethasone or 8 mg oral dexamethasone every 12 hours for four doses [99].

There was no difference between groups in the frequency of RDS, but the oral dexamethasone group had increased

rates of IVH and sepsis. The authors concluded that oral dexamethasone should not be given in place of

intramuscular administration.

Repeated courses of therapy — The original data of Liggins and Howie [1] and subsequent trials [100] did not

demonstrate a difference in the incidence of RDS between drug and placebo groups seven or more days after

administration. This finding led to controversy as to whether antenatal corticosteroid therapy should be repeated

after seven days.

The biologic rationale for repeating antenatal corticosteroid therapy is based upon the observation that biochemical

stimulation of surfactant production appears to be reversible in cell culture models (eg, surfactant protein mRNA

levels decline to control levels after cortisol is removed) [21,101]. However, other beneficial effects, such as

cytostructural maturation, persist (in rhesus monkeys) after steroid exposure is withdrawn [102].

The possible benefits of multiple courses of antenatal corticosteroids must be tempered by evidence of harmful

developmental effects on lung growth and organization, retinal development, insulin resistance, renal glomerular

number, somatic growth, head circumference, and, in particular, maturation of the central nervous system [81,103-

116]. Although corticosteroids are necessary for normal brain development, repeated exposure to antenatal

corticosteroids in animal models results in decreased body and brain weight and delay in the maturational time-

table [117,118]. The decrease in brain weight and size persisted into adulthood in both sheep and monkey models

[119]. The functional consequences of the effects on adult brain weight are unknown. In addition, nonhuman

primates given repeated doses of dexamethasone showed impaired postnatal growth at one year of age, even when

birth weight was normal, as well as impaired glucose tolerance, hyperinsulinemia, increased systolic and diastolic

blood pressures, and an exaggerated cortisol response to mild stress [120].

Multiple courses of antenatal corticosteroids have no or minimal effects on neonatal hypothalamic pituitary-adrenal

axis (HPA) function. Cord serum cortisol concentrations in infants exposed to repeat doses of corticosteroids are

similar to those in infants exposed to a single course; however, data are conflicting as to whether the neonatal

adrenal response to stress is suppressed [121-123]. (See "Causes and clinical manifestations of central adrenal

insufficiency in children".)

No clinically important effects on bone metabolism have been observed [124].

Evidence from randomized trials — Three large, multicenter randomized clinical trials of single course versus

multiple courses of antenatal corticosteroid therapy have been reported: the Maternal Fetal Medicine Units network

(MFMU) trial [125], Guinn et al multicenter trial [126], and the Australasian Collaborative Trial of Repeat doses of

prenatal Steroids (ACTORDS) [127]. In addition, two small randomized trials addressed the short-term benefits and

long-term outcomes in neonates exposed to multiple courses of antenatal corticosteroids.

A systematic review of these five trials including over 2000 women reported the following results [128]:

Neonates exposed to repeat courses of corticosteroids had a reduction in RDS (RR 0.82, 95% CI 0.72-0.93)

and were less likely to have severe RDS (RR 0.60, 95% CI 0.48-0.75), particularly those infants delivered at

the earliest gestational ages (eg, less than 28 weeks of gestation).



Neonates exposed to repeat courses of corticosteroids were significantly less likely to have serious

composite morbidity (RR 0.79, 95% CI 0.67-0.93). This reduction in composite morbidity was due primarily

to the reduction in RDS rates. In neonates, there were no significant differences between treated and control

groups in rates of chronic lung disease, any grade of periventricular hemorrhage, mean birthweight, mortality,

periventricular leukomalacia, length of hospital stay, necrotizing enterocolitis, or retinopathy of prematurity.

In mothers, there were no significant differences between treated and control groups in rates of

chorioamnionitis or puerperal sepsis.

The trials included women at less than 32 weeks of gestation who remained at risk of preterm delivery seven or

more days after receiving a first course of antenatal corticosteroids. After their initial course of antenatal

corticosteroids, women randomly assigned to multiple course therapy received weekly injections of two doses of

betamethasone until 34 weeks in two trials [125,126], and a weekly injection of only one dose of betamethasone

until 32 weeks in the third trial (ACTORDS trial) [127]. For the Guinn et al [126] and ACTORDS trials [127], the

proportion of women in the multiple dosing group who received one, two, three, or four or more additional courses of

betamethasone was similar: 35 and 42, 22, 14 and 11, and 27 and 25 percent, respectively. In the MFMU trial, 63

percent of patients received four or more courses of therapy [125].

In the ACTORDS trial, although multiple steroid courses were associated with decreased birth weight and head

circumference at birth, this was no longer true at discharge, suggesting the potential for catch up growth [127]. In

the MFMU trials, the percentage of small for gestational age fetuses below the 10th percentile and below the 5th

percentile was significantly higher in the weekly course group compared to the single course group (for 10th

percentile: 19.3 versus 8.4 percent; for 5th percentile 10.4 versus 4.7 percent) [125]. These findings applied to both

singleton and multiple gestations. Since intrauterine growth restriction is associated with adverse long-term health

consequences, the overall impact of repeat courses on long-term health remains uncertain. In addition, after 32

weeks of gestation, placental weight was significantly less in the repeat corticosteroid group, and was related

inversely to the number of steroid courses [129]. The significance of this finding is unclear.

Although statistically insignificant, in the MFMU trial repeat courses were associated with an increased incidence of

cerebral palsy (one case of cerebral palsy in the control group and five in the weekly course group; RR 5.68, 95% CI

0.69-46.7) [125]. Interestingly, five of the six children with cerebral palsy were delivered near term or term, and five of

the six received four or more courses of antenatal corticosteroids.

Two of the trials also reported longer term follow-up results. At two to three years of age, physical (eg, growth) and

neurocognitive measures and rate of survival free of major disability were similar in the repeat corticosteroid and

placebo groups [130,131].

In addition, the ACTORDS trial showed that follow-up dosing with only a single injection of corticosteroids was as

effective as the two injection standard [127]. Further research of the single dose regimen for follow-up treatment is

needed.

Subsequent to this meta-analysis, the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study

(MACS trial) was published [132]. This international multicenter placebo-controlled randomized trial is the largest

trial on this issue and included 1858 women between 25 to 32 weeks of gestation who remained at risk for preterm

birth 12 to 21 days after an initial course of antenatal corticosteroids. These women were given either a repeat

course of corticosteroids or placebo every 14 days to a maximum gestational age of 33 weeks. Repeated courses

of corticosteroids after the initial course did not improve neonatal outcome, either composite or individual

parameters of morbidity, compared with placebo; mortality was also similar for both groups. However, neonates who

received multiple courses of corticosteroids had significantly lower mean birthweight, length, and head

circumference than those in the placebo group.

The risk-to-benefit ratio of repeated corticosteroid administration increasingly appears to favor avoidance of repeated

dosing. In our opinion, the goal of antenatal corticosteroid therapy is to both minimize exposure to antenatal



corticosteroids and maximize the number of pregnancies that receive corticosteroids in the week prior to preterm

birth. After review of the above data, we continue to support the conclusions of the 2000 NIH consensus conference

and ACOG that weekly courses of antenatal corticosteroids should not be used outside of randomized controlled

trials [18,103]. Further study of the number of repeat doses and the regimen used in repeat dosing is warranted

[133].

Salvage (rescue) therapy — Salvage (rescue) therapy is an attractive alternative to repeated weekly courses of

antenatal corticosteroids, as discussed above. Salvage therapy is restricted to pregnancies at high risk of delivering

within seven days and, in theory, would allow a single booster or rescue course of therapy to those pregnancies

most likely to benefit. This could result in decreased rates of RDS without increasing the risk of adverse CNS

outcomes.

Two large placebo-controlled randomized trials of salvage therapy have been published; one (n = 249 pregnancies)

did not show a reduction in the incidence of RDS (52 percent with betamethasone versus 48 percent with placebo)

[134], while the other (n = 437 pregnancies) showed a significant reduction in the incidence of RDS (41.4 percent

with betamethasone versus 61.6 percent with placebo) [135]. Neither trial reported a significant reduction in IVH or

perinatal death. A third placebo-controlled randomized trial (n = 85 pregnancies) found that a rescue course of

betamethasone significantly increased respiratory compliance (primary outcome) and, in deliveries less than 34

weeks, significantly decreased the incidence of RDS (15/44 [34 percent] versus 22/39 [56 percent] in the placebo

group) [136]. No increase in adverse effects was observed.

These discordant findings were likely due to differences in study design. In the first trial, salvage therapy consisting

of a single dose of 12 mg betamethasone was offered to women <34 weeks of gestation who were seven or more

days beyond a complete course of antenatal corticosteroids and at risk of imminent delivery (ie, expected within 48

hours); women with PPROM were included [134]. Seventy-nine percent of subjects delivered within 24 hours of any

intervention, and those who received a single dose of betamethasone had a lower intact survival rate and higher rate

of RDS than those who had received placebo. In the second trial, a complete course of betamethasone (two 12 mg

injections) was offered to women <33 weeks of gestation who were ≥14 days beyond a complete course of

antenatal corticosteroids and at risk of delivery within the next 7 days; women with PPROM were excluded [135].

Only 11 percent of subjects delivered before completing the course of rescue therapy. The higher proportion of

subjects that actually received the intervention in the second trial compared to the first trial likely accounted for the

significant reduction in RDS. In the third trial, 86 percent of women received a full course (two doses) of rescue

steroids [136].

From a clinical perspective, none of the currently utilized testing strategies (fibronectin, cervical length, clinical

assessment of preterm labor or prior obstetrical history) allow us to identify women who will deliver within seven

days with precision. Each of these tests has low positive predictive values (range 24 to 33 percent). Therefore,

clinical judgment in individual cases will be required to determine the potential risk to benefit ratio of salvage therapy

in pregnancies at high risk of delivery within a few days. If clinicians believe that such a preterm delivery is likely

and that they can delay delivery for 24 hours, then it would be reasonable to consider salvage therapy in selected

cases at early gestational ages (ie, <33 weeks). Based on data from the large ACTORDS trial, we believe one dose

of betamethasone is adequate for the rescue course [127]. ACOG has stated a single rescue course of antenatal

corticosteroids can be considered if antecedent corticosteroid treatment was given more than two weeks previously,

the gestational age is less than 33 weeks, and the patient is likely to delivery within the next seven days [18].

AMNIOCENTESIS AFTER ANTENATAL CORTICOSTEROID THERAPY — Standard tests for predicting fetal lung

maturity may be less predictive of RDS after antenatal corticosteroids. Although some studies have reported an

increased lecithin-sphingomyelin ratio or TDx-FLM II five days to two weeks after corticosteroid therapy

[52,137,138], several other series found no change in this ratio [1,5,139].

We do NOT recommend routine amniocentesis following antenatal corticosteroid therapy because current tests for

fetal lung maturation may not be sensitive enough to detect subtle changes in the surfactant concentration of

amniotic fluid. In addition, these tests measure surfactant and do not address the effects of architectural changes in



the fetal lung. (See "Assessment of fetal lung maturity".)

PRETERM PREMATURE RUPTURE OF MEMBRANES — The peripartum period, especially in the setting of

preterm premature rupture of membranes (PPROM), is a high risk period for maternal, fetal, and neonatal infection.

There have been concerns that the immunosuppressive properties of corticosteroids may augment this risk. In

1994, the NIH consensus panel concluded that the benefits of antenatal corticosteroids outweighed the infection

risk and, therefore, recommended antenatal corticosteroid therapy for pregnancies complicated by PPROM at less

than 30 to 32 weeks of gestation, as long as there was no clinical evidence of chorioamnionitis [17].

Data supporting this recommendation have been provided by two systematic reviews [25,140] that showed neonatal

death, RDS, IVH, NEC, and duration of neonatal respiratory support were significantly reduced by corticosteroid

treatment, without an increase in either maternal or neonatal infection. Mean risk reduction for these adverse events

ranged from 30 to 60 percent.

The effect of single versus weekly courses of antenatal corticosteroids specifically in women with PPROM was

evaluated in a planned secondary analysis of participants in the large, randomized trial of single versus repeated

courses of antenatal corticosteroid therapy discussed above [126]. In pregnancies complicated by PPROM, weekly

courses of antenatal corticosteroids did not significantly improve neonatal outcome, except severe RDS (which was

reduced from 39 to 19 percent), beyond that achieved with a single treatment course [141]. Weekly courses were

associated with shorter latency and increased risks of chorioamnionitis and neonatal sepsis. The decrease in

severe RDS with multi-course therapy resulted in less composite neonatal morbidity among neonates delivered at

24 to 27 weeks of gestation (severe RDS was decreased from 100 to 26 percent in this age group); however, the

decrease in composite morbidity did not reach statistical significance after adjusting for multiple comparisons.

Secondary analysis of this trial also demonstrated that there was no benefit to receiving antenatal corticosteroids

between 32 and 34 weeks of gestation, and that exposure at this gestational age increased the likelihood of

chorioamnionitis. Moreover, the risk of chorioamnionitis outweighed any risk of complications related to prematurity

after 32 weeks of gestation.

Given limitations in available data, there are wide practice variations in antenatal corticosteroid treatment of

PPROM. Based on the findings discussed above and NIH recommendations, we do not use antenatal

corticosteroids beyond 32 weeks of gestation in PPROM. ACOG has stated treatment at 32 to 33 completed

weeks may be beneficial if pulmonary immaturity has been documented, although efficacy has not been proven

[18].

As discussed above, retreatment can be considered if multiple weeks have elapsed since the initial course of

antenatal corticosteroid therapy and the gestational age remains less than 28 weeks. The overall management of

PPROM is discussed in detail separately. (See "Preterm premature rupture of membranes".)

SURFACTANT THERAPY — Postnatal surfactant administration is not a substitute for antenatal corticosteroid

therapy; in fact, antenatal corticosteroids appear to enhance the effectiveness of surfactant therapy. The benefit of

sequential antenatal corticosteroid-postnatal surfactant therapy was illustrated in the Exosurf Neonatal Treatment

Investigational New Drug study of 11,077 infants in whom antenatal corticosteroid treatment substantially

augmented the reductions in morbidity and mortality observed with surfactant alone [142].

SUMMARY AND RECOMMENDATIONS

Antenatal corticosteroid therapy leads to improvement in neonatal lung function by enhancing maturational

changes in lung architecture and by inducing lung enzymes resulting in biochemical maturation. (See

'Mechanism of action' above.)

Antenatal corticosteroid therapy reduces the incidence of respiratory distress syndrome, intraventricular

hemorrhage, necrotizing enterocolitis, sepsis, and neonatal mortality by approximately 50 percent. These

effects are not limited by gender or race; efficacy in multiple gestations is unclear, as high quality data are

sparse. (See 'Evidence of clinical efficacy' above.)



Given these benefits, we recommend antenatal corticosteroids be administered to pregnant woman at 23 to

34 weeks who are at increased risk of preterm delivery within the next seven days (Grade 1A). In our

practice, this means we restrict administration of the first course of antenatal corticosteroids to women who

rupture membranes or are receiving tocolysis for active preterm labor, or in whom delivery for maternal or fetal

indications is anticipated within the next seven days. This approach minimizes the need for salvage therapy

while allowing the vast majority of women to receive a course of antenatal corticosteroids prior to preterm

delivery. A course of antenatal corticosteroids consists of betamethasone suspension 12 mg intramuscularly

every 24 hours for two doses or four doses of 6 mg dexamethasone intramuscularly 12 hours apart. (See

'Choice of agent' above and 'Timing before delivery' above.)

The lower limit of gestational age for administration is approximately 23 weeks since only a few primitive

alveoli are present below this gestational age. Earlier administration is reasonable if aggressive neonatal

intervention is planned for a delivery prior to 23 weeks of gestation. After 34 weeks of gestation, we suggest

administration be limited to women with documented fetal pulmonary immaturity and obstetrical issues

requiring prompt delivery (Grade 2B). (See 'Gestational age at administration' above.)

The absence of consistent and long-term data precludes making an evidence-based recommendation for the

number of courses that are safe for the fetus, the appropriate time interval between courses, the optimal

dose for repeated courses of therapy, or the full ramifications of the single course approach to therapy. Given

the potential for harm from repeated courses of antenatal corticosteroid therapy:

We suggest a single course of salvage therapy only if more than two weeks have elapsed since the

initial course of antenatal corticosteroid therapy, the gestational age at administration of the initial

course was <28 weeks of gestation, the current gestational age is less than 33 weeks, AND the risk of

preterm birth has increased (eg, deterioration in the maternal or fetal status, contractions with newly

positive fetal fibronectin test result, further cervical effacement or dilatation) (Grade 2C).

We also suggest that providers who elect to give salvage therapy use one dose of 12 mg

betamethasone and limit treatment to this one additional course of antenatal corticosteroids (Grade

2C). One dose appears to be effective and may minimize complications related to steroid use. Patients

should be informed of potential adverse effects. (See 'Repeated courses of therapy' above and 'Salvage

(rescue) therapy' above.)

We recommend antenatal corticosteroids for women with preterm premature rupture of membranes (Grade

1A). We give them at 23 to 32 weeks of gestation in the absence of any clinical signs of chorioamnionitis.

Some experts will administer antenatal corticosteroids at 32 to 34 weeks if pulmonary immaturity has been

documented, although efficacy has not been proven. (See 'Preterm premature rupture of membranes' above.)

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Topic 6796 Version 14.0



GRAPHICS

Recommendations for use of antenatal corticosteroids

The benefits of antenatal administration of corticosteroids to fetuses at risk of pretermdelivery vastly outweigh the potential risks. These benefits include not only a reduction inthe risk of RDS, but also a substantial reduction in mortality and IVH.

All fetuses between 24 and 34 weeks of gestation at risk of preterm delivery should beconsidered candidates for antenatal treatment with corticosteroids.

The decision to use antenatal corticosteroids should not be altered by fetal race or genderor by the availability of surfactant replacement therapy.

Patients eligible for therapy with tocolytics should also be eligible for treatment withantenatal corticosteroids.

Treatment consists of two doses of 12 mg of betamethasone given intramuscularly 24 hoursapart or four doses of 6 mg of dexamethasone given intramuscularly 12 hours apart. Optimalbenefit begins 24 hours after initiation of therapy and lasts seven days.

Because treatment with corticosteroids for less than 24 hours is still associated withsignificant reductions in neonatal mortality, RDS, and IVH, antenatal corticosteroids shouldbe given unless immediate delivery is anticipated.

In premature rupture of membranes at less than 30 to 32 weeks of gestation in the absenceof clinical chorioamnionitis, antenatal corticosteroid use is recommended because of the highrisk of IVH at these early gestational ages.

In complicated pregnancies where delivery prior to 34 weeks of gestation is likely, antenatalcorticosteroid use is recommended unless there is evidence that corticosteroids will have anadverse effect on the mother or delivery is imminent.

RDS: respiratory distress syndrome; IVH: intraventricular hemorrhage. Adapted from data in the

Report of the Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation

on Perinatal Outcomes. National Institute of Child Health and Human Development. November 1994.

NIH Publication No. 95-3784.



Model for glucocorticoid action



Relative risk of selected adverse outcomes

OutcomeBetamethasone versus

controlDexamethasone versus

control

Respiratory distresssyndrome

0.57* 0.70*

Intraventricularhemorrhage

0.27* 0.60*

Perinatal infection 0.72 0.99

Neonatal death 0.47* 0.84

Stillbirth 0.80 0.95

Maternal infection 1.33 1.17

* Difference between study drug and controls was statistically significant. Adapted from: Jobe, AH,

Soll, RF. Am J Obstet Gynecol 2004; 190:878.



Odds ratio of selected adverse outcomes

OutcomeBetamethasone versus

controlDexamethasone versus

control

Intraventricularhemorrhage

0.63* 0.76*

Neonatal death 0.44* 0.73

Periventricularleukomalacia

0.67 0.63

Retinopathy ofprematurity

1.16 1.12

* Difference between study drug and controls was statistically significant. Adapted from Lee, BH,

Stoll, BJ, McDonald, SA, et al. Pediatrics 2006; 117:1503.



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Antenatal Use of Corticosteroids in Women at Risk for Preterm Delivery

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