Antenatal Use of Corticosteroids in Women at Risk For Preterm Delivery

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Antenatal use of corticosteroids in women at risk for preterm delivery
Official reprint from UpToDate www.uptodate.com 2012 UpToDate
Antenatal use of corticosteroids in women at risk for preterm delivery Authors Men-Jean Lee, MD Debra Guinn, MD 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 steroidreceptor 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
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Section Editor Charles J Lockwood, MD
Deputy Editor Vanessa A Barss, MD
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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 0.590.73, 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:
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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
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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
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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.
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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
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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 receptorsteroid 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
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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 [81,103116]. 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 timetable [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).
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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
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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
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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.)
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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.)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972; 50:515. 2. Schutte MF, Treffers PE, Koppe JG, Breur W. The influence of betamethasone and orciprenaline on the incidence of respiratory distress syndrome in the newborn after preterm labour. Br J Obstet Gynaecol 1980; 87:127. 3. Doran TA, Swyer P, MacMurray B, et al. Results of a double-blind controlled study on the use of betamethasone in the prevention of respiratory distress syndrome. Am J Obstet Gynecol 1980; 136:313. 4. Teramo K, Hallman M, Raivio KO. Maternal glucocorticoid in unplanned premature labor. Controlled study on
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the effects of betamethasone phosphate on the phospholipids of the gastric aspirate and on the adrenal cortical function of the newborn infant. Pediatr Res 1980; 14:326. 5. Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am J Obstet Gynecol 1981; 141:276. 6. Morales WJ, Diebel ND, Lazar AJ, Zadrozny D. The effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome in preterm gestations with premature rupture of membranes. Am J Obstet Gynecol 1986; 154:591. 7. Garite TJ, Rumney PJ, Briggs GG, et al. A randomized, placebo-controlled trial of betamethasone for the prevention of respiratory distress syndrome at 24 to 28 weeks' gestation. Am J Obstet Gynecol 1992; 166:646. 8. Block MF, Kling OR, Crosby WM. Antenatal glucocorticoid therapy for the prevention of respiratory distress syndrome in the premature infant. Obstet Gynecol 1977; 50:186. 9. Taeusch HW Jr, Frigoletto F, Kitzmiller J, et al. Risk of respiratory distress syndrome after prenatal dexamethasone treatment. Pediatrics 1979; 63:64. 10. Schmidt PL, Sims ME, Strassner HT, et al. Effect of antepartum glucocorticoid administration upon neonatal respiratory distress syndrome and perinatal infection. Am J Obstet Gynecol 1984; 148:178. 11. Gamsu HR, Mullinger BM, Donnai P, Dash CH. Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicentre trial. Br J Obstet Gynaecol 1989; 96:401. 12. Kari MA, Hallman M, Eronen M, et al. Prenatal dexamethasone treatment in conjunction with rescue therapy of human surfactant: a randomized placebo-controlled multicenter study. Pediatrics 1994; 93:730. 13. Papageorgiou AN, Desgranges MF, Masson M, et al. The antenatal use of betamethasone in the prevention of respiratory distress syndrome: a controlled double-blind study. Pediatrics 1979; 63:73. 14. Morrison JC, Whybrew WD, Bucovaz ET, Schneider JM. Injection of corticosteroids into mother to prevent neonatal respiratory distress syndrome. Am J Obstet Gynecol 1978; 131:358. 15. Carlan, SJ, Parsons, M, O'Brien, WF, Krammer, J. Pharmacologic pulmonary maturation in preterm premature rupture of membranes [abstract]. Am J Obstet Gynecol 1991; 164:371. 16. Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev 2000; :CD000065. 17. Report on the Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. U.S. Department of Health and Human Services, Public Health Service, NIH Pub No. 953784, November 1994. 18. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 475: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2011; 117:422. 19. RCOG Guidelines. Number 7. ACS to prevent respiratory distress syndrome. London:RCOG 1996. 20. Smolders-de Haas H, Neuvel J, Schmand B, et al. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year followup. Pediatrics 1990; 86:65. 21. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995; 173:254. 22. Ballard PL. Hormonal regulation of surfactant in fetal life. Mead Johnson Symp Perinat Dev Med 1978; :25. 23. Walther FJ, David-Cu R, Mehta EI, et al. Higher lung antioxidant enzyme activity persists after single dose of corticosteroids in preterm lambs. Am J Physiol 1996; 271:L187. 24. Polk DH, Ikegami M, Jobe AH, et al. Preterm lung function after retreatment with antenatal betamethasone in preterm lambs. Am J Obstet Gynecol 1997; 176:308. 25. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006; :CD004454. 26. Gates S, Brocklehurst P. Decline in effectiveness of antenatal corticosteroids with time to birth: real or artefact? BMJ 2007; 335:77.
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27. Smith LM, Altamirano AK, Ervin MG, et al. Prenatal glucocorticoid exposure and postnatal adaptation in premature newborn baboons ventilated for six days. Am J Obstet Gynecol 2004; 191:1688. 28. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995; 173:322. 29. Gyamfi C, Mele L, Wapner RJ, et al. The effect of plurality and obesity on betamethasone concentrations in women at risk for preterm delivery. Am J Obstet Gynecol 2010; 203:219.e1. 30. Della Torre M, Hibbard JU, Jeong H, Fischer JH. Betamethasone in pregnancy: influence of maternal body weight and multiple gestation on pharmacokinetics. Am J Obstet Gynecol 2010; 203:254.e1. 31. Ballard PL, Gluckman PD, Liggins GC, et al. Steroid and growth hormone levels in premature infants after prenatal betamethasone therapy to prevent respiratory distress syndrome. Pediatr Res 1980; 14:122. 32. Ballard PL, Granberg P, Ballard RA. Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome. J Clin Invest 1975; 56:1548. 33. Hashima JN, Lai Y, Wapner RJ, et al. The effect of maternal body mass index on neonatal outcome in women receiving a single course of antenatal corticosteroids. Am J Obstet Gynecol 2010; 202:263.e1. 34. Moore LE, Martin JN Jr. When betamethasone and dexamethasone are unavailable: hydrocortisone. J Perinatol 2001; 21:456. 35. Jobe AH, Soll RF. Choice and dose of corticosteroid for antenatal treatments. Am J Obstet Gynecol 2004; 190:878. 36. Lee BH, Stoll BJ, McDonald SA, et al. Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics 2006; 117:1503. 37. Elimian A, Garry D, Figueroa R, et al. Antenatal betamethasone compared with dexamethasone (betacode trial): a randomized controlled trial. Obstet Gynecol 2007; 110:26. 38. Spinillo A, Viazzo F, Colleoni R, et al. Two-year infant neurodevelopmental outcome after single or multiple antenatal courses of corticosteroids to prevent complications of prematurity. Am J Obstet Gynecol 2004; 191:217. 39. Baud O, Foix-L'Helias L, Kaminski M, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999; 341:1190. 40. O'Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 1999; 104:15. 41. Reist M, Marshall KA, Jenner P, Halliwell B. Toxic effects of sulphite in combination with peroxynitrite on neuronal cells. J Neurochem 1998; 71:2431. 42. Haynes LE, Griffiths MR, Hyde RE, et al. Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: implications for mood disorders. Neuroscience 2001; 104:57. 43. Murphy BP, Inder TE, Huppi PS, et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics 2001; 107:217. 44. Lee BH, Stoll BJ, McDonald SA, et al. Neurodevelopmental outcomes of extremely low birth weight infants exposed prenatally to dexamethasone versus betamethasone. Pediatrics 2008; 121:289. 45. Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004; 350:1304. 46. Baud O, Laudenbach V, Evrard P, Gressens P. Neurotoxic effects of fluorinated glucocorticoid preparations on the developing mouse brain: role of preservatives. Pediatr Res 2001; 50:706. 47. Dani C, Vestri V, Bertini G, et al. Toxicity of corticosteroids and catecholamines for mice neuronal cell cultures: Role of preservatives. J Matern Fetal Neonatal Med 2007; 20:325. 48. Brownfoot FC, Crowther CA, Middleton P. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2008; :CD006764. 49. Onland W, de Laat MW, Mol BW, Offringa M. Effects of antenatal corticosteroids given prior to 26 weeks'
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gestation: a systematic review of randomized controlled trials. Am J Perinatol 2011; 28:33. 50. Carlo WA, McDonald SA, Fanaroff AA, et al. Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks' gestation. JAMA 2011; 306:2348. 51. Moore, KL, Persaud, TVN. The respiratory system. In: The Developing Human, 5th Ed. Philadelphia: W.B. Saunders, 1993; 226. 52. Shanks A, Gross G, Shim T, et al. Administration of steroids after 34 weeks of gestation enhances fetal lung maturity profiles. Am J Obstet Gynecol 2010; 203:47.e1. 53. Stutchfield P, Whitaker R, Russell I, Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ 2005; 331:662. 54. Porto AM, Coutinho IC, Correia JB, Amorim MM. Effectiveness of antenatal corticosteroids in reducing respiratory disorders in late preterm infants: randomised clinical trial. BMJ 2011; 342:d1696. 55. Whitelaw A, Thoresen M. Antenatal steroids and the developing brain. Arch Dis Child Fetal Neonatal Ed 2000; 83:F154. 56. Gross I, Ballard PL, Ballard RA, et al. Corticosteroid stimulation of phosphatidylcholine synthesis in cultured fetal rabbit lung: evidence for de novo protein synthesis mediated by glucocorticoid receptors. Endocrinology 1983; 112:829. 57. Ikegami M, Polk D, Jobe A. Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs. Am J Obstet Gynecol 1996; 174:1408. 58. Elimian A, Figueroa R, Spitzer AR, et al. Antenatal corticosteroids: are incomplete courses beneficial? Obstet Gynecol 2003; 102:352. 59. Subtil D, Tiberghien P, Devos P, et al. Immediate and delayed effects of antenatal corticosteroids on fetal heart rate: a randomized trial that compares betamethasone acetate and phosphate, betamethasone phosphate, and dexamethasone. Am J Obstet Gynecol 2003; 188:524. 60. Mulder EJ, Derks JB, Visser GH. Antenatal corticosteroid therapy and fetal behaviour: a randomised study of the effects of betamethasone and dexamethasone. Br J Obstet Gynaecol 1997; 104:1239. 61. Senat MV, Minoui S, Multon O, et al. Effect of dexamethasone and betamethasone on fetal heart rate variability in preterm labour: a randomised study. Br J Obstet Gynaecol 1998; 105:749. 62. Rotmensch S, Liberati M, Vishne TH, et al. The effect of betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities. A prospective randomized trial. Acta Obstet Gynecol Scand 1999; 78:493. 63. Rotmensch S, Lev S, Kovo M, et al. Effect of betamethasone administration on fetal heart rate tracing: a blinded longitudinal study. Fetal Diagn Ther 2005; 20:371. 64. Kelly MK, Schneider EP, Petrikovsky BM, Lesser ML. Effect of antenatal steroid administration on the fetal biophysical profile. J Clin Ultrasound 2000; 28:224. 65. Rotmensch S, Liberati M, Celentano C, et al. The effect of betamethasone on fetal biophysical activities and Doppler velocimetry of umbilical and middle cerebral arteries. Acta Obstet Gynecol Scand 1999; 78:768. 66. Katz M, Meizner I, Holcberg G, et al. Reduction or cessation of fetal movements after administration of steroids for enhancement of lung maturation. I. Clinical evaluation. Isr J Med Sci 1988; 24:5. 67. Schwab M, Coksaygan T, Nathanielsz PW. Betamethasone effects on ovine uterine and umbilical placental perfusion at the dose used to enhance fetal lung maturation. Am J Obstet Gynecol 2006; 194:572. 68. Derks JB, Giussani DA, Jenkins SL, et al. A comparative study of cardiovascular, endocrine and behavioural effects of betamethasone and dexamethasone administration to fetal sheep. J Physiol 1997; 499 ( Pt 1):217. 69. Koenen SV, Mecenas CA, Smith GS, et al. Effects of maternal betamethasone administration on fetal and maternal blood pressure and heart rate in the baboon at 0.7 of gestation. Am J Obstet Gynecol 2002; 186:812. 70. Smith RP, Miller SL, Igosheva N, et al. Cardiovascular and endocrine responses to cutaneous electrical stimulation after fentanyl in the ovine fetus. Am J Obstet Gynecol 2004; 190:836. 71. Miller SL, Supramaniam VG, Jenkin G, et al. Cardiovascular responses to maternal betamethasone
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administration in the intrauterine growth-restricted ovine fetus. Am J Obstet Gynecol 2009; 201:613.e1. 72. Wijnberger LD, Bilardo CM, Hecher K, et al. Effect of antenatal glucocorticoid therapy on arterial and venous blood flow velocity waveforms in severely growth-restricted fetuses. Ultrasound Obstet Gynecol 2004; 23:584. 73. Edwards A, Baker LS, Wallace EM. Changes in umbilical artery flow velocity waveforms following maternal administration of betamethasone. Placenta 2003; 24:12. 74. Robertson MC, Murila F, Tong S, et al. Predicting perinatal outcome through changes in umbilical artery Doppler studies after antenatal corticosteroids in the growth-restricted fetus. Obstet Gynecol 2009; 113:636. 75. Wallace EM, Baker LS. Effect of antenatal betamethasone administration on placental vascular resistance. Lancet 1999; 353:1404. 76. Simchen MJ, Alkazaleh F, Adamson SL, et al. The fetal cardiovascular response to antenatal steroids in severe early-onset intrauterine growth restriction. Am J Obstet Gynecol 2004; 190:296. 77. Effects of antenatal dexamethasone administration in the infant: long-term follow-up. J Pediatr 1984; 104:259. 78. Doyle LW, Kitchen WH, Ford GW, et al. Antenatal steroid therapy and 5-year outcome of extremely low birth weight infants. Obstet Gynecol 1989; 73:743. 79. MacArthur BA, Howie RN, Dezoete JA, Elkins J. School progress and cognitive development of 6-year-old children whose mothers were treated antenatally with betamethasone. Pediatrics 1982; 70:99. 80. Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of antenatal corticosteroid treatment. Pediatrics 2000; 105:E77. 81. Dalziel SR, Walker NK, Parag V, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 2005; 365:1856. 82. Dalziel SR, Lim VK, Lambert A, et al. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial. BMJ 2005; 331:665. 83. Kelly BA, Lewandowski AJ, Worton SA, et al. Antenatal glucocorticoid exposure and long-term alterations in aortic function and glucose metabolism. Pediatrics 2012; 129:e1282. 84. Stubblefield PG. Pulmonary edema occurring after therapy with dexamethasone and terbutaline for premature labor: a case report. Am J Obstet Gynecol 1978; 132:341. 85. Ogburn PL Jr, Julian TM, Williams PP, Thompson TR. The use of magnesium sulfate for tocolysis in preterm labor complicated by twin gestation and betamimetic-induced pulmonary edema. Acta Obstet Gynecol Scand 1986; 65:793. 86. Ogunyemi D. Risk factors for acute pulmonary edema in preterm delivery. Eur J Obstet Gynecol Reprod Biol 2007; 133:143. 87. Amorim MM, Santos LC, Fandes A. Corticosteroid therapy for prevention of respiratory distress syndrome in severe preeclampsia. Am J Obstet Gynecol 1999; 180:1283. 88. Fisher JE, Smith RS, Lagrandeur R, Lorenz RP. Gestational diabetes mellitus in women receiving betaadrenergics and corticosteroids for threatened preterm delivery. Obstet Gynecol 1997; 90:880. 89. Bedalov A, Balasubramanyam A. Glucocorticoid-induced ketoacidosis in gestational diabetes: sequela of the acute treatment of preterm labor. A case report. Diabetes Care 1997; 20:922. 90. Mastrobattista JM, Patel N, Monga M. Betamethasone alteration of the one-hour glucose challenge test in pregnancy. J Reprod Med 2001; 46:83. 91. Gurbuz A, Karateke A, Ozturk G, Kabaca C. Is 1-hour glucose screening test reliable after a short-term administration of antenatal betamethasone? Am J Perinatol 2004; 21:415. 92. Vaisbuch E, Levy R, Hagay Z. The effect of betamethasone administration to pregnant women on maternal serum indicators of infection. J Perinat Med 2002; 30:287. 93. Kadanali S, Inge M, Kkzkan T, et al. Changes in leukocyte, granulocyte and lymphocyte counts following antenatal betamethasone administration to pregnant women. Int J Gynaecol Obstet 1997; 58:269. 94. Ballard, PL. Hormones and lung maturation. In: Monographs on endocrinology, Vol 28. Berlin: SpringerVerlag, 1986; 1-345. 95. Howie, RN, Liggins, GC: The New Zealand study of antepartum glucocorticoid treatment. In: Farrell, PM, (Ed)
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Lung development: biological and clinical perspectives, Vol 2. New York: Academic Press, 1982; 255. 96. Ballard PL, Ballard RA. Glucocorticoid receptors and the role of glucocorticoids in fetal lung development. Proc Natl Acad Sci U S A 1972; 69:2668. 97. Oakley RH, Cidlowski JA. Homologous down regulation of the glucocorticoid receptor: the molecular machinery. Crit Rev Eukaryot Gene Expr 1993; 3:63. 98. Khandelwal M, Chang E, Hansen C, et al. Betamethasone dosing interval: 12 or 24 hours apart? A randomized, noninferiority open trial. Am J Obstet Gynecol 2012; 206:201.e1. 99. Egerman RS, Mercer BM, Doss JL, Sibai BM. A randomized, controlled trial of oral and intramuscular dexamethasone in the prevention of neonatal respiratory distress syndrome. Am J Obstet Gynecol 1998; 179:1120. 100. McLaughlin KJ, Crowther CA, Walker N, Harding JE. Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Aust N Z J Obstet Gynaecol 2003; 43:101. 101. Vidaeff AC, Ramin SM, Gilstrap LC 3rd, Alcorn JL. In vitro quantification of dexamethasone-induced surfactant protein B expression in human lung cells. J Matern Fetal Neonatal Med 2004; 15:155. 102. Bunton TE, Plopper CG. Triamcinolone-induced structural alterations in the development of the lung of the fetal rhesus macaque. Am J Obstet Gynecol 1984; 148:203. 103. Antenatal Corticosteroids Revisited: Repeat Courses. NIH Consensus Statement. August 17-18, 2000. 104. Walfisch A, Hallak M, Mazor M. Multiple courses of antenatal steroids: risks and benefits. Obstet Gynecol 2001; 98:491. 105. Thorp JA, Jones PG, Knox E, Clark RH. Does antenatal corticosteroid therapy affect birth weight and head circumference? Obstet Gynecol 2002; 99:101. 106. Kumar P, Seshadri R. Neonatal morbidity and growth in very low birth-weight infants after multiple courses of antenatal steroids. J Perinatol 2005; 25:698. 107. Vermillion ST, Soper DE, Newman RB. Neonatal sepsis and death after multiple courses of antenatal betamethasone therapy. Am J Obstet Gynecol 2000; 183:810. 108. Banks BA, Cnaan A, Morgan MA, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group. Am J Obstet Gynecol 1999; 181:709. 109. Smith LM, Qureshi N, Chao CR. Effects of single and multiple courses of antenatal glucocorticoids in preterm newborns less than 30 weeks' gestation. J Matern Fetal Med 2000; 9:131. 110. Rotmensch S, Vishne TH, Celentano C, et al. Maternal infectious morbidity following multiple courses of betamethasone. J Infect 1999; 39:49. 111. French NP, Hagan R, Evans SF, et al. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999; 180:114. 112. French NP, Hagan R, Evans SF, et al. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004; 190:588. 113. Esplin, MS, Fausett, MB, Smith, S, et al. Multiple courses of antenatal steroids are associated with a delay in long-term psychomotor development in children with birth weights <1500 grams. Am J Obstet Gynecol 2000; 182:S24. 114. Davis EP, Townsend EL, Gunnar MR, et al. Effects of prenatal betamethasone exposure on regulation of stress physiology in healthy premature infants. Psychoneuroendocrinology 2004; 29:1028. 115. Glover V, Miles R, Matta S, et al. Glucocorticoid exposure in preterm babies predicts saliva cortisol response to immunization at 4 months. Pediatr Res 2005; 58:1233. 116. Norberg H, Stlnacke J, Heijtz RD, et al. Antenatal corticosteroids for preterm birth: dose-dependent reduction in birthweight, length and head circumference. Acta Paediatr 2011; 100:364. 117. Aghajafari F, Murphy K, Matthews S, et al. Repeated doses of antenatal corticosteroids in animals: a systematic review. Am J Obstet Gynecol 2002; 186:843. 118. Stonestreet BS, Watkins S, Petersson KH, Sadowska GB. Effects of multiple courses of antenatal
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corticosteroids on regional brain and somatic tissue water content in ovine fetuses. J Soc Gynecol Investig 2004; 11:166. 119. Moss TJ, Doherty DA, Nitsos I, et al. Effects into adulthood of single or repeated antenatal corticosteroids in sheep. Am J Obstet Gynecol 2005; 192:146. 120. de Vries A, Holmes MC, Heijnis A, et al. Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function. J Clin Invest 2007; 117:1058. 121. Ashwood PJ, Crowther CA, Willson KJ, et al. Neonatal adrenal function after repeat dose prenatal corticosteroids: a randomized controlled trial. Am J Obstet Gynecol 2006; 194:861. 122. Battin MR, Bevan C, Harding JE. Repeat doses of antenatal steroids and hypothalamic-pituitary-adrenal axis (HPA) function. Am J Obstet Gynecol 2007; 197:40.e1. 123. Schffer L, Luzi F, Burkhardt T, et al. Antenatal betamethasone administration alters stress physiology in healthy neonates. Obstet Gynecol 2009; 113:1082. 124. Fonseca L, Ramin SM, Mele L, et al. Bone metabolism in fetuses of pregnant women exposed to single and multiple courses of corticosteroids. Obstet Gynecol 2009; 114:38. 125. Wapner RJ, Sorokin Y, Thom EA, et al. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol 2006; 195:633. 126. Guinn DA, Atkinson MW, Sullivan L, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: A randomized controlled trial. JAMA 2001; 286:1581. 127. Crowther CA, Haslam RR, Hiller JE, et al. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006; 367:1913. 128. Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database Syst Rev 2007; :CD003935. 129. Sawady J, Mercer BM, Wapner RJ, et al. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Beneficial Effects of Antenatal Repeated Steroids study: impact of repeated doses of antenatal corticosteroids on placental growth and histologic findings. Am J Obstet Gynecol 2007; 197:281.e1. 130. Wapner RJ, Sorokin Y, Mele L, et al. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007; 357:1190. 131. Crowther CA, Doyle LW, Haslam RR, et al. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 2007; 357:1179. 132. Murphy KE, Hannah ME, Willan AR, et al. Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 2008; 372:2143. 133. Stiles AD. Prenatal corticosteroids--early gain, long-term questions. N Engl J Med 2007; 357:1248. 134. Peltoniemi OM, Kari MA, Tammela O, et al. Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth. Pediatrics 2007; 119:290. 135. Garite TJ, Kurtzman J, Maurel K, et al. Impact of a 'rescue course' of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009; 200:248.e1. 136. McEvoy C, Schilling D, Peters D, et al. Respiratory compliance in preterm infants after a single rescue course of antenatal steroids: a randomized controlled trial. Am J Obstet Gynecol 2010; 202:544.e1. 137. Spellacy WN, Buhi WC, Riggall FC, Holsinger KL. Human amniotic fluid lecithin-sphingomyelin ratio changes with estrogen or glucocorticoid treatment. Am J Obstet Gynecol 1973; 115:216. 138. Piazze JJ, Maranghi L, Nigro G, et al. The effect of glucocorticoid therapy on fetal lung maturity indices in hypertensive pregnancies. Obstet Gynecol 1998; 92:220. 139. Farrell PM, Engle MJ, Zachman RD, et al. Amniotic fluid phospholipids after maternal administration of dexamethasone. Am J Obstet Gynecol 1983; 145:484. 140. Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm rupture of membranes? Am J Obstet Gynecol 2001; 184:131.
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141. Lee MJ, Davies J, Guinn D, et al. Single versus weekly courses of antenatal corticosteroids in preterm premature rupture of membranes. Obstet Gynecol 2004; 103:274. 142. Andrews EB, Marcucci G, White A, Long W. Associations between use of antenatal corticosteroids and neonatal outcomes within the Exosurf Neonatal Treatment Investigational New Drug Program. Am J Obstet Gynecol 1995; 173:290. Topic 6796 Version 14.0
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GRAPHICS
Recommendations for use of antenatal corticosteroids
The benefits of antenatal administration of corticosteroids to fetuses at risk of preterm delivery vastly outweigh the potential risks. These benefits include not only a reduction in the 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 be considered candidates for antenatal treatment with corticosteroids. The decision to use antenatal corticosteroids should not be altered by fetal race or gender or by the availability of surfactant replacement therapy. Patients eligible for therapy with tocolytics should also be eligible for treatment with antenatal corticosteroids. Treatment consists of two doses of 12 mg of betamethasone given intramuscularly 24 hours apart or four doses of 6 mg of dexamethasone given intramuscularly 12 hours apart. Optimal benefit begins 24 hours after initiation of therapy and lasts seven days. Because treatment with corticosteroids for less than 24 hours is still associated with significant reductions in neonatal mortality, RDS, and IVH, antenatal corticosteroids should be given unless immediate delivery is anticipated. In premature rupture of membranes at less than 30 to 32 weeks of gestation in the absence of clinical chorioamnionitis, antenatal corticosteroid use is recommended because of the high risk of IVH at these early gestational ages. In complicated pregnancies where delivery prior to 34 weeks of gestation is likely, antenatal corticosteroid use is recommended unless there is evidence that corticosteroids will have an adverse 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.
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Model for glucocorticoid action
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Relative risk of selected adverse outcomes

Outcome
Respiratory distress syndrome Intraventricular hemorrhage Perinatal infection Neonatal death Stillbirth Maternal infection
Betamethasone versus control

0.57* 0.27* 0.72 0.47* 0.80 1.33
Dexamethasone versus control

0.70* 0.60* 0.99 0.84 0.95 1.17
* Difference between study drug and controls was statistically significant. Adapted from: Jobe, AH, Soll, RF. Am J Obstet Gynecol 2004; 190:878.
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Odds ratio of selected adverse outcomes

Outcome
Intraventricular hemorrhage Neonatal death Periventricular leukomalacia Retinopathy of prematurity
Betamethasone versus control

0.63* 0.44* 0.67 1.16
Dexamethasone versus control

0.76* 0.73 0.63 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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Antenatal Use of Corticosteroids in Women at Risk For Preterm Delivery

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Antenatal use of corticosteroids in women at risk for preterm delivery

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Section Editor Charles J Lockwood, MD

Deputy Editor Vanessa A Barss, MD

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Antenatal use of corticosteroids in women at risk for preterm delivery

Model for glucocorticoid action

Antenatal use of corticosteroids in women at risk for preterm delivery

Relative risk of selected adverse outcomes

Betamethasone versus control

Dexamethasone versus control

Antenatal use of corticosteroids in women at risk for preterm delivery

Odds ratio of selected adverse outcomes

Betamethasone versus control

Dexamethasone versus control

Antenatal use of corticosteroids in women at risk for preterm delivery

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