Antenatal corticosteroids for fetal maturation in women at risk for preterm delivery

Clin Perinatol 30 (2003) 825 – 840

Antenatal corticosteroids for fetal maturation in women at risk for preterm delivery Alex C. Vidaeff, MD, MPHa,*, Nora M. Doyle, MD, MPHb, Larry C. Gilstrap III, MDc a

Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Medical School at Houston, The University of Texas Medical School at Houston, 6431 Fannin St., Suite 3.604 Houston, TX 77030, USA b Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Medical School at Houston, 6431 Fannin St., Suite 3.604 Houston, TX 77030, USA c Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Medical School at Houston, 6431 Fannin St., Suite 3.604 Houston, TX 77030, USA

The obstetric literature is replete with publications that support the beneficial role of antenatal corticosteroid therapy for fetal maturation. [1 –8] Although there is little question that antenatal corticosteroid therapy decreases the risk of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and neonatal mortality, there are several questions that are still incompletely addressed, especially with regards to corticosteroids use in women with preterm premature rupture of membranes (PPROM), the optimal corticosteroid preparation to be used, and the advisability of repeat or rescue courses. These unresolved aspects are discussed in this review.

Short-term and long-term fetal effects of antenatal corticosteroids The effects of corticosteroids are mediated by way of intracellular corticosteroid receptors or corticosteroid-induced paracrine effects between cells. Corticosteroids have been shown to stimulate cytodifferentiation in fetal lungs and at least 14 other tissues [9]. Their maturational effects are multiple, biochemical and structural, and, in addition, corticosteroids have the potential to induce metabolic and physiologic changes, immune response modulations, and behavioral modifications. Concern * Corresponding author. E-mail address: [email protected] (A.C. Vidaeff). 0095-5108/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0095-5108(03)00102-7

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has been expressed that besides the immediate beneficial effects on preventing prematurity-related complications, corticosteroids might also have short- and longterm adverse effects on the fetus and newborn. There are few, if any known adverse short-term effects to either mother or fetus from the administration of a single course of antenatal corticosteroids for fetal maturation. On the contrary, the results of numerous randomized clinical trials unequivocally support the beneficial short-term neonatal effects of antenatal corticosteroid administration in women at risk for preterm delivery (24 to 34 weeks gestation) [1,10,11]. Short-term neonatal benefits of maternal administration of antenatal corticosteroids include a decrease in the frequency of RDS, IVH, and neonatal mortality. Finally, there may be a decrease in the frequency of periventricular leukomalacia with the antenatal use of betamethasone (BTM) [6,12]. It seems reasonable to conclude that, presently, the majority of eligible women with threatened preterm labor receive antenatal corticosteroids for fetal maturation [13]. Surveys from different countries report a 92% to 97% usage rate [14 – 16]. There are currently no categorical data indicating long-term adverse effects of single-course antenatal corticosteroid therapy. No adverse effects in neurodevelopment were found in children up to 12 years of age who had been exposed to antenatal corticosteroids in the Amsterdam trial [17]. In a follow-up study of children at age 14 whose mothers had received antenatal corticosteroids, Doyle and associates [18] reported no adverse effects on growth, pulmonary, or cognitive function, however, adverse effects from multiple courses of antenatal corticosteroids may theoretically occur. There are no reliable data on the long-term developmental effects of repetitive or prolonged antenatal corticosteroid exposures in humans, and further studies are needed in this area. Addressing the concern about the benefit or risk ratio in relation to the prescription of repeat courses of corticosteroids is crucial for the future of antenatal corticosteroids use for fetal maturation.

Preterm premature rupture of membranes Preterm premature rupture of membranes (PPROM) occurs in 3% of pregnancies and is responsible for approximately one third of all preterm births. [19] Thus, PPROM is an important cause of perinatal morbidity and mortality. Even with conservative management, 50% to 60% of women with PPROM will deliver within 1 week of membrane rupture. [19] Neonatal outcomes are dependent on gestational age at rupture and at delivery. For very premature infants, the risks of prematurity would seem to outweigh the risk for infection, and the optimal management relies on balancing the risks of prematurity versus the risks for maternal or fetal infection. Corticosteroids and antibiotic treatment are two effective interventions in the presence of PPROM, although the use of the first one has stimulated a prolonged debate. In 1994, an obstetric committee opinion from the American College of Obstetricians and Gynecologists (ACOG) [20] endorsed every recommendation of

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the 1994 National Institutes of Health (NIH) consensus conference [8] except the recommendation to administer corticosteroids for women with PPROM from 24 to 32 weeks’ gestation. There has been conflicting evidence of the efficacy of corticosteroids in preventing RDS in women with PPROM, especially in the very low birth weight group, with concerns of infection further compounding the controversy. Based on retrospective data, Arias and associates [21] supported the view that steroids, tocolysis, and prolongation of the latent phase are beneficial to patients with PPROM, but only when the birth weight is between 751 and 1000 g or the gestational age is 27 to 28 weeks. Chapman and associates [22], in a prospective, observational study reported no benefits of maternal corticosteroid therapy in infants weighing less than 1000 g born after PPROM. Although Van Dorsten and associates [23] reported in 1985 a 3-year institutional experience indicating that antenatal corticosteroids influenced neither maternal nor neonatal infection, other results published in the early 1980s raised concerns about a possibly increased risk of maternal and neonatal infection [24 – 26]. At the 1994 NIH Consensus Conference it was recommended that corticosteroids be given, for women with PPROM between 24 and 32 weeks’ gestation, based on data presented that corticosteroids lower the incidence of IVH in very preterm infants regardless of the membrane status of the mother [8,27]. The recommendation was based on the conclusion that the potential risk for increased neonatal infection was balanced by the benefits of reduced mortality and IVH rates among treated infants. Gardner and colleagues [28] subsequently supported this conclusion with a formal decision analysis. In her 1995 meta-analysis, Crowley [7] also examined infections reported from four randomized trials that studied antenatal corticosteroid use in women with PPROM. The author found a significant reduction in the incidence of RDS in treated infants (OR = 0.44; 95% CI, 0.32 –0.60), whereas no statistically significant effect on neonatal infection was noted; the odds ratio being 0.82, with the 95% confidence interval 0.42 to 1.60. More recently, Vermillion and associates [29] reported their findings of 159 women with singleton pregnancies who were given a single antenatal course of betamethasone and delivered between 24 and 32 weeks’ gestation after PPROM. After controlling for gestational age, birth weight, chorioamnionitis, and earlyonset neonatal sepsis, they confirmed that a single course of BTM was independently associated with large and statistically significant reductions in the likelihoods of neonatal RDS (OR = 0.16; 95%CI, 0.1 – 0.4) and grade III/IV intraventricular hemorrhage (OR = 0.18; 95%CI, 0.1– 0.4) and found no difference in the frequency of perinatal infectious outcomes or neonatal death. Some of the studies mentioned earlier were conducted at a time when administration of antibiotics for group B streptococcus prophylaxis or for prolongation of the latency period was not routine practice. In the Dexiprom Study [30], a multicenter randomized trial conducted in South Africa, antibiotics were administered concomitantly with dexamethasone (DXM) in 102 pregnancies. A trend toward an improved perinatal outcome was demonstrated in the women who received antibiotics and DXM, compared with the women receiving antibiotics and placebo.

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The trend became significant with a subanalysis of mothers who delivered more than 24 hours after enrollment. More importantly, there was no increased infection rate in the mothers and infants exposed to DXM. These findings reconfirm the safety of corticosteroids administered in combination with antibiotics in women with PPROM. In 2001, Harding and associates [31] reported on patients with PPROM in a new meta-analysis combining data from 15 controlled trials, including the original Liggins and Howie study [1]. Their meta-analysis, involving more than 1400 women with rupture of membranes, confirmed that corticosteroids reduce by about half the risks of respiratory distress syndrome (RR = 0.56; 95% CI, 0.46– 0.70) and intraventricular hemorrhage (RR = 0.47; 95% CI 0.31 – 0.70). The apparent, one-third reduction in neonatal death rate did not reach statistical significance (RR = 0.68; 95% CI, 0.43 – 1.07). Corticosteroids did not seem to increase the risk for infection in either mother (RR = 0.86; 95% CI, 0.61 – 1.20) or baby (RR = 1.05; 95% CI, 0.66 – 1.68). The investigators further noted that the duration of rupture of membranes did not alter the outcomes. They concluded that available data would indicate that corticosteroid administration is beneficial in the setting of rupture of membranes. There is some new evidence, in experimental studies [32] and clinical studies, [33] that the inflammation associated with PPROM would enhance fetal lung maturation independently of corticosteroids, and that corticosteroid treatments may actually have an additive effect. Newnham and associates [34] demonstrated that simultaneous administration of intra-amniotic endotoxin and maternal corticosteroids to sheep resulted in better lung maturation than did administration of maternal corticosteroids alone. Antenatal corticosteroids may modulate the fetal exposure to inflammation without increasing the risk of infection [35]. Shimoya and associates [36] found that infants born to women with chorioamnionitis had increased interleukin-8 (IL-8) plasma levels, and antenatal corticosteroids suppressed the plasma IL-8 levels in the newborns almost to control levels. Elimian and associates [37], in a retrospective study of 1260 newborns weighing less than 1750 g, found that major adverse outcomes and death were decreased in those infants exposed to histologic chorioamnionitis and also treated with corticosteroids. Consistent with this observation, it has also been reported that two factors predict increased survival in infants born before 26 weeks’ gestation: exposure to antenatal corticosteroids (OR = 0.51) and chorioamnionitis (OR = 0.57). [38]

Betamethasone versus dexamethasone The two most widely used corticosteroid preparations for fetal maturation in humans are BTM and DXM. Both are synthetic, fluorinated steroids. The fluorine substitution in the steroid molecule greatly increases the glucocorticoid potency and minimizes the mineralocorticoid and immunosuppressive effects. Another synthetic fluorinated corticosteroid, triamcinolone, although used in experimental animals, [39] has never been studied for fetal maturation in humans, probably

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because of its increased teratogenic potential observed in nonhuman primates and other species [40]. Since 1972, when Liggins and Howie [1] published their pioneering study on antenatal corticosteroids, different regimens have been used with both BTM and DXM, although with very little variation in the total dose of corticosteroid administered per course (20 to 24 mg). This total dose achieves an almost total occupancy of corticosteroid receptors in fetal tissues. In the United States, the currently recommended regimens for intramuscular administration are either two 12 mg doses of BTM given 24 hours apart, or four 6 mg doses of DXM given 12 hours apart. [8] Although the US Collaborative Multicenter Trial, published in 1981, was conducted using DXM, [10] the preparation that was subsequently widely adopted in clinical practice in the United States was BTM, possibly reflecting the more convenient administration schedule. Over the last several years, because of availability issues, many institutions have witnessed a switch from BTM to DXM. Although the literature provides ample evidence of efficacy for both preparations, questions have recently been raised about the ideal form of corticosteroid to be used in clinical practice. Ultimately, the choice of one preparation over another will be based on a careful analysis of efficacy, potency, cost, convenience, side effects, and safety. BTM and DXM are diastereoisomers, the only structural difference between them being the orientation of a methyl group on position C16 (a configuration for DXM, and b configuration for BTM). With such minimal structural difference, their pharmacokinetics are similar. They both cross the placenta largely in biologically active form, have an approximate plasma half-life of 3 to 5 hours, a long biologic half-life of 36 to 54 hours, and similar binding to plasma proteins (78% to 88%). [41] Some minor differences have been reported, such as lower peak levels, but a longer time of biologic activity with DXM, [42] and a more rapid DXM passage through the blood-brain barrier. [41] Reporting on the relative potency of the two agents may be confusing, because there are different measures of potency. Using receptor binding activity as a measure of potency reveals no significant differences between BTM and DXM in binding affinity to human or animal corticosteroid receptors. After binding to the corticosteroid receptor, the hormones increase or inhibit gene expression through transactivation or transrepression. These are the so-called nuclear, receptor-dependent genomic effects, and their measurement may be another indicator of potency. The genomic effects start to be noticeable at about 30 minutes after receptor binding. [43] In a study comparing the relative transactivation potency by gene expression assay in different cell lines, Jaffuel and associates [44] found no significant differences between BTM and DXM. The same conclusion was reached by Tanigawa and colleagues [45] using a reporter assay in CV-1 cells transfected with either human or rat corticosteroid receptors. Corticosteroids also induce nongenomic effects, which are further subclassified as specific and unspecific nongenomic effects [46]. The nongenomic effects are observed at higher hormone concentrations, within seconds or minutes from exposure. The specific effects are mediated by steroid membrane receptors, whereas the

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unspecific ones result from direct physico-chemical interactions with cellular membranes. Buttgereit and associates demonstrated in vitro that the relative potency of DXM is higher than that of BTM for unspecific nongenomic effects. [43] The same investigators suggest that the unspecific nongenomic effects are of greater clinical relevance when higher doses are used. According to them, low doses produce exclusively classic genomic effects, whereas, as the dose increases, additional nongenomic effects become evident. One such unspecific nongenomic effect seems to be the effect on cellular energy metabolism. Corticosteroids have been shown to inhibit concanavalin A-stimulated cellular respiration, and ATPconsuming processes. DXM was found to be at least 7 times more potent than BTM in this effect [47]. It follows that, when talking about potency, it is important to differentiate between genomic and nongenomic effects, because the relative potency of any given corticosteroid may be different when genomic or nongenomic effects are considered. In the clinical context of antenatal corticosteroid administration, the fetal maturational effects targeted by relatively brief exposures to corticosteroids are most likely genomic effects, with BTM and DXM appearing to have similar potency. With increased doses, or a more prolonged exposure, the nongenomic effects may become relevant, and the increased potency of DXM for nongenomic effects might translate into undesired effects, rather than a therapeutic advantage. With repetitive doses of corticosteroids in mice, there was a greater reduction in lung and liver weight with DXM than BTM. [48] The growth restriction that can be observed in different tissues with corticosteroid therapy is thought to be related to apoptosis, inhibition of mitosis, and interference with cellular metabolism. [49] These effects may be the expression of a dissociation between transactivation and transrepression and, at least in part, may also be nongenomically induced in a dosedependent manner. Several animal experiments suggesting neurotoxicity secondary to DXM have generated justifiable concern. Rayburn and associates [50] compared the effect of a single dose of BTM 0.1 mg/Kg, DXM 0.1 mg/Kg, and placebo at 74% of gestation in mice. Mature offspring exposed to BTM demonstrated enhanced memory compared with placebo, whereas DXM exposed offspring had decreased memory. Data specific to human studies are still limited. Follow-up clinical studies have yielded conflicting results when BTM and DXM were compared with no treatment, rather than being compared head-to-head. Children exposed to BTM in the original Liggins and Howie trial scored lower than untreated controls on Raven’s progressive matrices and visual memory [51], whereas in the US Collaborative Multicenter Trial, DXM appeared to have a protective effect (fewer children were neurologically abnormal at follow-up in the treated group than in untreated controls) [52]. The first human study comparing BTM to DXM and untreated controls was reported by Baud and associates [12] in 1999. In a retrospective multicenter cohort of very premature infants, they noted that both betamethasone and dexamethasone decreased the incidence of RDS, IVH, and necrotizing enterocolitis. However, prenatal BTM exposure was associated with a reduced incidence of periventricular leukomalacia (PVL) (4.4% versus 8.4% in untreated controls), whereas DXM was

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associated with an increased incidence of PVL (10.9% versus 8.4% in controls). After adjustment by multivariate analysis, the odds ratio for cystic PVL was 0.5 (0.3 –0.9) for the BTM group and 1.5 (0.8 –2.9) in the DXM group. These findings are consistent with the reported decreased risk of PVL noted only with BTM in a Cochrane database meta-analysis [53], and with reports of increased neurologic impairment in preterm infants exposed to DXM after birth as prophylaxis or treatment for bronchopulmonary dysplasia [54,55]. When Baud and associates studied both in vitro and in vivo the neurotoxic effects of DXM on mouse brain, they observed that the undesired effects are obtained only when a commercial preparation of injectable DXM is used, not with pure, laboratory stock DXM [56]. They concluded that the neurotoxic effects may not be linked to the corticosteroid itself, but rather the sulfites present as preservatives in the commercial preparation. There is previous evidence that sulfites may be neurotoxic, especially when oxygen radicals are present, such as in conditions of inflammation or ischemia [57]. The findings of Baud and associates are very intriguing and, if replicated by others, might serve to explain the apparent discrepancy between human observational data suggesting a deleterious effect of DXM, and laboratory experiments in which DXM exhibited a similar protective effect with BTM on mouse neonatal brain exposed to excitotoxic ischemic injury [58]. In the latter experiments pure DXM was used, without preservatives. The issue of therapeutic efficacy targeting fetal maturation is another important consideration when BTM is compared with DXM. In Crowley’s Cochrane database meta-analysis, both BTM and DXM similarly reduced the incidence of RDS, but only BTM reduced mortality in a statistically significant degree. [53] In a mouse model, BTM was recently found to be more efficacious than DXM in accelerating fetal lung maturation, with less reduction in fetal growth, even with repeat administrations. [48] The efficacy of a specific therapeutic action, in the authors’ case acceleration of fetal maturation, is not always the corollary of drug potency. There is always the possibility of ‘‘too much of a good thing’’, and the targeted genomic effects may be seconded by undesired nongenomic effects based on dose and individual drug characteristics, as hypothesized by Buttgereit and associates. [43] Although, in view of the increased efficacy of BTM in experimental and clinical trials and the evidence of increased risks with DXM, it may be reasonable to prefer when possible BTM over DXM, the current recommendations from the NIH endorse either BTM or DXM.

Single versus multiple courses of corticosteroid Although the benefit of a single course of antenatal corticosteroids for the prevention of prematurity-related complications is indisputable, several concerns limit chronic treatment with these drugs. The validity of these concerns is still incompletely addressed by the experimental and clinical literature. The basis for a repetitive exposure to antenatal corticosteroids is the widely accepted concept of a 7-day limit in corticosteroids effect. Crowley’s meta-analysis of randomized

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clinical trials between 1972 and 1994 concluded that the optimal treatment-todelivery interval is 24 hours to 7 days. [7] Several animal studies also indicated a corticosteroid action limited to approximately 1 week [59,60], and the same conclusion can be derived from human in vitro data [61]. The putative side effects of repeated dosing have been emphasized by several studies over the last 30 years. In different animal models (rodents, rabbit, sheep, and primates) worrisome observations have been made, especially interference with fetal growth (body growth, head growth, or individual organs growth) and neurodevelopmental deficits [3,35]. The retrospective reports from human studies are varied. French and associates [62] reported that two or more courses of antenatal corticosteroids decreased birth weight, head circumference, and body length without decreasing the incidence of RDS more than a single course. The risk of severe chronic lung disease was also increased. While they reported no increase in the incidence of cerebral palsy or overall disabilities in the infants treated with repeated courses, they did note an increased incidence of behavioral abnormalities. Banks and colleagues [63] reported lower birth weights for infants exposed to two or more courses of antenatal corticosteroids, and an increased mortality rate when three or more courses were given. Bloom and associates [64] also reported decrease in birth weight among the infants treated with multiple antenatal corticosteroid courses. In contrast, Vermillion and colleagues [65] found that repeated courses of corticosteroids were not associated with a decrease in birth weight or a further decrease in incidence of RDS and IVH relative to a single course of corticosteroids. However, they did report an increased risk of infectious complications—chorioamnionitis, endometritis, early neonatal sepsis, and sepsis-associated neonatal death—with repeated courses of corticosteroids. Not all reports of multiple corticosteroid courses are negative. Abbasi and associates [66] found repeated courses of antenatal corticosteroids to decrease the incidence of RDS and patent ductus arteriosus, with no concomitant increase in mortality or other morbidity. Thorp and colleagues [67], in contrast to many other investigators, found repeated courses of corticosteroids to be associated with increased birth weight. In their study, there was no association between repeated doses and maternal or neonatal infections or death. Such conflicting reports may be explained by the retrospective nature of data and the systematic bias frequently inherent to retrospective studies. Guinn and associates [68] were the first to report results from a randomized, double-blind, placebo-controlled, intention-to-treat trial. In this US, multicenter trial including 13 institutions and 502 pregnant women, they found that weekly doses of antenatal corticosteroids did not significantly reduce composite neonatal morbidity, duration of hospital stay, or mortality compared with a single course of treatment. The investigators concluded that weekly regimens should not be routinely prescribed for women at risk for preterm delivery. Until recently, there had been three other ongoing randomized studies, expected to be completed in 2004, comparing single and multiple courses of antenatal corticosteroids. The trial sponsored by the NIH Maternal Fetal Medicine Units

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Network, started in March 2000, was scheduled to include 2400 women. The Multiple Antenatal Corticosteroid Study (MACS), funded by the Canadian Health Research Institute and launched in 2001, is intended to report on 1900 American and Canadian women. Finally, the Trial of the Effects of Antenatal Multiple Courses of Steroids (TEAMS), organized by England’s National Perinatal Epidemiology Unit, will enroll 4000 women [69]. Unfortunately, the trial sponsored by the NIH Maternal Fetal Medicine Units Network was prematurely stopped because of problems with enrollment. The other trials are still in progress at the time of this writing. The primary outcome measures of these studies are mainly reflective of short-term effects. There is now growing evidence from experimental studies that fetal exposure to excess corticosteroids at critical stages of development may have lifelong effects. Therefore, it is hoped that provisions have been made in all these studies for the long term follow-up of as many as possible exposed children. According to the Barker hypothesis of intrauterine programming, the reduced birthweight caused by corticosteroids may be a determinant of subsequent adult chronic morbidity. [70] The intrauterine exposure to increased levels of corticosteroids may also permanently program the fetus for elevated endogenous glucocorticoids levels, known risk factor for adult pathology and inappropriate reactivity to stressful stimuli [71]. Corticosteroids exercise direct genomic and nongenomic effects on the fetal tissues. The genomic effects are probably relevant in accelerating the maturation of different fetal organs, although they can also play a role in inducing apoptosis or transrepression. Arguments have been made that prolonged or repetitive exposure can increase the relative contribution of nongenomic effects, enhancing the risk for iatrogenic harm. Besides the direct genomic and nongenomic actions, an effect of corticosteroids on the placenta with indirect impairment of the fetus was theorized over 25 years ago. [72] Recent evidence can be invoked in support of this classic theory. Direct administration of a weight-adjusted dose of BTM to the ovine fetus did not cause fetal growth restriction after single or repetitive courses, in contrast to the maternal (transplacental) administration. [73] Such a result was obtained despite higher plasma corticosteroid levels after direct fetal administration. It seems that after direct fetal administration, fetal lung maturational effects are separated from fetal growth effects. It can be speculated that the fetal growth depressor effect observed with maternal administration denotes the cointervention of a placental factor or event. Benediktsson and associates [74] have reported that maternal exposure to exogenous corticosteroids decreases the activity of placental 11b-hydroxysteroid dehydrogenase type 2, an action that may allow increased passage of potent endogenous maternal glucocorticoids to the fetus. Thus, exogenous corticosteroid administration may inhibit the natural, protective placental barrier to glucocorticoids. An independent role of the placenta as an intermediary in corticosteroid action can also be inferred from experiments demonstrating differential effects of natural and synthetic corticosteroids in inducing labor in sheep, possibly through their actions on placental cytochrome 17 a-hydroxylase. [75] Thus, possible benefits from repetitive dosing must be weighed against increased risks of adverse effects.

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NIH Consensus Conference 1994 The National Institutes of Health sponsored it’s first of two conferences on the fetal effects of antenatal corticosteroids in 1994 [8]. The consensus panel from the first conference (‘‘Effects of corticosteroids for fetal maturation on perinatal outcomes’’) concluded that antenatal corticosteroids decreased the risk of RDS, IVH, and mortality in preterm infants born at a gestational age of 24 to 34 weeks. They also concluded that the benefits of antenatal corticosteroid use in pregnancies at risk for preterm birth outweigh any possible risks. These benefits were not affected by either gender or race. The use of corticosteroids was recommended regardless of the availability of exogenous surfactant therapy. The regimens recommended by the consensus conference are 12 mg of BTM intramuscularly for two doses, 24 hours apart, or 6 mg of DXM intramuscularly every 12 hours for four doses. The panel further noted that the ‘‘optimal benefit of antenatal corticosteroids lasted 7 days, and that the potential risks and benefits of repeat courses of antenatal corticosteroids greater than 7 days after the initial course were unknown.’’ This latter point was identified as an area of needed research to ‘‘guide clinical care.’’ The panel concluded by recommending that all women at risk for preterm delivery at 24 to 34 weeks gestational age should receive antenatal corticosteroids for fetal maturation, unless there are contraindications to their administration. The major recommendations of the 1994 NIH Consensus Conference are listed: 1. The benefits of antenatal glucocorticoids vastly outweigh the risks, and the benefits include a decreased incidence of intraventricular hemorrhage (IVH) and a decreased incidence of respiratory distress syndrome (RDS). 2. All fetuses between 24 and 34 weeks’ gestation are candidates for glucocorticoid treatment. 3. Decisions regarding antenatal glucocorticoid treatment should not be altered by fetal race, sex, or the availability of surfactant treatment. 4. If a patient is to receive tocolytic agents, antenatal glucocorticoids should be given. 5. Because there is benefit for treatment to delivery intervals of less than 24 hours, antenatal corticosteroids should be given unless delivery is imminent. 6. Because of the lack of beneficial evidence for corticosteroid administration after 32 weeks gestation in the setting of preterm premature rupture of membranes, the panel recommends to use caution in the use of antenatal corticosteroids after 32 weeks’ gestation in those pregnancies complicated with preterm premature rupture of membranes. 7. The panel identified the repeated administration of antenatal corticosteroids on a weekly basis after the initial course as an area in need of further research. Following this first consensus conference, there was a significant increase in the use of antenatal corticosteroids and many clinicians used repeat courses if the woman was undelivered greater than 7 days after the initial course. Some clinicians

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used a ‘‘rescue approach’’ in lieu of the weekly repeat courses. This latter approach, initially supported by the American College of Obstetricians and Gynecologists, involved giving another course of antenatal corticosteroids on an ‘‘as needed basis’’ for imminent preterm delivery [76].

NIH Conference 2000 Because of the widespread use of repeat courses of antenatal corticosteroids, including ‘‘rescue therapy’’, the NIH convened another consensus conference (August 2000) on antenatal corticosteroids, entitled ‘‘Antenatal Corticosteroids Revisited: Repeat Courses’’ [77]. The panel from this conference reaffirmed the clinical recommendations of the first consensus conference regarding candidates for antenatal corticosteroids therapy, the corticosteroid preparation (ie, DXM and BTM), and the dose of corticosteroids. They emphasized that ‘‘there is no proof of efficacy of any other regimen.’’ The panel very aptly pointed out that the scientific data were lacking regarding both the safety and efficacy of repeat courses of antenatal corticosteroids, and that such therapy should only be used in pregnant women enrolled in randomized clinical trials. The summarized recommendations of the conference were as follows: 1. Full support of the conclusions of the 1994 consensus conference that women between 24 and 34 weeks’ gestation at risk of preterm delivery within 7 days should receive antenatal corticosteroids. 2. Repeated courses of antenatal corticosteroids should not be used outside of randomized controlled trials because there is insufficient evidence of safety or efficacy.

American College of Obstetricians and Gynecologists Committee Opinion 2002 The recommendations of the NIH 2000 consensus panel were supported by a committee opinion (May 2002) from ACOG [78]. The ACOG’s committee of obstetric practice further recommended that antenatal corticosteroids should not be used after 34 weeks gestational age unless there was ‘‘evidence of fetal pulmonary immaturity.’’ Although the committee recommended either corticosteroid regimen, it did point out data from a meta-analysis of randomized controlled trials indicating that neonatal mortality was decreased with BTM but not with DXM [53]. Moreover, this committee presented data from a retrospective study indicating that BTM was superior to DXM in preventing periventricular leukomalacia [12].

Summary The data are overwhelming in support of antenatal corticosteroids for fetal maturation at gestational ages 24 to 34 weeks in women with threatened preterm

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delivery. Although the benefits of antenatal corticosteroid therapy may not be uniform throughout this gestational age range, in general the use of such therapy does appear to decrease the risk of RDS, IVH, and neonatal mortality. There are no apparent short- or long-term adverse fetal effects with a single course of therapy. Antenatal corticosteroids do seem to be beneficial for fetal maturation in women with PPROM, with minimal, if any adverse maternal or fetal effects influencing the risk of infection. Current data would also suggest that there are no beneficial effects of repeat courses of antenatal corticosteroids. Moreover, repeat courses of antenatal corticosteroids may be associated with adverse fetal effects, especially a decrease in birth weight. Data are insufficient to either recommend or discourage the use of a ‘‘rescue approach’’ to antenatal corticosteroids. Although there are limited data to support the use of BTM over DXM for fetal maturation, both regimens do seem to decrease the risk of RDS. Further research regarding the long-term outcomes of infants exposed to these two agents is needed. Finally, antenatal corticosteroids for fetal lung maturation are one of the most studied perinatal interventions. In addition to having demonstrated clinical efficacy, corticosteroids are cost-effective, with minimal therapy cost yielding significant cost savings. [79] The still-unresolved issues described in this review will have to be decided based on emerging data from randomized controlled trials and relevant experimental studies. It is hoped that future studies, both in vitro and in vivo, will address the effects of antenatal corticosteroids on various organ systems (at macro and molecular levels) and on the impact on fetal and postnatal growth, as suggested by the panels of both NIH consensus conferences. Clinical decisions based on such evidence will have to balance the positive short-term effects on newborn survival with potential harmful consequences later in life. Future therapeutic protocols will hopefully combine optimal therapeutic results with minimal side effects, both short-term and long-term. Editor’s note Although the 24- 34-week window for corticosteroid administration has become rather standard, it must be acknowledged that some fetuses under 24 weeks and some over 34 weeks might benefit from exposure to these drugs when imminent delivery is likely. Most of such younger fetuses probably cannot benefit, because of alveolar structural immaturity. However, with some 22- and 23-week fetuses currently surviving, the question that should be posed is what detriment would occur to the majority (nonsurvivable) of such fetuses if the accepted 24-week floor were to be slightly lowered. The hope in these cases would be to offer a possible survival advantage to the minority of them who might have the structural maturity to be able to respond. Showing a statistically significant advantage to the older (> 34 week) fetuses is made difficult by there being decreasingly fewer in that gestational-age range who have not already achieved pulmonary maturation. It is clear, however, that some 35- and 36-week neonates can have rather severe respiratory distress. If amniotic-

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fluid studies suggest marked pulmonary immaturity in these pregnancies, it might be reasonable to offer a course of corticosteroids. Further research is needed to clarify the use of these drugs for such ‘‘outlyers’’.

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