PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1503-1510 (doi:10.1542/10.1542/peds.2005-1749)
Adverse Neonatal Outcomes Associated With Antenatal Dexamethasone Versus Antenatal Betamethasone
a Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, Atlanta, Georgia
b Research Triangle Institute, Research Triangle Park, North Carolina
c National Institute of Child Health and Human Development, Washington, DC
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ABSTRACT |
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OBJECTIVE. Antenatal dexamethasone and betamethasone may not be equally efficacious in the prevention of adverse neonatal outcomes. We compared the risks of periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and neonatal death among very low birth weight infants who were exposed to dexamethasone, betamethasone, or neither steroid.
METHODS. Infants (401–1500 g) in the National Institute of Child Health and Human Development Neonatal Research Network were studied. Multivariate logistic regression analyses compared the 3 groups with regard to PVL, IVH, ROP, and neonatal death, adjusting for network center and selected covariates.
RESULTS. A total of 3600 infants met entry criteria. Compared with no antenatal steroids, there were trends for a reduced risk for PVL associated with dexamethasone and betamethasone but no difference in risk between dexamethasone and betamethasone. Dexamethasone reduced the risk for IVH and severe IVH, compared with no antenatal steroid exposure. Betamethasone reduced the risk for IVH, severe IVH, and neonatal death, compared with no antenatal steroids. Compared with betamethasone, dexamethasone had a statistically significant increased risk for neonatal death. There were trends for greater risks associated with dexamethasone compared with betamethasone for IVH and severe ROP.
CONCLUSIONS. Betamethasone was associated with a reduced risk for neonatal death, with trends of decreased risk for other adverse neonatal outcomes, compared with dexamethasone. It may be in the best interest of neonates to receive betamethasone rather than dexamethasone when available.
Key Words: antenatal glucocorticoids • dexamethasone • betamethasone • neonatal morbidity • neonatal mortality
Abbreviations: IVH—intraventricular hemorrhage • PVL—periventricular leukomalacia • ROP—retinopathy of prematurity • NICHD—National Institute of Child Health and Human Development • VLBW—very low birth weight • GA—gestational age • OR—odds ratio • CI—confidence interval • PROM—prolonged rupture of membranes
One of the chief advances in perinatal medicine in the past 25 years has been the administration of antenatal steroids for induction of fetal lung maturity to pregnant women with imminent delivery of an infant at 24 to 34 weeks' gestation. First introduced by Liggins in 1972, antenatal corticosteroid use has been associated with a reduced risk for respiratory distress syndrome, intraventricular hemorrhage (IVH), and overall neonatal mortality.1–7 Currently, the only antenatal steroids that are used for such therapy are the fluorinated steroids dexamethasone and betamethasone, with specific antenatal steroid usage patterns being dependent on commercial availability, institutional formulary listing, and provider preference.
Animal and human studies have raised concerns that dexamethasone, when compared with betamethasone, may be associated with an increased risk for adverse neonatal neurologic outcomes.8,9 Of particular concern was the finding by Baud et al8 that dexamethasone, compared with betamethasone, was associated with an increased risk for cystic periventricular leukomalacia (PVL), a degenerative process that involves the white matter of the brain and is associated with cerebral palsy, mental retardation, and other adverse long-term neurobehavioral outcomes. Several studies have investigated the effects of antenatal steroids on other adverse neonatal outcomes, with conflicting results. In general, antenatal steroids have been associated with both decreased and unaltered risk for retinopathy of prematurity (ROP)8,10,11; an increased, decreased, and unaltered risk for neonatal sepsis3,5,7; and an increased, decreased, and unaltered risk for necrotizing enterocolitis.3,7,8,12 However, other than the observational study by Baud et al,8 no studies have compared directly neonatal morbidities and mortality in infants who are exposed to dexamethasone or betamethasone.
Using registry data from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, the current study was designed with the primary aim of determining whether there is a difference in risk for developing PVL among very low birth weight (VLBW) infants who are exposed to dexamethasone compared with betamethasone. The secondary aim of this study was to compare the incidences of IVH, ROP, and neonatal death among VLBW infants who are exposed to dexamethasone versus betamethasone.
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METHODS |
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Data for this historical cohort study were abstracted from the NICHD Neonatal Research Network registry of VLBW infants who weighed 401 to 1500 g at birth and were born at or admitted before 14 days of life at participating centers.13 In January 2002, the network began monitoring the type of antenatal steroid used in participating centers, with current usage patterns of dexamethasone and betamethasone being 40% and 60%, respectively. The exposures of interest were dexamethasone or betamethasone exposure (neonates with no antenatal steroid exposure served as a referent group) with the primary outcome of PVL. Secondary outcomes were the presence of an IVH, severe IVH, ROP, severe ROP, and neonatal death.
Patients
Infants who had a birth weight between 401 g and 1500 g and were born at network centers between January 1, 2002, and April 30, 2003, were included in this study. Infants were excluded when they had a congenital anomaly, chromosomal anomaly, inborn error of metabolism, intrauterine infection, or exposure to both dexamethasone and betamethasone or died in the first 12 hours of life. Gestational age (GA) was determined by best obstetric estimates from last menstrual period, standard obstetric parameters, and ultrasonography. Outborn infants were excluded because documentation of antenatal steroid exposure from referring hospitals could not be reliably ascertained by the registry.
Exposure Definition
Antenatal steroid exposure was defined as maternal receipt of either dexamethasone or betamethasone during the admission for delivery. A complete course of dexamethasone was defined as four 6-mg intramuscular doses of a commercially obtained product (GensiaSicor Pharmaceuticals, Inc, Irvine, CA; American Regent Laboratories, Shirley, NY; American Pharmaceutical Partners, Inc, Schaumburg, IL; Baxter, Deerfield, IL) given at 12-hour intervals. A complete course of betamethasone was defined as two 12-mg intramuscular doses of a commercially obtained product (Schering-Plough, Kenilworth, NJ) given at 24-hour intervals. Dexamethasone and betamethasone were the only 2 agents used for antenatal steroid prophylaxis.
Outcome Definitions
PVL or cystic cerebral parenchymal lesions were diagnosed by pediatric radiologists using cranial sonography during the NICU hospitalization. Only infants who underwent at least 1 cranial sonogram at 
36 weeks' postmenstrual age were included in PVL analyses, as PVL may not become ultrasonographically evident until 36 weeks' postmenstrual age. Neonatal death was defined as death within the first 28 days of life, given survival for the first 12 hours of life. IVH was defined using Papile's classification,14 as diagnosed by pediatric radiologists using cranial sonography during the NICU hospitalization; severe IVH was defined as grade III or IV IVH. Only infants who underwent at least 1 cranial sonogram were included in IVH analyses. Severe ROP was defined as ROP with threshold or plus disease or that required surgical intervention before discharge or transfer. Only infants who received at least 1 ophthalmologic examination were included in ROP analyses.
Statistical Analysis
Continuous variables were summarized with arithmetic means and SDs. Preliminary logistic and linear regression models were performed on discrete and continuous variables, respectively, using only network center as an additional covariate to assess for associations between antenatal steroid exposure and outcomes. Unconditional multivariate logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of either dexamethasone or betamethasone with outcomes; network centers were coded as dummy covariates, with the center with the lowest incidence of the analyzed outcome being the reference group. Additional covariates were selected on the basis of the biological plausibility of and importance to the modeled associations15–17; these were gestational hypertension (preexisting, preeclamptic, or eclamptic), prolonged rupture of membranes (PROM) >18 hours, mode of delivery (cesarean versus vaginal), infant gender, number of gestations (singleton versus multiple), and birth weight by 250-g increments. Maternal marital status (single versus married), maternal race (white versus nonwhite), and receipt of at least 1 prenatal care visit also were included to model maternal socioeconomic status. GA was not included in the models because of the high degree of colinearity between birth weight and GA. Postnatal covariates such as early-onset sepsis, receipt of indomethacin within the first 24 hours of life, and patent ductus arteriosus that required surgical or medical intervention were not included in the reported model because of the inability to define definitively either their temporal relation to the study outcomes and/or their potential roles as mediating events in the causal chain relating antenatal steroid exposure and outcomes. Additional subanalyses were performed using conditional logistic regression models that stratified antenatal steroid exposure into partial and complete/multiple courses. The results of these dose-dependent conditional analyses, however, did not differ from that of the primary unconditional models; therefore, only the results from the primary models are presented. For all tests, statistical significance was established at a P < .05. All statistical analyses were performed using Statistical Analysis System software, version 8.02 (SAS Institute, Cary, NC).
Sample Size Calculation
Assuming a baseline incidence of PVL of 5% among VLBW infants18 and a 50% reduction in PVL risk associated with betamethasone versus no antenatal steroid exposure,8 it was estimated that a sample size of 938 VLBW infants with a 1:1 ratio of dexamethasone to betamethasone exposure was needed to detect a 30% increase in the risk for PVL associated with dexamethasone compared with no antenatal steroid exposure, with a 2-tailed 
of 5% and a power of 80%. This would provide for the detection of an absolute difference of 4 percentage points in PVL incidence rates between dexamethasone and betamethasone (ie, 6.5% versus 2.5%), or an OR of 2.71, with the allowed type I and type II errors.
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RESULTS |
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From January 1, 2002, to April 30, 2003, a total of 4939 VLBW infants were registered in the network database, 74% of whom received antenatal steroids. Within this group, 3600 VLBW infants met study entry criteria, 635 (18%) of whom received no antenatal steroids, 1227 (34%) of whom received dexamethasone, and 1738 (48%) of whom received betamethasone. Among infants who were exposed to dexamethasone, 445 (36%) received a partial course, 760 (62%) received a complete course, 20 (2%) received multiple courses, and 2 did not have documentation of the number of courses received. Among infants who were exposed to betamethasone, 428 (25%) received a partial course, 1228 (71%) received a complete course, 79 (4%) received multiple courses, and 3 did not have documented course numbers. A total of 2559 (71.1%) infants received at least 1 ophthalmologic examination, and 2947 (81.9%) underwent a cranial sonogram by 36 weeks' postmenstrual age.
Baseline Maternal and Neonatal Characteristics
Maternal characteristics are shown in Table 1. By preliminary regression modeling adjusting only for center, there were statistically significant differences among the 3 groups with regard to marital status, race, and receipt of prenatal care. Mothers who received antenatal steroids were more likely to be married, be white, and receive at least 1 prenatal care visit compared with those who did not.
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General neonatal characteristics are shown in Table 2. Adjusting only for network center, preliminary regression analyses revealed statistically significant differences among the 3 groups in several categories. Infants who were exposed to antenatal steroids tended to have lower birth weights and GAs at birth, PROM, intrapartum antibiotics, and higher cord pH compared with those with no antenatal steroid exposure. Postnatally, infants who were exposed to antenatal steroids were less likely to have early-onset sepsis and more likely to be given postnatal steroids for management of chronic lung disease than those who were not exposed to antenatal steroids. There were statistically significant but clinically nonsignificant differences in cesarean delivery rates and Apgar scores among the 3 steroid groups. The sample size for the subgroup of infants who received early indomethacin was too small to perform preliminary modeling, adjusting for network center, among the 3 groups.
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Selected Neonatal Outcomes
The incidence of selected neonatal outcomes among the 3 steroid groups is shown in Table 3. The overall rate of PVL in this cohort was 3.5%, and adjusting only for network center, there were no differences in the risk for PVL among the 3 study groups. However, infants who received antenatal steroids were less likely to have severe IVH than those who did not have antenatal steroid exposure. Furthermore, infants who received betamethasone had a decreased risk for IVH and for death within the first 28 days of life compared with infants without antenatal steroid exposure; however, infants with betamethasone exposure had an increased risk for ROP compared with this control group.
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Multivariate Analyses of Primary Neonatal Outcomes
In the multivariate regression analyses that compared the risks for selected neonatal outcomes (Table 4) by steroid exposure groups, there were statistically nonsignificant trends toward a reduction in risk for PVL for both dexamethasone (OR: 0.63; 95% CI: 0.35–1.15) and betamethasone (OR: 0.67; 95% CI: 0.37–1.21); there was no difference in risk for development of PVL when dexamethasone was compared with betamethasone (OR: 0.94; 95% CI: 0.51–1.72). The risks for IVH and severe IVH both were statistically decreased with dexamethasone (OR: 0.76 [95% CI: 0.58–0.99]; OR: 0.60 [95% CI: 0.41–0.88], respectively) and betamethasone (OR: 0.63 [95% CI: 0.47–0.83]; OR: 0.63 [95% CI: 0.43–0.92], respectively) compared with absence of antenatal steroid exposure, but when the 2 steroids were compared directly, there was a trend toward an increased risk associated with dexamethasone compared with betamethasone for IVH (OR: 1.21; 95% CI: 0.93–1.59). There was no alteration in risk for ROP or severe ROP associated with either dexamethasone (OR: 1.12 [95% CI: 0.81–1.54]; OR: 1.26 [95% CI: 0.75–2.13], respectively) or betamethasone (OR: 1.16 [95% CI: 0.83–1.62]; OR: 0.84 [95% CI: 0.49–1.46], respectively) when compared with no antenatal steroid exposure, but there was a statistically nonsignificant trend toward an increased risk for severe ROP associated with dexamethasone compared with betamethasone (OR: 1.50; 95% CI: 0.93–2.42). Notably, although dexamethasone showed a trend toward a decreased risk for neonatal death (OR: 0.73; 95% CI: 0.47–1.14), only betamethasone was associated with a statistically significant reduction in neonatal death (OR: 0.44; 95% CI: 0.29–0.68), compared with no antenatal exposure. Furthermore, dexamethasone was associated with an increased risk for neonatal death (OR: 1.66; 95% CI: 1.07–2.57) when compared with betamethasone.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONConclusionREFERENCES |
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In 1995, the National Institutes of Health and the American College of Obstetricians and Gynecologists formally issued a consensus statement advocating the use of antenatal corticosteroids for induction of fetal maturation, establishing it as a standard of care for perinatal management of preterm deliveries 24 to 34 weeks' GA,4 with the goal of reducing the risks for respiratory distress syndrome, IVH, and neonatal death.1–7 However, the 2 fluorinated steroids that are used for such antenatal prophylaxis, dexamethasone and betamethasone, may not be equally efficacious for protection against adverse neonatal outcomes.
This is the largest study to date to evaluate the differential neonatal effects of dexamethasone and betamethasone. In the only other human study that directly compared outcomes that are associated with dexamethasone versus betamethasone, Baud et al8 reported in an observational study that betamethasone but not dexamethasone was associated with a reduced risk for cystic PVL, after adjusting for selected covariates. In contrast to the findings by Baud et al, we found no differences in risk for cystic PVL associated with dexamethasone or betamethasone compared with no antenatal steroid exposure or between dexamethasone and betamethasone. However, in the multicenter study by Baud et al, there was no adjustment made for study center in the PVL analyses; this is of note given that the center with the lowest rate of cystic PVL also was the center with the highest utilization of betamethasone.
Consistent with previous reports,2,3 this study found statistically significant reductions in risk for IVH and severe IVH associated with both dexamethasone and betamethasone compared with no antenatal exposure. Notably, we found that both dexamethasone and betamethasone were equally efficacious in reducing the risk for IVH and severe IVH, consistent with the findings by Baud et al.8 However, we found a significant reduction in risk for neonatal death associated with betamethasone but not dexamethasone, compared with no exposure to antenatal steroids, a finding similar to that reported in the Cochrane meta-analysis by Crowley.7 Furthermore, dexamethasone was associated with an increased risk for neonatal death when compared with betamethasone as well. Neonatal death was defined as death within the first 28 days of life, in an attempt to remove confounding effects by postnatal risk factors for death beyond the immediate neonatal period. In addition, we excluded infants who died within the first 12 hours of life in an attempt to reduce the effects of catastrophic perinatal confounders, such as placental abruption or perinatal asphyxia, from antenatal steroid analyses. Therefore, the differences in neonatal mortality between dexamethasone and betamethasone may be related to effects of the antenatal steroid itself.
We also assessed the associations of antenatal steroids on ROP, as previous studies have documented a decreased risk for ROP associated with antenatal steroid exposure,10,11,19,20 possibly related to the glucocorticoid-mediated acceleration of retinal vascular maturation and inhibition of tumor necrosis factor production, a key factor in inflammatory and angiogenic mechanisms.21 It is unlikely that dexamethasone has a direct toxic effect on the developing retina; Rotschild et al19 previously reported with a neonatal ROP mouse model that there was no alteration in retinal development associated with dexamethasone. To date, no comparative studies have adjusted for selected risk factors in comparing the incidence of severe ROP associated with dexamethasone and betamethasone. The current study found a statistically nonsignificant trend toward a 50% increase in risk for severe ROP associated with dexamethasone compared with betamethasone. The causes for this potential differential retinotoxic effect between dexamethasone and betamethasone remain unclear and warrant additional study.
The suggestion that dexamethasone may be neurologically detrimental when compared with betamethasone has been raised by other studies. Rayburn et al9 reported that mice that were exposed to dexamethasone had decreased neurobehavioral functionality, specifically with regard to anxiety and memory, when compared with mice that were given betamethasone. In human subjects, Jobe and Soll,22 using the data from Crowley's meta-analysis, documented that although both dexamethasone and betamethasone were associated with statistically significant reductions in risk for IVH, only betamethasone was statistically associated with a reduction in risk for death. Similarly, Baud et al8 reported in their unadjusted analyses that betamethasone and not dexamethasone was associated with a reduction in death. Dexamethasone and betamethasone differ only in the orientation of the methyl group at position 16, being in the configuration in dexamethasone and in the ß configuration in betamethasone; however, this structural difference could be responsible for marked differences in nongenomic effects. In an in vitro study, Buttgereit et al23 found that dexamethasone was 5 times more potent than betamethasone in inhibiting thymocyte respiration. Similarly, there may be genomic and specific nongenomic differences between dexamethasone and betamethasone, including the expression of glutamate receptors and ion transport channels.24–26 There have also been concerns raised regarding the possible neurotoxic effects of the sodium metabisulfite preservative that is used in commercially available dexamethasone.27,28 The mechanisms of sulfite neurotoxicity may be related to the formation of cysteine-S-sulfate, a potentially excitotoxic metabolite of sulfites that is structurally similar to glutamate, and the generation of oxygen and sulfur radicals. However, there are questions as to whether the dose of sulfites administered antenatally to the mother has concentrated effects at the fetal level. Furthermore, postnatal exposure to sulfite preservatives in routine parental amino acid formulations and cardiovascular medications theoretically provides a higher exposure to sulfites than that in antenatal dexamethasone, making the contribution of sulfites in commercial dexamethasone less significant than other potential agents with regard to hypothesized induced brain injury.
There are several considerations that should be addressed when interpreting the findings of the current study, mostly related to the retrospective nature of the study design. Multivariate analyses are able to adjust for known, measurable covariates for the outcomes of interest. Significant unknown confounders may have affected our findings; this must be kept in mind when interpreting our results and when considering future studies. With regard to known confounders, a major weakness to our study was the lack of inclusion of chorioamnionitis, a major risk factor for PVL29,30 as a covariate, as the network database does not routinely collect data on this variable. Although the presence of PROM >18 hours was used as a proxy for chorioamnionitis, it is an incomplete measure. This weakness may have introduced a nondifferential misclassification bias that would have biased the PVL analyses toward the null value. Similarly, other known postnatal risk factors for adverse neonatal outcomes, including postnatal steroid exposure,31–33 were not included in the models because of the inability to define consistently the temporal relationship between postnatal risk factors and study outcomes; these limitations also must be considered when interpreting our results. The validity of the PVL and IVH definitions that were used in this study also can be debated given concerns of the incompleteness of the current IVH staging method, crude conceptualization of PVL, and exclusion of ventricular enlargement and cerebellar or brainstem lesions, as done in this study, to reflect accurately the spectrum of neonatal white matter damage that neuropathologically correlates to neurodevelopmental morbidity.34 Furthermore, the reliability of neonatal cranial ultrasounds for routine detection of neuropathologic entities may be lower than believed by neonatal practitioners.35,36 For these reasons, we are planning a neurodevelopmental follow-up of this cohort when they reach 18 to 22 months' corrected age to assess further the possible differential long-term neurodevelopmental effects of dexamethasone and betamethasone not reflected by neonatal cranial ultrasound imaging.
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Conclusion |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONConclusionREFERENCES |
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The current study provides evidence that betamethasone statistically reduces the risk for neonatal death, whereas dexamethasone does not, in agreement with the findings by Crowley.7 Furthermore, there were notable trends for a reduced risk for adverse neonatal outcomes associated with betamethasone compared with dexamethasone for IVH and severe ROP. However, there were no alterations in risk for PVL associated with either antenatal steroid compared with each other or with the absence of antenatal steroid exposure. On the basis of these findings and those of other authors, a randomized, clinical trial on the differing fetal and neonatal effects of dexamethasone and betamethasone should be considered. Given that no such clinical trial yet has been performed, the findings of the current study have implications regarding the selection of antenatal steroid for standard prophylactic purposes. Given the current body of literature favoring the use of betamethasone versus dexamethasone, it may be in the best interest of neonates to receive antenatal betamethasone rather than antenatal dexamethasone when the option is available to do so.
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ACKNOWLEDGMENTS |
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This study was conducted for and supported by the NICHD (Bethesda, MD).
We thank Augusto Sola, MD, for his invaluable contributions to the study design.
Members of the NICHD Neonatal Research Network (1996–2005), Steering Committee Chairman Alan H. Jobe, MD, PhD. University of California at San Diego (U10 HD40461): Neil N. Finer, MD*, Maynard Rasmussen, MD, Wade Rich; Case Western Reserve University (U10 HD21364): Michele Walsh, MD*, Avroy A. Fanaroff, MB, BCh, Nancy Newman, RN; University of Cincinnati (U10 HD27853): Edward F. Donovan, MD*, Vivek Narendran MD, MRCP, Cathy Grisby, RN; Duke University (U10 HD40492): Ronald N. Goldberg, MD*, Michael Cotten, MD, Kathy Auten, RN; Emory University (U10 HD27851): Barbara J. Stoll, MD*, Ellen Hale, RN; Indiana University (U10 HD27856): James A. Lemons, MD*, Brenda Poindexter, MD, Lucy Miller, RN; University of Miami (U10 HD21373): Shahnaz Duara, MD*, Emmalee S. Bandstra, MD, Ruth Everett, RN; NICHD: Rosemary D. Higgins, MD*, James Hansen, MD; Research Triangle Institute (U10 HD36790): W. Kenneth Poole, PhD*, Betty Hastings, Carolyn M. Petrie, MS; University of Rochester (U10 HD40521): Dale L. Phelps, MD*, Ronnie Guillet, MD, PhD, Linda Reubens, RN; Stanford University (U10 HD27880): David K. Stevenson, MD*, Krisa Van Meurs, MD, Bethany Ball, BS; University of Texas Health Science Center at Houston (U10 HD21373): Jon E. Tyson, MD, MPH*, Kathleen Kennedy, MD, MPH, Georgia McDavid, RN; University of Texas Southwestern Medical Center (U10 HD40689): Abbot R. Laptook, MD*, Walid Salhab, MD, Gay Hensley, RN; Wake Forest University: T. Michael O'Shea, MD*, Robert Dillard, MD, Nancy Peters, RN; Wayne State University (U10 HD21385): Seetha Shankaran, MD*, Ganesh Konduri, MD, Geraldine Muran, RN; Women and Infants Hospital (U10 HD27904): William Oh, MD*, Barbara Stonestreet, MD, Angelita Hensman, RN; Yale University (U10 HD27871): Richard A. Ehrenkranz, MD*, Patricia Gettner, RN; University of Alabama at Birmingham (U10 HD34216): Waldemar A. Carlo, MD*, Namasivayam Ambalavanan, MD, Monica V. Collins, RN.
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FOOTNOTES |
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Accepted Oct 18, 2005.
Address correspondence to Ben H. Lee, MD, 2015 Uppergate Dr, Division of Neonatal-Perinatal Medicine, Atlanta, GA 30322-1028. E-mail: ben_lee{at}oz.ped.emory.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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