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Antenatal Betamethasone Compared WithDexamethasone (Betacode Trial)A Randomized Controlled Trial

Andrew Elimian, MD, David Garry, DO, Reinaldo Figueroa, MD Alan Spitzer, MD,Vandy Wiencek, RN, and J. Gerald Quirk, MD, PhD

OBJECTIVE: To compare betamethasone with dexa-methasone in terms of effectiveness in reducing perinatalmorbidities and mortality among preterm infants.

METHODS: We enrolled 299 women at risk for pretermdelivery in a double-blind, placebo-controlled, random-

ized trial of antenatal betamethasone compared withdexamethasone at Stony Brook University Hospital fromAugust 2002 through July 2004. We excluded womenwith clinical chorioamnionitis, fetal structural and chro-mosomal abnormalities, prior antenatal steroid exposure,and steroid use for other indications. Statistical analysiswas performed in accordance of the intention-to-treatprinciple.

RESULTS: There were no significant differences betweenthe groups with regard to baseline characteristics. Therate of respiratory distress syndrome, need for vasopres-sor therapy, necrotizing enterocolitis, retinopathy of pre-maturity, patent ductus arteriosus, neonatal sepsis, and

neonatal mortality were not significant different betweenthe groups. However, the rates of intraventricular hem-orrhage (6 of 105 [5.7%] compared with 17 of 100 [17.0%],relative risk [RR] 2.97, 95% confidence interval [CI] 1.227.24, P .02) and any brain lesion (7 of 105 [6.7%] com-pared with 18 of 100 [18.0%], RR 2.7, 95% CI 1.186.19,P .02 ) were significantly lower in neonates exposed todexamethasone compared with betamethasone. The ab-solute risk reduction in the rate of intraventricular hem-

orrhage was 11.3 % ( 95% CI 2.711.9%), and the numberneeded to treat was 9 (95% CI 537) in favor of dexa-methasone.

CONCLUSION: Betamethasone and dexamethasone arecomparable in reducing the rate of most major neonatal

morbidities and mortality in preterm neonates. However,dexamethasone seems to be more effective in reducingthe rate of intraventricular hemorrhage compared withbetamethasone.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,www.clinicaltrials.gov, NCT00418353(Obstet Gynecol 2007;110:2630)

LEVEL OF EVIDENCE: I

Administration of a single course of antenatal steroidsresults in decrease in neonatal morbidity and mor-

tality as well as substantial savings in health care costs by

specifically reducing the risk of respiratory distress syn-drome, intraventricular hemorrhage, and neonataldeath among premature infants.13 The preferred corti-costeroids for antenatal therapy are betamethasone ad-ministered intramuscularly as two doses of 12 mg each24 hours apart or dexamethasone four doses of 6 mggiven intramuscularly every 12 hours. These agents arefavored over other forms of steroids because they are themost widely studied, seem to have identical biologicactivity, and readily cross the placenta. In addition, theyare devoid of mineralocorticoid activity, have relativelyweak immunosuppressive actions, and have longer

duration of action in comparison with cortisol andmethylprednisolone.4

However, there continue to be reports from uncon-trolled studies of differences in effectiveness betweenbetamethasone and dexamethasone. A meta-analysis3showed that although the two agents reduce therisks of respiratory distress syndrome and intraventricu-lar hemorrhage to a comparable extent, betamethasonewas more consistently associated with reduction in neo-

See related editorial on page 7.

From the Department of Obstetrics, Gynecology and Reproductive Medicine andDepartment of Pediatrics, Stony Brook University, Stony Brook, New York.

Corresponding author: Andrew Elimian, MD, Section of Maternal FetalMedicine, Department of Obstetrics and Gynecology, University of Oklahoma,Health Sciences Center, WP 2450, Oklahoma City, OK 73190; e-mail:[email protected].

Financial Disclosure

The authors have no potential conflicts of interest to disclose.

2007 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.

ISSN: 0029-7844/07

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natal death than dexamethasone. Furthermore a retro-spective study5 found that betamethasone but not dexa-methasone was associated with a decreased risk ofperiventricular leukomalacia, a major precursor of cere-bral palsy. On the other hand, dexamethasone is sub-stantially cheaper, more readily available and less likelyto decrease fetal breathing movements and fetal heartrate variability. In addition a recent retrospective

study6did not find any differences in effectiveness in thereduction of neonatal mortality and morbidity, includ-ing intraventricular hemorrhage and periventricularleukomalacia.

The choice of which of these agents to use iscurrently based on ease of administration, cost, availabil-ity, and results from conflicting observational studies.

Our hypothesis was that there are no differencesbetween betamethasone and dexamethasone with re-gards to effectiveness when used in the clinical settingof anticipated preterm delivery. Our objective was tocompare betamethasone with dexamethasone in

terms of effectiveness in reducing perinatal morbidi-ties and mortality among preterm infants.

MATERIALS AND METHODSWe conducted a randomized, double-blind, placebo-controlled trial involving pregnant women at risk fordelivering preterm at Stony Brook University Hospitalfrom August 1, 2002, through July 31, 2004. Theseincluded all women in preterm labor with intact mem-branes, those with preterm premature rupture of mem-branes, and those anticipated to deliver for fetal andmaternal indications between 24 and 33 weeks 6 days

gestation.Preterm labor with intact membranes was diag-

nosed in the presence of six to eight contractions perhour or four contractions in 20 minutes, associatedwith cervical changes but with no prelabor rupture ofmembranes. Preterm PROM included cases in whichdelivery followed prelabor rupture of membranes,documented by pooling of fluid on sterile speculumexamination, ferning, and alkaline pH of fluid col-lected from the posterior vaginal fornix. Fetal andmaternal indications included mainly intrauterinegrowth restriction, preeclampsia, and chronic hyper-

tension with superimposed preeclampsia. We ex-cluded women with clinical chorioamnionitis, knownmajor fetal structural anomalies, known fetal chromo-somal abnormalities, prior antenatal steroid exposure,steroid use for other indications, and quadruplets, aswell as women who declined enrollment.

Subjects meeting inclusion criteria were ap-proached by a resident or attending physician whoexplained the study and sought consent to participate in

the study. Those who elected to participate in the studysigned a formal consent form approved by our institu-tions Committee on Research on Human Subjects.

Consenting women were randomly allocated to oneof two groups. The random allocation sequence wascarried out by the Pharmacy using computer-generatedrandom numbers, and each participant was assigned toone of two groups, ie, betamethasone or dexametha-

sone. One group received 12 mg of betamethasone(Celestone Soluspan, Schering, Kenilworth, NJ) intra-muscularly at 0 and 24 hours and similar-appearingplacebo at 12 and 36 hours. The second group received6 mg of dexamethasone (dexamethasone sodium phos-phate, Baxter Healthcare Corporation Anesthesia andCritical Care, New Providence, NJ) intramuscularly at 0,12, 24, and 36 hours. Concealment was achieved bydelivering all doses in identical-looking syringes coveredby opaque material. Both subjects and health careproviders were blinded as to the group to which partic-ipants belonged.

After delivery, study personnel blinded to groupassignment reviewed the prenatal, delivery, neonatal,and postpartum records and documented maternaland neonatal independent outcome variables. Theprimary outcome variables were respiratory distresssyndrome, intraventricular hemorrhage, and neonataldeath. Secondary outcome variables included theneed for exogenous surfactant, oxygen dependency at28 days after birth or oxygen dependency at equiva-lent of 36 completed weeks gestational age, retinopa-thy of prematurity, inotropic support for hypotensioninitiated during the first 24 hours of life, treatment for

patent ductus arteriosus, necrotizing enterocolitis,neonatal sepsis, and histologic chorioamnionitis.Other variables recorded were maternal age, clinicaldiagnosis, gestational age at randomization and atdelivery, gender, and birth weight.

Respiratory distress syndrome was diagnosedclinically, by the need for mechanical ventilation andoxygen for at least 48 hours, and the presence ofradiologic chest findings. Each neonate had transfon-tanelle head ultrasound scans on days 3 and 7 of life.Neurosonograms were evaluated by an experiencedradiologist blinded to the antenatal steroid exposure

status of the parturient. Intraventricular hemorrhagewas graded as described by Papile et al7 Periventricu-lar leukomalacia was diagnosed by the presence ofecholucent areas or persistent echogenicity in theperiventricular areas on coronal and sagittal views.For study purposes, any brain lesion was defined asany grade of intraventricular hemorrhage or periven-tricular leukomalacia present exclusively or in com-bination. Necrotizing enterocolitis was diagnosed

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clinically and radiologically and confirmed at surgeryor autopsy. Proven neonatal sepsis included positiveblood, cerebrospinal fluid, or urine cultures.

Data analysis was performed in accordance of theintention-to-treat principle. Sample size computationsfor an equivalence study were performed according tothe work of Blackwelder.8 We assumed that approxi-mately 80% of neonates exposed to either betametha-

sone or dexamethasone will not develop respiratorydistress syndrome. We also defined a deviation ineffectiveness of 10% or less as been essentially equiva-lent. A sample size of 354 neonates (177 exposed tobetamethasone compared with 177 exposed to dexa-methasone) would provide more than 80% power todetect differences of more than 10% for a two-tailed testof significance at a critical level of 0.05. The distribu-tional characteristics of the variables were examined.Continuous data were normally distributed. As such,differences between groups defined by exposure toantenatal steroids were examined using Studentttest for

continuous variables and 2 for categorical variables.Fisher exact test was used when expected cell frequencywas equal to or less than five. A P value of.05 wasconsidered statistically significant.

RESULTSFive hundred forty-three women were screened foreligibility. One hundred sixty (29.5%) receivedantenatal steroids before their transport and subse-quently had completion of their course based onwhat was initiated in the transferring hospital.Fifty-five (10.1%) women declined participation

and were given antenatal steroids based on thediscretion of the treating physician and availability,whereas 29 (5.3%) women could not be approachedbecause of immediate or imminent delivery. Thus,the study cohort consisted of 299 (55.1%) womenand their 359 neonates. The profile of the studyparticipants is shown in Figure 1. There were nostatistically significant differences between thegroups in terms of maternal age, race, body massindex, smoking status, gestational age at random-ization, and diagnoses between women who partic-ipated in the trial and those who did not participate.

Similarly, the baseline characteristics of the womenand neonates randomly assigned to betamethasonewere not different from those that assigned todexamethasone, as depicted in Tables 1 and 2. Noadverse effect or side effects were reported in eithergroup.

There were no significant differences betweenneonates exposed to betamethasone and those ex-posed to dexamethasone with regard to the rates of

respiratory distress syndrome (73 of 181 [40.5%]compared with 79 of 178 [44.4%], P.53), necrotizingenterocolitis (0 of 181 [0%] compared with 2 of 178[1.1%], P.25), retinopathy of prematurity (28 of 181[15.5%] compared with 26 of 178 [14.6%], P.92),patent ductus arteriosus (12 of 181 [6.7%] compared

with 14 of 178 [7.9%], P.81), neonatal sepsis (16 of181 [8.9%] compared with 18 of 178 [10.1%], P.83),bronchopulmonary dysplasia (27 of 181 [15.0%] com-pared with 18 of 178 [10.1%], P.22), need forvasopressor (14 of 181 [7.8%] compared with 6 of 178[3.4%], P.07), and neonatal mortality (5 of 181[2.8%] compared with 6 of 178 [3.4%], P.98) (Table3). However, the rates of intraventricular hemorrhage(6 of 105 [5.7%] compared with 17 of 100 [17.0%],relative risk 2.97, 95% confidence interval [CI] 1.227.24, P.02) and any brain lesion (7 of 105 [6.7%]compared with 18 of 100 [18.0%], relative risk 2.7,

95% CI 1.186.19, P.02 ) were significantly lower inneonates exposed to dexamethasone compared withbetamethasone (Table 3).

The rate of grades III and IV intraventricularhemorrhage was 7% (7 of 100) in neonates exposed tobetamethasone compared with 1.9% (2 of 105) inneonates exposed to dexamethasone, P.09 (Table3). Furthermore, the rate of periventricular leukoma-lacia was 4.0% (4 of 100) in neonates exposed to

Fig. 1. Betacode trial profile.Elimian. The Betacode Trial. Obstet Gynecol 2007.

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betamethasone compared with 1.9% (2 of 105) inneonates exposed to dexamethasone, P.44 (Table3). The absolute risk reduction in the rate of intraven-tricular hemorrhage was 11.3% (95% CI 2.711.9%),and the number needed to treat was 9 (95% CI 537)in favor of dexamethasone.

DISCUSSIONA single course of antenatal steroids before pretermdelivery results in a significant decrease in neonatalmorbidity and mortality as well as substantial savings inhealth care costs. Betamethasone and dexamethasonecontinue to be the preferred steroids because of their

Table 2. Baseline Characteristics of Neonates in the Betamethasone and Dexamethasone Groups

Neonatal Characteristics Betamethasone (n 181) Dexamethasone (n 178) P

Mode of delivery .64Vaginal 80 (44.2) 84 (47.2)Cesarean 101 (55.8) 94 (52.8)

Sex .96Male 90 (49.7) 89 (50)Female 91 (50.3) 89 (50)

Birth weight 1983814 2036825 .56Surfactant use 52 (28.7) 53 (29.8) .92

Data are meanstandard deviation or n (%).

Table 3. Neonatal Outcomes in the Betamethasone and Dexamethasone Groups

Outcome Betamethasone (n 181) Dexamethasone (n 178) RR 95% CI P

RDS 73 (40.5) 79 (44.4) 0.91 0.721.16 .53IVHAny grade 17/100 (17.0) 6/105 (5.7) 2.97 1.227.24 .02Grade III/IV 7/100 (7.0) 2/105 (1.9) 3.67 0.7817.27 .09PVL 4/100 (4.0) 2/105 (1.9) 2.10 0.3911.21 .44Any brain lesion 18/100 (18) 7/105 (6.7) 2.7 1.186.19 .02Neonatal death 5 (2.8) 6 (3.4) 0.82 0.262.65 .98NEC 0 (0) 2 (1.1) 0.00 0.004.0 .25ROP 28 (15.5) 26 (14.6) 1.06 0.651.74 .92PDA 12 (6.7) 14 (7.9) 0.85 0.401.78 .81Sepsis 16 (8.9) 18 (10.1) 0.88 0.461.67 .83BPD 27 (15.0) 18 (10.1) 1.48 0.852.59 .22Vasopressor use 14 (7.8) 6 (3.4) 2.31 0.915.87 .07

RR, relative risk; CI, confidence interval; RDS, respiratory distress syndrome; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia;

NEC, necrotizing enterocolitis; ROP, retinopathy of prematurity; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia.Data are n (%) or n/N (%) unless otherwise specified.

Table 1. Baseline Characteristics of Mothers in the Betamethasone and Dexamethasone Groups

Maternal Characteristics Betamethasone (n 150) Dexamethasone (n 149) P

Maternal age (y) 30.66.1 29.96.2 .37Race

White 105 (70.0) 105 (70.5) .97African American 21 (14.0) 14 (9.4) .29Hispanic 12 (8.0) 19 (12.7) .25Other 12 (8.0) 11 (7.4) .99

GA presentation 29.32.9 29.52.9 .82BMI 30.06.7 29.45.0 .41Singleton gestation 124 (82.7) 125 (83.9) .90Smoking 26 (17.3) 32 (21.5) .45PTL 80 (53.3) 76 (51.0) .77Preterm PROM 21 (14.0) 29 (19.5) .27Medically indicated 49 (32.7) 44 (29.5) .64HCA 27 (18.0) 30 (20.1) .75

GA, gestational age; BMI, body mass index; PTL, preterm labor; PROM, premature rupture of membranes; HCA, histologic chorioamnionitis.Data are meanstandard deviation or n (%).

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unique biologic properties, ability to readily cross theplacenta, and because of their weak immunosuppressiveand mineralocorticoid activities. The choice betweenbetamethasone and dexamethasone is currently basedon ease of administration, cost, availability, and resultsfrom conflicting observational studies.

Our study found that both betamethasone anddexamethasone are largely comparable in reducing

most morbidities and mortality among preterm neo-nates. This finding is consistent with the reports of Baudet al5 and Bar-lev and colleaques,6 who did not demon-strate any differences in the rate of respiratory distresssyndrome, bronchopulmonary dysplasia, intraventricu-lar hemorrhage, neonatal mortality, and other compli-cations of prematurity among neonates exposed tobetamethasone and dexamethasone. However, contraryto the finding of a higher rate of periventricular leu-komalacia among neonates exposed to dexamethasonecompared with betamethasone reported by Baud et al,5

our study did not find any differences in the rate

periventricular leukomalacia between the groups. Infact, the rate of periventricular leukomalacia in thedexamethasone-exposed neonates was lower amongneonates exposed to betamethasone, although our studywas underpowered to detect differences in periventricu-lar leukomalacia. Three other groups of investigators6,9,10

have reported no differences in the rates of periventricu-lar leukomalacia among neonates exposed to beta-methasone and dexamethasone.

The differences in intraventricular hemorrhageafter steroid exposure seen in our study may berelated to potency, duration of exposure, and fetal

response after exposure. Dexamethasone is five timesmore potent than betamethasone in nongenomic ef-fects in addition to the stereoisomer difference of amethyl group at position 16 of ring D in theirmolecular structure.11,12 Derks et al12 described a morerapid fall in fetal sheep progesterone levels and asharper rise in serum cortisol levels after betametha-sone administration compared with dexamethasone,and the cortisol levels continued to rise at 72 hourspostexposure in the dexamethasone-treated fetalsheep. Ballard and Liggins13,14 showed umbilical cordcortisol levels increased more rapidly and with a

higher zenith after each 12 mg of betamethasonecompared with 6 mg of betamethasone, with noreported increased benefit to 24 mg betamethasonedosing. The exact difference in physiologic responsesof these stereoisomer molecules is not known andrequires further investigation.

Our study largely supports the continuing use ofboth betamethasone and dexamethasone in the treat-ment of women at risk of preterm delivery. However,

we found dexamethasone to be superior to betametha-sone in reducing the rate of intraventricular hemor-rhage. Other potential advantages of dexamethasoneinclude lower cost, widespread availability, and lesseffect on fetal biophysical variables that might lead topremature intervention or delivery. On the other hand,betamethasone requires two injections as opposed to thefour injections of dexamethasone.

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ment Conference on the Effect of Corticosteroids for FetalMaturation on Perinatal Outcomes (NIH Publication No.953784). Bethesda (MD): National Institutes of Health, NationalInstitute of Child Health and Human Development; 1994

2. Liggins GC, Howie RN. A controlled trial of antepartumglucocorticoid treatment for prevention of distress syndrome inpremature infants. Pediatrics 1972;50:51525.

3. Crowley PA. Antenatal corticosteroid therapy: a meta-analysisof the randomized trials, 1972 to 1994. Am J Obstet Gynecol1995;173:32235.

4. Ballard PL, Ballard RA. Scientific basis and therapeutic regi-mens for use of antenatal glucocorticoids. Am J ObstetGynecol 1995;173:25462.

5. Baud O, Foix-LHelias L, Kaminski M, Audibert F, JarreauPH, Papiernik E, et al Antenatal glucocorticoid treatment andcystic periventricular leukomalacia in very premature infants.N Engl J Med 1999;341:11906.

6. Bar-Lev MR, Maayan-Metzger A, Matok I, Heyman Z, SivanE, Kuint J. Short-term outcomes in low birth weight infantsfollowing antenatal exposure to betamethasone versus dexa-methasone. Obstet Gynecol 2004;104:4848.

7. Papile LA, Burstein J, Koffler H. Incidence and evolution ofsubependymal and intraventricular hemorrhage: a study ofinfants with birth weights less than 1,500 gm. J Pediatr 1978;92:52934.

8. Blackwelder WC. Proving the null hypothesis in clinicaltrials. Control Clin Trials 1982;3:34553.

9. LeFlore JL, Salhab WA, Broyles RS, Engle WD. Association ofantenatal and postnatal dexamethasone exposure with out-comes in extremely low birth weight neonates. Pediatrics2002;110:2759.

10. Lee BH, Stoll BJ, McDonald SA, Higgins RD, NationalInstitute of Child Health and Human Development NeonatalResearch Network. Adverse neonatal outcomes associatedwith antenatal dexamethasone versus antenatal betametha-sone. Pediatrics 2006;117:150310.

11. Derks JB, Giussani DA, Van Dam LM, Jenkins SL, Winter JA,Zhao XF, et al. Differential effects of betamethasone anddexamethasone fetal administration of parturition in sheep.

J Soc Gynecol Investig 1996;3:33641.12. Buttgereit F, Brand MD, Burmester GR. Equivalent doses and

relative drug potencies for non-genomic glucocorticoid effects:a novel glucocorticoid hierarchy. Biochem Pharmacol 1999;58:3638.

13. Ballard PL, Liggins GC. Glucocorticoid activity in cord serum:comparison of hydrocortisone and betamethasone regimens.

J Pediatr 1982;101:46870.

14. Ballard PL. Scientific rationale for the use of antenatal glu-cocorticoids to promote fetal development. Pediatr Rev2000;1:E8390.

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