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Betamethasone dosing interval: 12 or 24 hours apart? A randomized, noninferiority open trial

      Objective

      We sought to determine whether the incidence of neonatal respiratory distress syndrome (RDS) is similar with 12- vs 24-hour dosing interval of betamethasone.

      Study Design

      This was a prospective, randomized, open, noninferiority trial. Mothers (n = 228) with a singleton or multiple pregnancies (fetuses = 260), between gestational age of 23-34 weeks, at risk for preterm delivery, received standard 2 doses of betamethasone either 12 or 24 hours apart in 2:1 ratio, respectively.

      Results

      Incidence of RDS was similar in the 2 cohorts (36.5% vs 37.3%; P = not significant). Women unable to receive the complete course of corticosteroids with the 24-hour interval can be reduced by half with the 12-hour interval. However, increased incidence of necrotizing enterocolitis was seen with 12-hour dosing (6.2% vs 0%; P = .03).

      Conclusion

      The 12-hour dosing interval is equivalent to the 24-hour dosing interval for prevention of RDS in neonates of mothers delivering prematurely. A larger multicenter study is needed to confirm our findings.

      Key words

      The administration of glucocorticoids to accelerate lung development in the fetus in patients at risk for preterm delivery is one of the cornerstones of present-day obstetrics and neonatal care. Pioneering studies by Liggins and Howie
      • Liggins G.C.
      • Howie R.N.
      A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
      and subsequently by many others
      • Nelson L.H.
      • Meis P.J.
      • Hatjis C.G.
      • Ernest J.M.
      • Dillard R.
      • Schey H.M.
      Premature rupture of membranes: a prospective, randomized evaluation of steroids, latent phase, and expectant management.
      The effect of corticosteroids for fetal maturation on perinatal outcomes.
      • Schmidt P.L.
      • Sims M.E.
      • Strassner H.T.
      • Paul R.H.
      • Mueller E.
      • McCart D.
      Effect of antepartum glucocorticoid administration upon neonatal respiratory distress syndrome and perinatal infection.
      • Papageorgiou A.N.
      • Desgranges M.F.
      • Masson M.
      • Colle E.
      • Shatz R.
      • Gelfand M.M.
      The antenatal use of betamethasone in the prevention of respiratory distress syndrome: a controlled double-blind study.
      • Morrison J.C.
      • Whybrew W.D.
      • Bucovaz E.T.
      • Schneider J.M.
      Injection of corticosteroids into mother to prevent neonatal respiratory distress syndrome.
      • Ballard R.A.
      • Ballard P.L.
      • Granberg J.P.
      • Sniderman S.
      Prenatal administration of betamethasone for prevention of respiratory distress syndrome.
      Collaborative Group on Antenatal Steroid Therapy
      Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome.
      • Gamsu H.R.
      • Mullinger B.M.
      • Donnai P.
      • Dash C.H.
      Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicenter trial.
      have repeatedly shown that maternal administration of glucocorticoids has a significant beneficial effect in decreasing the incidence of respiratory distress syndrome (RDS) in infants delivered between 24-34 weeks' gestation. In addition, these studies and metaanalysis
      • Roberts D.
      • Dalziel S.
      Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
      • Crowley P.
      • Chalmers I.
      • Keirse M.J.
      The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials.
      of available data provide strong evidence that glucocorticoid administration also significantly reduces the incidence of intraventricular hemorrhage (IVH) and overall neonatal mortality, improves circulatory stability in the premature infant, and reduces requirements for oxygen and ventilatory support.
      The effect of corticosteroids for fetal maturation on perinatal outcomes.
      The regimen endorsed by the National Institutes of Health (NIH) involves maternal administration of 2 doses of 12 mg of betamethasone intramuscularly 24 hours apart. The NIH has acknowledged that this dosage interval was selected arbitrarily and has recognized an urgent need for studies on dosage variation.
      • Brownfoot F.C.
      • Crowther C.A.
      • Middleton P.
      Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth.
      • Jobe A.H.
      • Nitsos I.
      • Pillow J.J.
      • Polglase G.R.
      • Kallapur S.G.
      • Newnham J.P.
      Betamethasone dose and formulation for induced lung maturation in fetal sheep.
      For Editors' Commentary, see Table of Contents
      The total dosage of 24 mg was based on animal studies and later shown to achieve fetal concentrations comparable to normal physiologic stress levels of cortisol occurring after birth. Administration of total dosage, rather than the interval, is probably more important to attain maximal neonatal benefit. This is supported by data from the National Institute of Health and Human Development Neonatal Research Network that suggest that ≥2 doses of corticosteroids (complete treatment) was more effective than partial treatment (<2 doses).
      • Wright L.L.
      • Verter J.
      • Younes N.
      • et al.
      Antenatal corticosteroid administration and neonatal outcome in very low birth weight infants: the NICHD neonatal research network.
      • Elimian A.
      • Figueroa R.
      • Spitzer A.R.
      • Ogburn P.L.
      • Wiencek V.
      • Quirk J.G.
      Antenatal corticosteroids: are incomplete courses beneficial?.
      However, approximately 25-45% of women at risk for preterm delivery deliver within 24 hours, prior to receiving the complete course of steroids.
      • Liggins G.C.
      • Howie R.N.
      A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
      • Papageorgiou A.N.
      • Desgranges M.F.
      • Masson M.
      • Colle E.
      • Shatz R.
      • Gelfand M.M.
      The antenatal use of betamethasone in the prevention of respiratory distress syndrome: a controlled double-blind study.
      • Morrison J.C.
      • Whybrew W.D.
      • Bucovaz E.T.
      • Schneider J.M.
      Injection of corticosteroids into mother to prevent neonatal respiratory distress syndrome.
      • Gamsu H.R.
      • Mullinger B.M.
      • Donnai P.
      • Dash C.H.
      Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicenter trial.
      • Horbar J.D.
      Antenatal corticosteroid treatment and neonatal outcomes for infants 501 to 1500 gm in the Vermont-Oxford trials network.
      • Garite T.J.
      • Rumney P.J.
      • Briggs G.G.
      • et al.
      A randomized, placebo-controlled trial of betamethasone for the prevention of respiratory distress syndrome at 24 to 28 weeks' gestation.
      Only ∼5% of these women deliver within 12 hours.
      • Morrison J.C.
      • Whybrew W.D.
      • Bucovaz E.T.
      • Schneider J.M.
      Injection of corticosteroids into mother to prevent neonatal respiratory distress syndrome.
      Prospective randomized trials have used varying dosage intervals (8,
      • Gamsu H.R.
      • Mullinger B.M.
      • Donnai P.
      • Dash C.H.
      Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicenter trial.
      12,
      • Nelson L.H.
      • Meis P.J.
      • Hatjis C.G.
      • Ernest J.M.
      • Dillard R.
      • Schey H.M.
      Premature rupture of membranes: a prospective, randomized evaluation of steroids, latent phase, and expectant management.
      • Ballard R.A.
      • Ballard P.L.
      • Granberg J.P.
      • Sniderman S.
      Prenatal administration of betamethasone for prevention of respiratory distress syndrome.
      or 24
      • Liggins G.C.
      • Howie R.N.
      A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
      • Schmidt P.L.
      • Sims M.E.
      • Strassner H.T.
      • Paul R.H.
      • Mueller E.
      • McCart D.
      Effect of antepartum glucocorticoid administration upon neonatal respiratory distress syndrome and perinatal infection.
      • Papageorgiou A.N.
      • Desgranges M.F.
      • Masson M.
      • Colle E.
      • Shatz R.
      • Gelfand M.M.
      The antenatal use of betamethasone in the prevention of respiratory distress syndrome: a controlled double-blind study.
      hours)
      • Crowley P.
      • Chalmers I.
      • Keirse M.J.
      The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials.
      to administer the total dose of 24 mg of a long-acting corticosteroid (betamethasone or dexamethasone).
      • Newnham J.P.
      • Moss T.J.
      Antenatal glucocorticoids and growth: single versus multiple doses in animal and human studies.
      In fact, the metaanalysis
      • Crowley P.
      Prophylactic corticosteroids for preterm birth.
      of these studies emphasizes the total dose rather than the interval and, “A policy of administering corticosteroids (24 mg betamethasone, or 24 mg dexamethasone, or 2 g hydrocortisone) to women who are expected to deliver preterm can be expected to achieve substantial reductions in neonatal morbidity and mortality. No adverse consequences of this policy have been identified.” Higher doses did not result in a dose-related response for RDS prevention.
      • Howie R.N.
      • Liggins G.C.
      The New Zealand study of antepartum glucocorticoid treatment.
      The timing of the dosages that was performed in the initial studies was arbitrarily selected, according to the authors. Since preterm delivery is the major cause of infant mortality and morbidity and a quarter to one third of patients deliver within 24 hours of the start of betamethasone therapy, it would be beneficial to ascertain whether a different regimen of administration of betamethasone (12 vs 24 hours apart) would be equally efficacious in preventing the incidence of RDS in preterm infants.

      Materials and Methods

      This is a prospective, randomized, semiblinded noninferiority study conducted at Cooper University Hospital, Camden, NJ, from July 2006 through May 2009, after obtaining approval from the institutional review board. The trial was also registered with clinicaltrial.gov NCT00453141. The study population consists of mothers with a singleton or multiple pregnancies, between the gestational ages of 23-34 weeks, who presented with spontaneous preterm labor, preterm premature rupture of membranes, or medically indicated preterm delivery. The only difference in inclusion criteria between trials included in the Cochrane Review
      • Roberts D.
      • Dalziel S.
      Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
      and this trial is that we chose to include women starting from gestational age of 23 weeks instead of 24 weeks, as neonatal advancements in the last 20 years has made this a viable gestational age.
      • Carlo W.A.
      • McDonald S.A.
      • Fanaroff A.A.
      • et al.
      Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks' gestation.
      Also, we chose to restrict the trial participants to the use of betamethasone alone to avoid variability that maybe associated with use of different corticosteroids.
      • Brownfoot F.C.
      • Crowther C.A.
      • Middleton P.
      Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth.
      No rescue doses of steroids were used during the study period. Trials included in the metaanalyses
      • Roberts D.
      • Dalziel S.
      Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
      and consensus guidelines
      The effect of corticosteroids for fetal maturation on perinatal outcomes.
      have used corticosteroids in various doses and intervals and still shown improvements in RDS rates. We hypothesized that 12 mg of intramuscular betamethasone administered at a 12-hour interval is equally efficacious in the reduction of incidence of RDS, when compared to the same dose of betamethasone given 24 hours apart. Other secondary outcomes evaluated included maternal fever and postpartum length of stay, neonatal frequency of IVH, chronic lung disease (CLD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, need for antibiotics >5 days, admission to neonatal intensive care unit (NICU), and length of NICU stay.
      Once mothers were identified at risk for delivering preterm, the first dose of betamethasone was administered and only then women were offered participation in the study. Women <23 or >34 weeks' gestation, or elapsed time >12 hours since administration of the first dose of betamethasone, known drug allergy to betamethasone, given steroid other than betamethasone for lung maturation, or any contraindication to steroid therapy were excluded. After informed consent was obtained, patients were allocated into 4 groups depending on gestational age: 23.1-26.0 weeks (A); 26.1-29.0 weeks (B); 29.1-32.0 weeks (C); and 32.1-34.0 weeks (D). The patients in each group were randomly assigned to receive 2 doses of 12 mg of betamethasone intramuscularly either 12 or 24 hours apart. Consenting patients were matched to the appropriate group for gestational age and the next opaque envelope was drawn for that group, which became her assigned study number. The obstetrical care and delivery plan was determined by the treating obstetrician in the usual manner. Every attempt was made to contact mothers delivering elsewhere and obtain hospital records for accurate delivery and neonatal data.
      The neonatologists were informed if the patient received steroid therapy, and whether she received 1 or 2 doses, but were not informed of the dosing interval. The 12- vs 24-hour allocation was revealed only after outcome data extraction was completed. The diagnosis of RDS was defined as an infant who has a PaO2 <50 mm Hg on room air, central cyanosis in room air, or a requirement for supplemental oxygen to maintain PaO2 >50 mm Hg, in conjunction with a chest radiograph with findings consistent with RDS and/or need for surfactant therapy. CLD was defined as oxygen dependency at ≥28 days of life. Neurosonograms were performed on neonates delivering preterm and were read by an experienced neuroradiologist for evidence of IVH and graded as described by Papile et al.
      • Papile L.A.
      • Burstein J.
      • Burstein R.
      • Koffler H.
      Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.
      NEC was diagnosed clinically (bilious gastric aspiration or emesis, abdominal distention, or occult/gross blood in stool) and confirmed radiographically (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum). Neonatal sepsis was defined by positive blood cultures; but antibiotic use for >5 days in the neonate was also recorded. ROP was diagnosed by an indirect ophthalmologic examination. The secondary outcomes were not further graded due to small numbers. Fetal and neonatal deaths occurring within 24 hours after birth were excluded when neonatal outcomes and length of NICU stay were analyzed. Also, neonates in whom evaluation for chronic condition (IVH, ROP, or CLD) was not deemed clinically relevant (eg, term birth) were excluded from the analysis of these outcomes.

      Randomization

      The randomization scheme used was generated in Excel (Microsoft, Redmond, WA) using its “random function” in 4 groups of 50 each. Randomization was performed in 2:1 ratio (for 12:24-hour dosing interval) by K.H. and study assignments placed in sealed opaque envelopes with a study number and group number on each envelope by C.H. Participant enrolment was done by E.C., M.K., and the obstetrical residents. Unequal allocation
      • Dumville J.C.
      • Hahn S.
      • Miles J.N.V.
      • Torgerson D.J.
      The use of unequal randomization ratios in clinical trials: a review.
      was used to provide a large sample size for the 12-hour dosing group, for which there is little published information on short- or longer-term neonatal outcomes. After 200 patients were enrolled, further randomization was done in blocks of 30 resulting in unequal distribution in groups C and D, as frequency of disease occurrence was much higher in this gestational age group.

      Power analysis

      A prior power analysis suggested sample sizes of 140 pregnancies for the experimental group (12-hour dosing interval) and 70 for the standard group (24-hour dosing interval) to achieve 80% power to detect a noninferiority margin of 20% using a 1-sided Fisher exact test of proportion differences between groups assuming a 24-hour non-RDS rate of 65% and at minimum a 45% non-RDS rate among 12-hour patients. The margin was set at the expected lower 95% confidence limit of a 24-hour non-RDS rate based on informal historical observation at sites included in the study. To obtain this power the sampled 12-hour rate is assumed to be ∼67%.

      Data analysis

      Noninferiority was tested by a 1-tail Fisher exact test and by comparison of the lower bound of the percent difference in non-RDS rates observed for the 12- and the 24-hour maternal treatment groups. Means and SD are reported for continuous short- and longer-term neonatal and maternal parameters; medians and interquartile ranges for categorical measures; and percents for binary measures. Independent sample t tests with homogeneity of variance adjustment where indicated by the Levene test were used to compare parametric continuous variables between the 12- and 24-hour group. The Mann-Whitney U test was used to compare nonparametric continuous variables. Pearson χ2 and Fisher exact tests were used to compare discreet variables. SPSS 15.1 (IBM, Armonk, NY) and Confidence Interval Analysis (BMJ Books, University of Southampton, London, UK) were used for analysis.

      Results

      The study population included 228 mothers (260 neonates) who were consented for participation and intent-to-treat analysis was conducted. Incomplete information was available for 4 neonates in the 12-hour group and 3 in the 24-hour group. Seven neonates (1 set of triplets) received the incorrect dosing interval due to either failure of order placement or execution, and in 1 case obstetrician preference due to urgency of delivery (Figure). By study design, approximately 70% (161/228 mothers; 180/260 fetuses) were assigned to the 12-hour interval dosing; 30% (67/228 mothers; 80/260 fetuses) were assigned the 24-hour interval dosing. Group A included 47 mothers (56 fetuses); group B included 39 mothers (44 fetuses); group C included 72 mothers (84 fetuses); and group D included 70 mothers (76 fetuses).
      Figure thumbnail gr1
      FIGURECONSORT flow diagram for betamethasone dosing interval trial
      CONSORT, Consolidated Standards of Reporting Trials.
      Khandelwal. Betamethasone 12/24. Am J Obstet Gynecol 2012.
      Women in the 2 treatment arms were similar with respect to gravidity, parity, race, and body mass index (Table 1). The women in the 24-hour arm were about 2 years older than in the 12-hour arm. In the 24-hour cohort, there were more African American women at risk for delivery <26 weeks and more Caucasians at risk in the 32- to 34-week group (but the racial differences were statistically significant only in group D). The groups were enrolled at similar gestational ages with similar frequency of indications for delivery (Table 2), and similar number of growth-restricted neonates (Table 3). Even though the 2 cohorts, overall, delivered at similar gestational ages and intervals from first dose of betamethasone, group B delivered approximately 3 weeks earlier in the 12-hour arm compared to the 24-hour arm (Table 2). Neonatal mode of delivery, birth weights, and sex were also similar in the groups (Table 3).
      TABLE 1Maternal demographics at randomization
      Characteristic12 hour24 hour95% CI
      nMeanSDnMeanSD
      Maternal age, y
       Overall16127.206.826729.676.83−4.42 to −0.51
       Group A3128.876.241631.195.91−6.12 to 1.49
       Group B2728.787.791228.255.14−3.77 to 4.83
       Group C5026.866.162229.828.99−7.26 to 1.34
       Group D5325.757.011729.065.62−7.04 to 4.27
      Gravidity16167
       Overall3.112.163.552.34−1.08 to 0.19
       Parity (median)10–210–3−1 to 0
      Race, n (%)
       Overall16167
        White57 (35.4)29 (43.3)
        Black64 (39.8)19 (28.4)
        Hispanic35 (21.7)16 (23.9)
        Asian2 (1.2)1 (1.5)
        Other3 (1.9)2 (3.0)−0.23 to 0.26
      Group A, n (%)3116
       White11 (35.5)3 (18.8)
       Black10 (32.3)11 (68.8)
       Hispanic10 (32.3)2 (12.5)−0.7 to 0.48
      Group B, n (%)2712
       White11 (40.7)6 (50.0)
       Black10 (37.0)2 (16.7)
       Hispanic4 (14.8)4 (33.3)
       Asian1 (3.7)0 (0.0)
       Other1 (3.7)0 (0.0)−0.54 to 0.52
      Group C, n (%)5022
       White20 (40.0)10 (45.5)
       Black21 (42.0)4 (18.2)
       Hispanic7 (14.0)6 (27.3)
       Asian0 (0.0)1 (4.5)
       Other2 (4.0)1 (4.5)−0.38 to 0.48
      Group D, n (%)5317
       White15 (28.3)10 (58.8)
       Black23 (43.4)2 (11.8)
       Hispanic14 (26.4)4 (23.5)
       Asian1 (1.9)0 (0.0)
       Other0 (0.0)1 (5.9)−0.61 to −0.003
      Maternal BMI, lbs/ft2nMeanSDnMeanSD95% CI
      Overall13528.946.254129.677.76−3.06 to 1.60
      Group A2432.886.42835.7212.70
      Group B2628.955.24830.716.53
      Group C3726.925.371626.995.27
      Group D4828.536.57928.133.98
      BMI, body mass index; CI, confidence interval; SD, standard deviation.
      Khandelwal. Betamethasone 12/24. Am J Obstet Gynecol 2012.
      TABLE 2Pregnancy data variables
      Characteristic12 hour24 hour95% CI
      GA at betamethasone, wks (mean/SD)nMeanSD
       Overall17929.693.268029.203.19−0.38 to 1.33
       Group A3724.510.951925.580.85−0.58 to 0.46
       Group B3027.820.891327.620.75−0.37 to 0.78
       Group C5530.750.872930.470.81−0.10 to 0.67
       Group D5732.990.541933.000.45−0.28 to 0.26
      GA at delivery, wks (mean/SD)
       Overall17732.304.397832.054.66−1.04 to 1.34
       Group A3726.954.271925.882.20−1.02 to 3.17
       Group B2930.513.001433.094.22−5.21 to 0.05
       Group C5533.783.202634.133.56−1.92 to 1.22
       Group D5634.992.131934.621.90−0.72 to 1.48
      Interval to delivery after 1st dose, hnMedianIQR
       Overall177200.2360.41–649.2576213.5374.20–806.03−37.73 to 215.12
       Group A30128.8064.65–366.4019101.0263.68–317.92−14.65 to 86.6
       Group B29207.5045.93–735.4012904.19169.37–1800.98100.13–1263.39
       Group C55305.7059.50–933.4326722.7096.01–919.29−44.37 to 202.57
       Group D56185.9164.59–530.8819162.6869.75–530.47−36.47 to 147.85
      Indication of betamethasoneN(%)N(%)
       Overall16167
        PPROM56(34.8)25(37.3)
        Preterm labor70(43.5)23(34.3)
        Preeclampsia28(17.4)10(14.9)
        Other7(4.3)9(13.4)−0.18 to 0.11
       Group A3116
        PPROM13(41.9)11(68.8)
        Preterm labor13(41.9)1(6.3)
        Preeclampsia4(12.9)3(18.8)
        Other1(3.2)1(6.3)−0.54 to 0.57
       Group B2712
        PPROM10(37.0)3(25.0)
        Preterm labor12(44.4)5(41.7)
        Preeclampsia5(18.5)2(16.7)
        Other0(0.0)2(16.7)−0.38 to 0.04
       Group C5022
        PPROM17(34.0)5(22.7)
        Preterm labor23(46.0)10(45.5)
        Preeclampsia7(14.0)3(13.6)
        Other3(6.0)4(18.2)−0.30 to 0.26
       Group D5317
        PPROM16(30.2)6(35.3)
        Preterm labor22(41.5)7(41.2)
        Preeclampsia12(22.6)2(11.8)
        Other3(5.7)2(11.8)−0.31 to 0.30
      Other includes fetal distress, fetal growth restriction, and bleeding.
      CI, confidence interval; IQR, interquartile range; n, number of fetuses; N, number of mothers; PPROM, preterm premature rupture of membranes.
      Khandelwal. Betamethasone 12/24. Am J Obstet Gynecol 2012.
      TABLE 3Delivery and neonatal data variables
      Variable12 hour24 hour95% CI
      Mode of delivery, n (%)
       Overall17778
        Vaginal120(67.8)44(56.4)
        C-section57(32.2)34(43.6)−0.02 to 0.24
       Group A3719
        Vaginal24(64.9)11(57.9)
        C-section13(35.1)8(42.1)−0.20 to 0.34
       Group B2914
        Vaginal16(55.2)8(57.1)
        C-section13(44.8)6(42.9)−0.34 to 0.30
       Group C5526
        Vaginal38(69.1)11(42.3)
        C-section17(30.9)15(57.7)0.04−0.49
       Group D5619
        Vaginal42(75.0)14(73.7)
        C-section14(25.0)5(26.3)−0.22 to 0.24
      Neonatal sex, n (%)
       Overall17778
        Male90(50.8)42(53.8)
        Female87(49.2)36(46.2)−0.16 to 0.10
      BirthweightMeanSDnMeanSD
       Overall1771804.5882.2781720.9847.6−149.7 to 316.9
       Group A371002.8870.219762.6350.0−177.8 to 658.2
       Group B291449.6736.8141872.0914.9−946.0 to 102.0
       Group C552024.7720.9261991.5632.4−295.7 to 362.0
       Group D562301.7639.5192197.4676.7−239.0 to 447.6
      SGA, n (%)
       Overall17725(14.1)7818(23.1)−0.2 to 0.2
       Group A375(13.5)195(26.3)−0.1 to 0.36
       Group B294(13.8)143(21.4)−0.17 to 0.33
       Group C557(12.7)264(15.4)−0.14 to 0.19
       Group D569(16.1)196(31.6)−0.08 to 0.39
      CI, confidence interval; SGA, small for gestational age.
      Khandelwal. Betamethasone 12/24. Am J Obstet Gynecol 2012.
      Neonatal outcomes analyzed are presented in TABLE 4, TABLE 5. Overall the 12- and 24-hour-interval cohorts were similar in most outcomes. The incidence of RDS in the 12-hour arm of group B, when corrected for earlier gestational age of delivery, was not significantly different from the 24-hour arm (P = .14). The longer NICU stay in group D most likely represents a type 1 error with small numbers and seen in only 1 group. However, an increased frequency of NEC was noted in neonates of mothers receiving 12-hour interval dosing, although this complication occurred infrequently and so presented small numbers for analysis. There was no difference in maternal infectious morbidity although longer maternal length of stay was noted for the 24-hour group (Table 6).
      TABLE 4Neonatal outcomes
      Group12 hour24 hourP value95% CIs
      LowerUpper
      Respiratory distress syndrome, N, n (%)
       Overall16761(36.5)7528(37.3)0.91−0.140.12
       Group A3226(81.3)1717(100.0)0.08−0.020.35
       Group B2717(63.0)133(23.1)0.020.100.69
       Group C5514(25.5)267(26.9)0.89−0.220.19
       Group D534(7.5)191(5.3)1.00−0.100.15
      Perinatal mortality, N, n (%)
       Overall17721(11.9)7810(12.8)0.83−0.100.08
       Group A3714(37.8)199(47.4)0.49−0.370.18
       Group B294(13.8)141(7.1)1.00−0.120.25
       Group C551(1.8)260(0.0)1.00−0.110.10
       Group D562(3.6)190(0.0)1.00−0.130.12
      Neonatal sepsis, N, n (%)
       Overall16516(9.7)716(8.5)0.76−0.070.09
       Group A3111(35.5)154(26.7)0.74−0.200.37
       Group B271(3.7)131(7.7)1.00−0.200.12
       Group C554(7.3)241(4.2)1.00−0.070.14
       Group D00
      Antibiotic use >5 days, N, n (%)
       Overall16546(27.9)7121(29.6)0.79−0.140.11
       Group A3118(58.1)1510(66.7)0.58−0.380.21
       Group B271348.1)13646.2)0.91−0.310.35
       Group C551018.2)24312.5)0.74−0.110.22
       Group D5259.6)19210.5)1.00−0.170.15
      Admission to neonatal intensive care unit, N, n (%)
       Overall169131(77.5)7868(87.2)0.08−0.190.001
       Group A3229(90.6)1919(100.0)0.29−0.210.01
       Group B2824(85.7)1413(92.9)0.65−0.260.12
       Group C5541(74.5)2620(76.9)0.82−0.220.18
       Group D5437(68.5)1916(84.2)0.19−0.360.05
      Neonatal intensive care unit, dNMedianIQRNMedianIQR
       Overall164204.25–43.7572227.25–480.39−510
       Group A308717.75–107.251476.514–99.500.52−2810
       Group B274116–5413289.5–520.59−142
       Group C55215–3426216.5–44.50.61−811
       Group D5293–1919207–230.0247
      CI, confidence interval; IQR, interquartile range; n, number of affected fetuses; N, total number of at-risk fetuses.
      Khandelwal. Betamethasone 12/24. Am J Obstet Gynecol 2012.
      TABLE 5Long-term neonatal outcomes
      Outcome12 hour24 hourP value95% CIs
      LowerUpper
      Necrotizing enterocolitis, n (%)
       Overall16110(6.2)700(0.0)0.030.020.10
       Group A295(17.2)130(0.0)0.30−0.080.35
       Group B261(3.8)130(0.0)1.00−0.190.19
       Group C554(7.3)260(0.0)0.30−0.060.17
       Group D00
      Retinopathy of prematurity, n (%)
       Overall7826(33.3)3111(35.5)0.83−0.220.18
       Group A2218(81.8)98(88.9)1.00−0.330.19
       Group B207(35.0)80(0.0)0.08−0.020.57
       Group C251(4.0)103(30.0)0.06−0.550.03
       Group D00
      Intraventricular hemorrhage, n (%)
       Overall9432(34.0)4110(24.4)0.27−0.070.26
       Group A2617(65.4)125(41.7)0.17−0.100.57
       Group B228(36.4)91(11.1)0.22−0.030.54
       Group C306(20.0)153(20.0)1.00−0.250.25
       Group D161(6.3)51(20.0)0.43−0.510.24
      Chronic lung disease, n (%)
       Overall16036(22.5)7020(28.6)0.32−0.180.06
       Group A2822(78.6)1211(91.7)0.65−0.350.09
       Group B2510(40.0)135(38.5)1.00−0.310.34
       Group C553(5.5)264(15.4)0.20−0.250.05
       Group D521(1.9)190(0.0)1.00−0.020.06
      CI, confidence interval.
      Khandelwal. Betamethasone 12/24. Am J Obstet Gynecol 2012.
      TABLE 6Maternal outcomes
      Category12 hour24 hourP value95% CIs
      LowerUpper
      Maternal temperature >100.4°F, n (%)
       Overall1539(5.9)605(8.3)0.54−0.100.05
       Group A294(13.8)161(6.3)0.64−0.100.25
       Group B253(12.0)110(0.0)0.54−0.15.030
       Group C491(2.0)172(11.8)0.16−0.020.34
       Group D501(2.0)162(12.5)0.14−0.020.34
      Maternal postpartum LOS, dMeanSDMeanSD
       Overall1552.821.24603.552.040.01−1.29−0.28
       Group A313.651.78164.383.240.32−2.200.74
       Group B242.791.02113.551.370.08−1.600.09
       Group C502.661.08173.471.380.02−1.41−0.16
       Group D502.480.81162.811.110.20−0.840.18
      CI, confidence interval; LOS, length of stay.
      Khandelwal. Betamethasone 12/24. Am J Obstet Gynecol 2012.
      If all women were to receive the 24-hour dosing, ∼12% (27/221 mothers; 30/250 neonates) would not have received the full course of betamethasone. With 12-hour dosing, this number would be reduced to only 5% (12/221 mothers; 13/250 neonates). Overall 19.7% (50/254) of neonates were delivered within 48 hours of receiving the first dose of betamethasone; 47.2% (120/254) within 1 week; and 60.2% (153/254) within 14 days. Within the 4 groups, delivery within 2, 7, and 14 days were 13.7%, 62.5%, 75% for group A; 19%, 40.5%, 52.4% for group B; 18.5%, 38.3%, 50.6% for group C; and 21.3%, 49.3%, 64% for group D, respectively. There was no difference in incidence of delivery within the 3 time periods between the 12- or 24-hour cohorts, nor was the incidence of RDS different in those delivering within 7 days (P = .81). As expected, all neonates delivering within 7 days in group A developed RDS, irrespective of dosing interval.

      Comment

      This prospective randomized trial suggests equal efficacy of betamethasone when the 2 doses are administered 12 or 24 hours apart in the prevention of RDS. Similar results were shown in a retrospective study comparing the 2 dosage schedules.
      • Haas D.M.
      • McCullough W.
      • Olsen C.H.
      • et al.
      Neonatal outcomes with different betamethasone dosing regimens: a comparison.
      • Haas D.M.
      • McCullough W.
      • McNamara M.F.
      • Olsen C.
      The first 48 hours: comparing 12-hour and 24-hour betamethasone dosing when preterm deliveries occur rapidly.
      Older trials using 6 mg of betamethasone at 12-hour interval for 4 doses also showed benefit in decreasing incidence of RDS, although they did not compare it to the 24-hour dosing interval.
      • Nelson L.H.
      • Meis P.J.
      • Hatjis C.G.
      • Ernest J.M.
      • Dillard R.
      • Schey H.M.
      Premature rupture of membranes: a prospective, randomized evaluation of steroids, latent phase, and expectant management.
      • Doran T.A.
      • 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.
      • Guerrini P.
      • Vesce F.
      • Colla F.
      • Travagli S.
      • Cocilovo G.
      Contribution to the assessment of steroid therapy in the prevention of respiratory distress syndrome in the neonate.
      Maximum benefits are noted in women receiving both doses of betamethasone
      • Wright L.L.
      • Verter J.
      • Younes N.
      • et al.
      Antenatal corticosteroid administration and neonatal outcome in very low birth weight infants: the NICHD neonatal research network.
      • Elimian A.
      • Figueroa R.
      • Spitzer A.R.
      • Ogburn P.L.
      • Wiencek V.
      • Quirk J.G.
      Antenatal corticosteroids: are incomplete courses beneficial?.
      ; with 12-hour dosing, 50% more women could achieve that goal.
      There remain many unanswered questions on the ideal corticosteroid, its dosage, and interval of dosing to achieve maximal fetal benefits with minimal side effects. Greater benefits seen with completed course of betamethasone when compared to partial course could be due to adequate dosage or due to the longer time of fetal exposure for the steroid to become effective. It is also plausible that 1 dose of 24 mg, instead of 2 doses of 12 mg each, of a less soluble, more slowly absorbed steroid may be adequate for clinical benefits. Different trial designs will be needed to answer all the questions. In this trial, we chose to address whether a shorter dosing interval (which is practiced by some physicians without scientific evidence) would result in comparable clinical effects to the 24-hour dosing interval recommended by the NIH consensus statement.
      The effect of corticosteroids for fetal maturation on perinatal outcomes.
      There are many theoretical advantages to the 12-hour dosing schedule, particularly in women who deliver within 24 hours of presentation. Pharmacokinetic data suggest betamethasone levels decrease to less than half in maternal blood by 6 hours postadministration, and are at the lowest level by 12 hours.
      • Ballard P.L.
      • Granberg P.
      • Ballard R.A.
      Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.
      At all times during treatment, fetal serum levels of betamethasone were found to be approximately one third of maternal levels in matched comparisons. A single dose of betamethasone phosphate did not result in fetal lung maturity in sheep, but that of betamethasone acetate did.
      • Jobe A.H.
      • Nitsos I.
      • Pillow J.J.
      • Polglase G.R.
      • Kallapur S.G.
      • Newnham J.P.
      Betamethasone dose and formulation for induced lung maturation in fetal sheep.
      Sustained elevated levels of glucocorticoids are required to maintain maximal occupancy of glucocorticoid receptors in target tissues, which is the rationale for administering 2 consecutive doses of the 1:1 mixture of betamethasone phosphate and acetate (only form currently available for clinical use). Cord blood betamethasone levels decrease to levels found in untreated infants prior to the second dose (given 24 hours later) being administered to the mother, suggesting suboptimal levels for several hours before the second dose is given at 24-hour interval.
      • Ballard P.L.
      • Granberg P.
      • Ballard R.A.
      Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.
      Therefore, there is a possibility of positive effect on fetal lung maturation if the total dose of 24 mg of betamethasone were to be administered at 12- vs 24-hour interval. In addition, Ballard et al
      • Ballard P.L.
      • Gluckman P.D.
      • Liggins G.C.
      • Kaplan S.L.
      • Grumbach M.M.
      Steroid and growth hormone levels in premature infants after prenatal betamethasone therapy to prevent respiratory distress syndrome.
      showed no neonatal cortisol suppression with varying dosage intervals of betamethasone. This led to many physicians administering the 2 doses 12 hours apart when imminent delivery was feared, especially as the 24-hour dosing interval was arbitrarily chosen. However, the Cochrane Review
      • Brownfoot F.C.
      • Crowther C.A.
      • Middleton P.
      Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth.
      in 2008 concluded that no recommendations could be made regarding the optimal antenatal corticosteroid regimen and “trials of dosage and other variations in regimens” were urgently needed.
      The current study has much strength as this is the first randomized study comparing 2 dosing intervals prospectively. In addition, our study population was similar in the 2 groups and a robust representative sample with high actual preterm delivery rates within 14 days (>60%) of receiving betamethasone. Limitations of this study are the relatively small sample size and inability to detect differences in other more rare neonatal outcomes. In addition, an equal proportion of mothers and fetuses in each group were not possible due to higher incidence of preterm delivery in the later gestational age groups. This resulted in unequal distribution of participants in the 2 dosing intervals in groups C and D, explaining the differences in maternal age and race in the 12- vs 24-hour arms. However, these differences appear to have little clinical relevance.
      Despite equivalence in beneficial effects of the 12-hour dosing interval, safety of this regimen has not been established. Our data suggest an increased incidence of NEC in this group of infants. Haas et al
      • Haas D.M.
      • McCullough W.
      • Olsen C.H.
      • et al.
      Neonatal outcomes with different betamethasone dosing regimens: a comparison.
      showed a higher surfactant use and CLD in the 12-hour dosing group. However, no adjustments were made for multiplicity in the power analysis of either study. In addition, if we define NEC differently, no statistical difference was noted in the 12- vs the 24-hour arms (based on clinical diagnosis alone 18 vs 3 cases with P = .09; based on NEC cases requiring surgery 4 vs 0 cases respectively with P = .32 were noted). Therefore, these results may not be real (type 1 error) due to the extremely small sample size of our population. In addition, subgroup analysis is liable to considerable bias. These findings are in contrast to earlier trials that failed to demonstrate any harmful effects when 6 mg of betamethasone was administered at 12-hour interval for 4 doses. Even though some early trials have shown a lack of effect of antenatal steroids on NEC, or even an increased incidence,
      The effect of corticosteroids for fetal maturation on perinatal outcomes.
      the majority of recent studies concluded that betamethasone decreases the incidence of NEC.
      • Roberts D.
      • Dalziel S.
      Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
      • Reber K.M.
      • Nankervis C.A.
      Necrotizing enterocolitis: preventative strategies.
      Future larger prospective randomized trials are needed to confirm our findings and establish the safety of the 12-hour regimen with certainty.

      Acknowledgments

      We are very grateful to the patients, obstetric residents, and nurses of Cooper University Hospital, who helped with the project and encouraged its completion. We would also like to thank Dr Richard Fischer for always promoting the practice of evidence-based medicine and inspiring the generation of this project. No compensation was provided to the above acknowledged. Dr Fischer is Professor, Department of Obstetrics and Gynecology, at Cooper University Hospital.

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