Bar-Lev, Michal R. Rozenfeld MD*; Maayan-Metzger, Ayala MD*; Matok, Ilan MSc†; Heyman, Zahava MD‡; Sivan, Eyal MD§; Kuint, Jacob MD*
Antenatal steroid therapy is recommended for every woman at risk of premature labor during the period from 24 to 34 weeks of gestational age. According to the 1995 published board recommendations of the National Institutes of Health, this treatment reduces the risk of neonatal mortality, respiratory distress syndrome (RDS), intraventricular hemorrhage, and necrotizing enterocolitis in premature infants.1–3 It has also been shown, however, that multiple doses of steroids may increase the risk of neurological and behavioral disorders.3–9
The recommended steroid regimens are either betamethasone or dexamethasone. Both are long-acting synthetic adrenocorticosteroids with identical biological activity (primarily glucocorticoid activity). Both are weak immunosuppressors with a long half-life (up to 72 hours), and they cross the placenta in their active form. Their chemical composition is identical; they differ, however, in the configuration of the methyl group in position 16.10 Another difference between the 2 steroids is found in the drug regimens used. The dexamethasone regimen has sulfites that may be neurotoxic, especially in combination with peroxy nitrite.2,10–11 In a number of randomized studies, betamethasone (although not dexamethasone) was found to temporarily reduce fetal movement and heart-rate variability.1,11–15 In the last few years, some animal models have shown better neurological outcomes using betamethasone rather than dexamethasone.16
In 1999, Baud et al13 published a large retrospective analysis demonstrating a connection between antenatal exposure to betamethasone and a decrease in the risk of periventricular leukomalacia (PVL), a primary risk factor for cerebral palsy in premature infants. This decrease in risk was not observed in the premature infants exposed to dexamethasone in the study. One possible explanation was the preservative used in dexamethasone but not in betamethasone.
Our study compared the short-term outcomes of infants exposed in the antenatal period to betamethasone and with those exposed to dexamethasone to find possible differences between the groups.
MATERIALS AND METHODS
This retrospective study was conducted in a single perinatal center, the Chaim Sheba Medical Center, Tel-Hashomer, Israel. We studied 550 of the 580 infants born in the center between January 1, 1999, and December 31, 2001, weighing 1,750 g or less at birth, whose mothers were treated in the antenatal period with either dexamethasone (263 infants, first 18 months) or betamethasone (287 infants, second 18 months), and who were subsequently admitted to the neonatal department (to either the neonatal intensive care unit or the intermediate care nursery) and then discharged home. We reviewed all the records of the mothers and their infants, including maternal diseases and treatment during pregnancy, as well as infant characteristics, treatment such as postnatal steroids, and complications including RDS, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, and cystic PVL during hospitalizations. Bronchopulmonary dysplasia was defined as oxygen requirement on day 28 or later with a typical chest X-ray. Postnatal systemic steroids were not administered to any of the infants in the study group. Cystic PVL was diagnosed when a brain ultrasound study revealed one or more cysts of any size in the periventricular white matter.
At the time of the study, the recommended antenatal steroid regimen consisted of either 2, 12-mg doses of betamethasone administered intramuscularly 24 hours apart or dexamethasone. In some women, additional courses were given at 7-day intervals if the mothers had not delivered and were still at risk for preterm delivery.
Until June 2000, our center routinely treated the mothers with dexamethasone. As a result of the Baud et al13 study, in June 2000, our obstetricians switched to treatment with betamethasone.
Apart from the change in the steroid treatment, there were no major changes in the organizational structure, key personnel, or medical approaches in either the obstetrics or the neonatal departments during the entire study period.
The trade name of the dexamethasone used by our obstetrician is Dexacort (Teva, Petah-Tikva, Israel); it contains dexamethasone phosphate as its active ingredients, as well as inactive ingredients such as sodium citrate, creatinine, methylparaben (preservative), sodium metabisulfite (preservative), propyl paraben, sodium hydroxide normal 1 N (excipient), and water for injection. The trade name of the dexamethasone described by Baud et al13 is Soludecadron (Merck, Paris, France) and contained the same active and inactive ingredients.
The trade name of the betamethasone used by our obstetricians is Celestone Chronodose (Schering-Plough, Kenilworth, NJ), the same agent described by Baud et al; it contains betamethasone acetate, betamethasone (as disodium phosphate), and benzalkonium chloride (preservative).
Continuous variables were compared using analysis of variance. Categorical variables were compared using the Pearson χ2 test. P ≤ .05 was considered significant.
The study was approved by the institutional review board of the Chaim Sheba Medical Center.
During the study period, 580 infants with a birth weight of 1,750 g or less were born at our institution and were exposed during the antenatal period to either dexamethasone or betamethasone. Eighteen infants (9 in each group) died during hospitalization, and an additional 6 were excluded because of genetic syndromes or major congenital anomalies (trisomy 22, Down syndrome, Beckwith-Wiedemann syndrome, Turner syndrome, convulsive encephalopathy, and major heart valve congenital defect). Six more infants were excluded because of the lack of sufficient data in their maternal records. The remaining 550 infants, who fit the study criteria, defined the study cohort.
No statistically significant differences were found between the 2 groups with regard to the following variables: gestational age, birth weight, percentage of small for gestational age (SGA, defined as birth weight below the third percentile for gestational age using Usher charts), gender, multiplicity, and mode of delivery (Table 1).
A statistically significant difference in the number of steroid courses given to the mothers was found between the groups. In the dexamethasone group, a higher number of courses (2.6 ± 1.6) were given than in the betamethasone group (1.85 ± 1), P < .001.
No statistically significant differences were found between the 2 groups with regard to the number of mothers suffering from hypertension or amnionitis, as well as in the number of mothers who were treated with magnesium sulfate. There were, however, a statistically significantly greater number of mothers with premature rupture of membranes (PROM), and more mothers received tocolytic therapy in the betamethasone group.
There were no statistically significant differences between the 2 groups in the incidence of respiratory and other neonatal complication of prematurity, nor were there differences in the incidence of sepsis and antibiotic treatment (Table 2)
No statistically significant differences were found in the incidence or the severity of intraventricular hemorrhage. There was, however, a difference, although not statistically significant, in the frequency of cystic PVL, which was higher in the betamethasone group (Table 3).
A logistic regression analysis including gestational age, birth weight, gender, multiple pregnancies, delivery mode, amnionitis, maternal hypertension, tocolisis, PROM, number of steroid courses, and type of steroids showed that gestational age was the only significant predictor of PVL, with an odds ratio of 0.8 (95% confidence interval 0.7–0.9).
Low birth weight infants weighing 1,750 g or less were found to have the same short-term outcomes, including rate of cystic PVL and intraventricular hemorrhage, when exposed prenatally to either dexamethasone or betamethasone, despite the fact that infants in the dexamethasone group were exposed to more courses. This finding contradicts the finding of Baud et al13 in their large-cohort study published in 1999, in which more infants with cystic PVL were found in the dexamethasone group. The current study also shows that both agents are equally effective in reducing the incidence of RDS and bronchopulmonary dysplasia, as well as other short-term complications such as necrotizing enterocolitis, retinopathy of prematurity, and infection rate. Consistent with our study results, Baud et al13 also did not find any difference in the incidence of respiratory morbidity (RDS, bronchopulmonary dysplasia), intraventricular hemorrhage, and other complications of prematurity among neonates who were exposed antenatally to dexamethasone or betamethasone. Crowley17 included separate meta-analyses of dexamethasone and betamethasone that demonstrated a similar rate of morbidity prevention by the 2 steroids. However, according to that survey, betamethasone significantly decreased neonatal mortality, whereas mortality was decreased to a lesser extent with dexamethasone.10–11,13 Another study18 has also shown that dexamethasone and PVL are not associated.
This retrospective analysis did not find a significant difference between maternal characteristics in either group, with the exception of more courses in the dexamethasone group, reflecting a change in policy over the years. This finding can only reinforce our conclusion that dexamethasone does not pose a major risk for the development of cystic PVL in comparison with betamethasone. More women in the betamethasone group had their membranes ruptured 24 hours and more before birth, and a higher number of women were treated with tocolysis, as was found by Baud’s study as well13. We do not know whether these 2 parameters are related, but the results might reflect greater efforts over the years devoted to delaying labor to improve the maternal steroid effect.
Although the current study is observational, it has the advantage of being a large study conducted at a single medical center, thus representing a uniform diagnostic and therapeutic approach with no changes in therapy other than the type and number of courses of the steroid used as antenatal therapy administered to the mothers. Baud’s study13 was conducted in 3 different perinatal centers, which might reflect different obstetric practice patterns as well as different neonatal intensive care unit protocols. The rate of SGA in our study was similar in both study groups, in contrast to Baud’s study. Although the increased use of tocolysis in the betamethasone group may have led to higher rates of amnionitis and neonatal sepsis, no such differences were found. The rate of intraventricular hemorrhage was similar in the 2 groups, despite a possible protective influence resulting from repeated doses of dexamethasone. The main aim of this study was to discover whether there is a trend toward differences in short-term outcomes, such as PVL, intraventricular hemorrhage, and necrotizing enterocolitis, in antenatal treatment with dexamethasone versus that with betamethasone. The sample size should be larger to achieve more statistical validity.
To summarize, the results of this study seem to indicate that there is no advantage to betamethasone over dexamethasone as an antenatal steroid therapy in low birth weight infants with respect to reducing brain damage (cystic PVL). Furthermore, there is no difference between the 2 steroids in their capacity to decrease respiratory and other complications related to low birth weight. Additional larger human-based prospective studies and longer follow-up periods are needed to confidently recommend one steroid over the other.
1. Salim R, Nachum Z, Shalev E. Glucocorticoid treatment in preterm birth. Harefuah 1999;137:481–6.
2. Goldenberg RL, Wright LL. Repeated courses of antenatal corticosteroids. Obstet Gynecol 2001;97:316–7.
3. Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement No. 112. 2000 Aug 17–18;17:1–18.
4. Bolt RJ, van Weissenbruch MM, Lafeber HN, Delemarre-van de Waal HA. Glucocorticoids and lung development in the fetus and preterm infant. Pediatr Pulmonol 2001;32:76–91.
5. Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC III, Hauth JC, Wenstrom KD. Preterm birth. In: Williams obstetrics. 21st ed. New York (NY): McGraw-Hill; 2001. p. 690–718.
6. Smith GN, Kingdom JC, Penning DH, Matthews SG. Antenatal corticosteroids: is more better? Lancet 2000;355:251–2.
7. Guinn DA, Atkinson MW, Sullivan L, Lee M, MacGregor S, Parilla BV, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial. JAMA 2001;286:1581–7.
8. French NP, Hagan R, Evans SF, Mullan A, Newnham JP. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004;190:588–95.
9. Quinlivan JA, Archer MA, Evans SF, Newnham JP, Dunlop SA. Fetal sciatic nerve growth is delayed following repeated maternal injections of corticosteroid in sheep. J Perinat Med 2000;28:26–33.
10. Nelson KB, Grether JK. Causes of cerebral palsy. Curr Opin Pediatr 1999;11:487–91.
11. Walfisch A, Hallak M, Mazor M. Multiple courses of antenatal steroids: risks and benefits. Obstet Gynecol 2001;98:491–7.
12. Senat MV, Minoui S, Multon O, Fernandez H, Frydman R, Ville Y. Effect of dexamethasone and betamethasone on fetal heart rate variability in preterm labour: a randomised study. Br J Obstet Gynaecol 1998;105:749–55.
13. Baud O, Foix-L’Helias L, Kaminski M, Audibert F, Jarreau PH, Papiernik E, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999;341:1190–6.
14. Mushkat Y, Ascher-Landsberg J, Keidar R, Carmon E, Pauzner D, David MP. The effect of betamethasone versus dexamethasone on fetal biophysical parameters. Eur J Obstet Gynecol Reprod Biol 2001;97:50–2.
15. Rotmensch S, Liberati M, Vishne TH, Celentano C, Ben-Rafael Z, Bellati U. The effect of betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities: a prospective randomized trial. Acta Obstet Gynecol Scand 1999;78:493–500.
16. Rayburn WF, Christensen HD, Gonzalez CL. A placebo-controlled comparison between betamethasone and dexamethasone for fetal maturation: differences in neurobehavioral development of mice offspring. Am J Obstet Gynecol 1997;176:842–51.
17. Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue 2, 2000. Oxford: Update Software.
18. LeFlore JL, Salhab WA, Broyles RS, Engle WD. Association of antenatal and postnatal dexamethasone exposure with outcomes in extremely low birth weight neonates. Pediatrics 2002;110:275–9.