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Antenatal corticosteroid therapy: a comparative study of dexamethasone and betamethasone effects on fetal Doppler flow velocity waveforms
European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 170–174 www.elsevier.com/locate/ejogrb
Antenatal corticosteroid therapy: a comparative study of dexamethasone and betamethasone effects on fetal Doppler flow velocity waveforms Remigiusz Urbana,*, Adam Lemancewicza, Jerzy Przepies´c´a, Jan Urbana, Małgorzata Kre˛towskab a
Department of Perinatology, Medical Academy of Bialystok, University Hospital, Sklodowska-Curie 24a, 15-276 Bialystok, Poland b Technical University, Bialystok, Poland
Received 14 June 2004; received in revised form 4 September 2004; accepted 23 September 2004
Abstract Objective: To compare the effects of antenatal administration of dexamethasone and betamethasone, used in two different regimens, on fetal Doppler flow velocities. Study design: Sixty-seven women at risk for preterm delivery received course of corticosteroids by means of a computer-generated randomization table. The Doppler examination of the pulsatility index (PI) of the umbilical artery (UA), the middle cerebral artery (MCA) and the middle cerebral artery/umbilical artery PI ratio (MCA PI/UA PI) were performed before treatment, 24 and 72 h after the first dose of corticosteroids. The SAS system was used to perform statistical analysis. Results: No significant change was observed in UA PI through dexamethasone therapy. In MCA there was a significant decrease in PI at 72 h (2 0.43 before and 1.68 0.31 after, p = 0.0001). Similarly a significant decrease in MCA PI/UA PI ratio was noted (2.09 0.51 before and 1.83 0.4 after, p = 0.0137). No significant changes were observed in UA PI, MCA PI and MCA PI/UA PI ratio during betamethasone treatment. Conclusions: Our results indicate significant decrease in fetal middle cerebral artery impedance at 72 h after maternal administration of the first dose of dexamethasone. Effects of dexamethasone on fetal brain warrants further research. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Dexamethasone; Betamethasone; Antenatal corticosteroids; Doppler velocimetry
1. Introduction The use of antenatal corticosteroids for the prevention of neonatal respiratory distress syndrome (RDS) stems from the animal work by Liggins and Howie [1]. Since then, 15 additional prospective randomized controls trials have been performed. Crowley [2] conducted a meta-analysis of these trials confirming that maternal steroid therapy significantly decreased the incidence and severity of RDS. Neonatal mortality was also reduced, as was the incidence of intraventricular hemorrhage and necrotizing enterocolitis.
* Corresponding author. Tel.: +48857468662; fax: +48857468662. E-mail address: [email protected] (R. Urban).
Previous studies have shown that maternal management of synthetic corticosteroids can cause a transient reduction in fetal heart rate (FHR) variability and can also alter biophysical profile parameters [3–7]. Doppler examination is another important tool to assess fetal well being. In fact, conflicting results concerning the effects of exogenous corticosteroids on fetal hemodynamics have been reported. Cohlen et al. [8] found, following antenatal betamethasone therapy, no significant change in the pulsatility index (PI) of any of the fetal vessels. Senat and Ville [7] recorded no significant effects of maternal steroids on Doppler flow velocity measurements in intrauterine growth retardation fetuses (IUGR). Chitrit et al. [9] observed a transient, significant and unexplained decrease in fetal middle cerebral artery (MCA) impedance on the fourth day
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.09.009
R. Urban et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 170–174
following maternal dexamethasone administration. Deren et al. [10] and Rotmensch et al. [11] in different investigations, demonstrated that betamethasone administration can cause a significant but transient, suppression of fetal breathing and body movements, however the middle cerebral and umbilical artery (UA) Doppler indices were found to be unaffected. Piazze et al. [12] found that betamethasone treatment is associated with significant reduction of the middle cerebral pulsatility index, especially at gestation before 32 weeks. The purpose of present study was to compare the effects of antenatal administration of dexamethasone and betamethasone, used in two different regimens, on fetal Doppler flow velocity waveforms in pregnancies with normal fetoplacental vascular resistance.
2. Materials and methods The study was performed in the Department of Perinatology, Medical Academy of Bialystok, Poland. This investigation received approval from University Ethic Committee. Sixty-seven women with singleton pregnancies were approached for participation, and informed consent was obtained. At the time of initial scanning, all pregnancies had umbilical artery flow velocity waveforms values between the 5th and the 95th centile, consistent with reference limits as published by Arduini and Rizzo [13]. There were no infants with major structural malformations or abnormal karyotype. Gestational age was calculated according to the date of last menstrual period and confirmed by first trimester ultrasound. All patients were considered at risk for preterm delivery by medical indication (preterm contractions of the uterus, preterm premature rupture of the membranes, cervical length less 20 mm, placenta praevia) before 34 weeks and received course of corticosteroids. Two different corticosteroid regimens were used: (1) four intramuscular injections of 6 mg dexamethasone (Dexaven, Jelfa, Poland) were given 12 h apart and (2) two intramuscular injections of 12 mg betamethasone (Diprophos, Schering-Plough, Belgium) were given 24 h apart, accordingly to National Institutes of Health (NIH) recommendations [14]. Subjects were assigned to dexamethasone or betamethasone by means of a computer-generated randomization table, and their allocation was placed in consecutively numbered and sealed opaque envelopes. Tocolytic agent, used to stop the preterm contractions of the uterus, was introduced before the first Doppler examination and discontinued after the last evaluation. Fenoterol (Partusisten, Boehringer Ingelheim, Germany) was administered via infusion pump. The initial infusion was 0.5–1 mg/min, with the rate increased when necessary every 10–15 min to maximum of 3.0 mg/min. The Doppler examination included the assessment of the pulsatility index of the umbilical artery, the fetal middle cerebral artery and the middle cerebral artery/umbilical artery PI ratio (MCA PI/UA PI). The measurements of color
171
Doppler flow were performed in all patients before treatment, 24 and 72 h after the first dose of dexamethasone or betamethasone with Toshiba SSH 140 A/G with a 3.75 MHz convex probe. The spatial peak temporal average power did not exceed 87 mW/cm2 and the Doppler angle of insonation was less than 468. The measurements were taken between the contractions during fetal quiescence. The women rested in a semi-recumbent position throughout the Doppler examination. The umbilical artery was examined on the free umbilical loop and the fetal middle cerebral artery about 1 cm distal to its origin from the internal carotid artery. For each artery, the image was frozen when three or more consecutive similar waveforms of good quality were obtained. The PI was calculated by averaging the first two pulsatility indexes from two consecutive velocity waveforms. The Doppler examinations were performed by two of the authors (UR and LA) and each subject was evaluated always by the same operator. Intra- and interobserver variation was calculated as a coefficient of variation (standard deviation/mean 100%). The intraobserver coefficients of variation, for measurements in UA and MCA were less than 4% and similar for the observers (UR and LA). To asses the interobserver differences the repeated measurements of Doppler indexes were performed by both operators in 31 pregnancies, before 34 weeks of gestation, without medical indication for antenatal corticosteroids treatment. The interobserver coefficients of variations were 5.6 and 6.3% for measurements in UA and MCA, respectively. In both treatment groups the same clinical monitoring routine was followed. Continuous FHR and uterine activity monitoring was performed in all patients using system Sonicaid 8002 (Oxford Instruments Plc. Medical Systems Division) before, during and after the course of steroids. FHR patterns were classified in the manner described by Kubli et al. [15]. Abnormal fetal heart rate patterns were defined as the presence of fetal tachycardia or bradycardia, late decelerations, or moderate to severe variable decelerations of fetal heart rate. The statistical analysis was performed using SAS System Release 6.12. Data were analyzed with Student’s unpaired ttest (maternal demographic data, neonatal outcome) and Fisher’s exact test (abnormal fetal heart rate patterns). To compare mean values of UA PI, MCA PI and MCA PI/UA PI coefficients before treatment, and 24 and 72 h after the first dose of dexamethasone or betamethasone Student’s paired ttest was applied. p-values less than 0.05 were considered statistically significant. The data are expressed as mean standard deviation. An abbreviation, NS means no significant differences.
3. Results There were 67 patients assigned to receive either dexamethasone (n = 34) or betamethasone (n = 33). Mean gestational age and S.E.M. at dexamethasone and betha-
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R. Urban et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 170–174
Table 1 Umbilical (UA), fetal middle cerebral (MCA) blood velocity values and number of abnormal fetal heart rate (FHR) patterns before treatment, 24 and 72 h after the first dose of dexamethasone
UA PI MCA PI MCA PI/UA PI Abnormal FHR patterns (%) *
Before treatment
24 h after first dose
Significance (p)
72 h after first dose
Significance (p)
0.98 0.17 2 0.43 2.09 0.51 0
0.94 0.1 1.84 0.34 2.04 0.46 6 (17.6%)
NS NS NS NS
0.93 0.13 1.68 0.31 1.83 0.4 4 (11.8%)
NS 0.0001* 0.0137* NS
Statistically significant differences at 0.05 significance level.
metasone administration was 31.5 0.3 and 31.4 0.5 weeks. Mean maternal age and S.E.M. was 29.7 1.1 and 27.1 0.9 years. There were no statistically significant differences between numbers of nulliparous (12 versus 10) and multiparous (22 versus 23) in both groups. Tocolytic therapy was used in 18 subjects (53%) who received dexamethasone and in 16 (48.5%) given betamethasone. Observations regarding neonatal outcome, including: gestational age at delivery (37.7 0.49 weeks versus 36.3 0.66 weeks), neonatal weight (3038 144 g versus 3035 153 g), Apgar score in 1 min (8.4 0.32 versus 8.0 0.45), Apgar score in 5 min (9.5 0.19 versus 9.3 0.3), umbilical cord artery pH (7.27 0.02 versus 7.26 0.02) and base deficit (4.16 0.9 versus 4.6 0.8) were compared in dexamethasone and betamethasone groups, respectively and presented at mean S.E.M. There were no statistically significant differences. Umbilical and middle cerebral blood velocity values and number of abnormal fetal heart rate patterns before treatment, and 24 and 72 h after the first dose of dexamethasone are shown in Table 1. Compared with mean value at initial presentation no significant changes were observed in UA PI and number of abnormal FHR patterns. In middle cerebral artery, there was a significant decrease in PI at 72 h (2 0.43 before and 1.68 0.31 after, p = 0.0001). Similarly, compared with pretreatment mean value, a significant decrease in MCA PI/UA PI ratio was noted at 72 h after the administration of first dose of dexamethasone (2.09 0.51 before and 1.83 0.4 after, p = 0.0137). The changes are presented graphically on Figs. 1 and 2. A separate analyzes of MCA PI before treatment, and 24 and 72 h after the first dose of dexamethasone were made for
Fig. 1. Fetal middle cerebral artery pulsatility index (MCA PI) values before treatment, (0), 24 and 72 h after the first dose of dexamethasone.
subgroups receiving (n = 18) and not receiving (n = 16) tocolysis. Compared with mean value at initial presentation, there were significant decreases in MCA PI at 72 h in both subgroups (2.04 0.46 before and 1.73 0.33 after, p = 0.013 and 1.96 0.39 before and 1.62 0.27 after, p = 0.0045 in a subgroups receiving and not receiving tocolytic, respectively). Umbilical and middle cerebral blood velocity values and number of abnormal fetal heart rate patterns before treatment, and 24 and 72 h after the first dose of betamethasone are shown in Table 2. Compared with mean values at initial presentation no significant changes were observed in UA PI, MCA PI and MCA PI/UA PI ratio and number of abnormal FHR patterns.
4. Discussion The commonly utilized corticosteroids for enhancement of fetal maturity are dexamethasone and betamethasone. These two steroids have been identified as the most appropriate for antenatal use as they readily cross the placenta and have long half-lives and limited mineralocorticoid activity. In the present study, we have observed that in pregnancies with normal umbilical artery velocimetry, middle cerebral artery PI decreased significantly 72 h following the first dose of dexamethasone. Moreover, compared with pretreatment mean value, a significant decrease in the middle cerebral artery/umbilical artery PI ratio was noted at 72 h after the administration of first dose of dexamethasone. The changes
Fig. 2. The middle cerebral artery/umbilical artery P1 ratio (MCA PI/UA PI) values before treatment, (0), 24 and 72 h after the first dose of dexamethasone.
R. Urban et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 170–174
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Table 2 Umbilical (UA), fetal middle cerebral (MCA) blood velocity values and number of abnormal fetal heart rate (FHR) patterns before treatment, 24 and 72 h after the first dose of betamethasone
UA PI MCA PI MCA PI/UA PI Abnormal FHR patterns (%)
Before treatment
24 h after first dose
Significance (p)
72 h after first dose
Significance (p)
0.97 0.16 1.93 0.41 2.04 0.51 0
0.92 0.015 1.74 0.29 1.97 0.64 7 (21.2%)
NS NS NS NS
0.92 0.15 1.79 0.32 2.01 0.53 3 (9.1%)
NS NS NS NS
* Statistically significant differences at 0.05 significance level.
in MCA PI were also significant in subgroups receiving and not receiving tocolysis. Since tocolytic agent was introduced before the first Doppler examination and discontinued after the last evaluation, it should not have influenced the changes during steroid therapy. These findings are in agreement with data, published by Chitrit et al. [9]. They observed in healthy fetuses a transient and significant decrease in fetal MCA PI and an increase in UA PI/ MCA PI ratio on the fourth day after maternal dexamethasone administration. Senat and Ville [7] examined the effect of steroids on blood flow waveforms in intrauterine growth retardation fetuses and found no significant changes of PI values in the different vessels during the dexamethasone course. PI recorded from the umbilical arteries, descending aorta and middle cerebral artery were similar before, 24–48 h and 4–7 days after first injection were given to the mother. However, the MCA PI showed a trend to decrease within the course and after the treatment was stopped. The trend might be explained by either the physiological decrease in resistance in the fetal brain with gestation that would be expected to be even more marked in IUGR fetuses, or the early sign of redistribution of the blood flow. Decrease in MCA PI may be caused by a direct effect of corticosteroids on the fetal brain. Cerebral areas where corticosteroid receptors are present, in particular a number of brainstem nuclei, are part of the presumptive sleep center in the pons, and are thought to control motor activity of the fetus in the third trimester [16]. Vasomotor factors are also stimulated by corticosteroid administration. Experimental studies on fetal sheep have shown that steroids may cause considerable changes in fetal blood pressure, heart rate and blood volume [17]. It has been stated that maternal administration of corticosteroids up-regulates placental expression and secretion of corticotrophin-releasing hormone (CRH) [18,19]. Recent investigations have shown that CRH causes vasodilatation via induction of nitric oxide synthase in human placental and fetal circulations [20,21]. It is therefore, possible that such mechanism may be operating in the regulation of the fetal cerebral blood flow. In our study the numbers of abnormal FHR patterns at 24 and 72 h after the first dose of steroids were similar in dexamethasone and betamethasone groups. Our data show no significant changes in umbilical artery impedance during and after the course of steroids administration. These results, obtained from UA are consistent with all previous studies
[3,7–12] except one. Wallace and Baker [22] reported an association between betamethasone treatment and decreased placental vascular resistance as reflected by waveforms obtained from umbilical artery. Subsequently, the different impact of corticosteroids in UA flow velocity waveforms in their study may be due to fetoplacental dysfunction observed in those pregnancies before treatment. Compared with the mean values at initial presentation, there were any significant changes in MCA PI and MCA PI/ UA PI ratio at 24 and 72 h after the first dose of betamethasone. Ballard and Ballard [23] analyzed the pharmacokinetics of dexamethasone and betamethasone and found that the two recommended regimens should produce only minor differences in the circulating level of glucocorticoid activity in the treated fetus, with lower peak levels for dexamethasone but a somewhat longer time of elevated activity. This may explain that the significant decrease in MCA PI and MCA PI/ UA PI was observed in our study only after dexamethasone administration. There is no evidence that these effects on blood flow are harmful to the fetus, however more concerning are data suggesting a neurotoxic effect of dexamethasone [24]. Our results indicate significant decrease in fetal middle cerebral artery impedance at 72 h after maternal administration of the first dose of dexamethasone. No significant changes were observed in blood velocity values during betamethasone treatment. Effects of dexamethasone on fetal brain warrants further research.
Acknowledgment The study compares the effects of corticosteroids on fetal Doppler flow velocity, observing significant decrease in middle cerebral artery impedance at 72 h after the first dose of dexamethasone.
References [1] Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50(4):515–25. [2] Crowley PA. Corticosteroids prior to preterm delivery. In The Cochrane Library. Oxford: Update software. Search date 1996: primary sources Cochrane Pregnancy and Childbirth Group Trials Register 2000 (1).
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[3] Derks JB, Mulder EJ, Visser GH. The effects of maternal betamethasone administration on the fetus. Br J Obstet Gynaecol 1995;102(1):40–6. [4] Mulder EJ, Derks JB, Zonneveld MF, Bruinse HW, Visser GH. Transient reduction in fetal activity and heart rate variation after maternal betamethasone administration. Early Hum Dev 1994;36(1):49–60. [5] Mulder EJ, Derks JB, Visser GH. Antenatal corticosteroid therapy and fetal behaviour: a randomised study of the effects of betamethasone and dexamethasone. Br J Obstet Gynaecol 1997;104(11):1239–47. [6] Magee LA, Dawes GS, Moulden M, Redman CW. A randomised controlled comparison of betamethasone with dexamethasone: effects on the antenatal fetal heart rate. Br J Obstet Gynaecol 1997;104(11):1233–8. [7] Senat MV, Ville Y. Effect of steroids on arterial Doppler in intrauterine growth retardation fetuses. Fetal Diagn Ther 2000;15(1):36–40. [8] Cohlen BJ, Stigter RH, Derks JB, Mulder EJ, Visser GH. Absence of significant hemodynamic changes in the fetus following maternal betamethasone administration. Ultrasound Obstet Gynecol 1996;8(4):252–5. [9] Chitrit Y, Caubel P, Herrero R, Schwinte AL, Guillaumin D, Boulanger MC. Effects of maternal dexamethasone administration on fetal Doppler flow velocity waveforms. Br J Obstet Gynaecol 2000;107(4): 501–7. [10] Deren O, Karaer C, Onderoglu L, Yigit N, Durukan T, Bahado-Singh RO. The effect of steroids on the biophysical profile and Doppler indices of umbilical and middle cerebral arteries in healthy preterm fetuses. Eur J Obstet Gynecol Reprod Biol 2001;99(1):72–6. [11] Rotmensch S, Liberati M, Celentano C, et al. The effect of betamethasone on fetal biophysical activities and Doppler velocimetry of umbilical and middle cerebral arteries. Acta Obstet Gynecol Scand 1999;78(9):768–73. [12] Piazze JJ, Anceschi MM, La-Torre R, Amici F, Maranghi L, Cosmi EV. Effect of antenatal betamethasone therapy on maternal-fetal Doppler velocimetry. Early Hum Dev 2001;60(3):225–32. [13] Arduini D, Rizzo G. Normal values of pulsatility index from fetal vessels: a cross-sectional study on 1556 healthy fetuses. J Perinat Med 1990;18:165–72.
[14] Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. J Am Med Assoc 1995;273(5):413–8. [15] Kubli FW, Hon EH, Khazin AF. Observations on heart rate and pH in human fetus during labor. Am J Obstet Gynecol 1969;104:1190–206. [16] de-Kloet ER, Reul JM, Sutanto W. Corticosteroids and the brain. J Steroid Biochem Mol Biol 1990;37(3):387–94. [17] Derks JB, Giussani DA, Jenkins SL, et al. A comparative study of cardiovascular, endocrine and behavioural effects of betamethasone and dexamethasone administration to fetal sheep. J Physiol 1997;499(Pt 1):217–26. [18] Robinson BG, Emanuel RL, Frim DM, Majzoub JA. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci USA 1988;85(14):5244–8. [19] Korebrits C, Yu DH, Ramirez MM, Marinoni E, Bocking AD, Challis JR. Antenatal glucocorticoid administration increases corticotrophinreleasing hormone in maternal plasma. Br J Obstet Gynaecol 1998;105(5):556–61. [20] Clifton VL, Read MA, Leitch IM, et al. Corticotropin-releasing hormone-induced vasodilatation in the human fetal-placental circulation: involvement of the nitric oxide-cyclic guanosine 30 ,50 -monophosphate-mediated pathway. J Clin Endocrinol Metab 1995;80(10): 2888–93. [21] Challis JR, Matthews SG, Van-Meir C, Ramirez MM. Current topic: the placental corticotrophin-releasing hormone-adrenocorticotrophin axis. Placenta 1995;16(6):481–502. [22] Wallace EM, Baker LS. Effect of antenatal betamethasone administration on placental vascular resistance. Lancet 1999;353(9162): 1404–7. [23] Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995;173(1): 254–62. [24] Baud O, Foix-L-Helias L, Kaminski M, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999;341(16):1190–6.
Antenatal corticosteroid therapy: a comparative study of dexamethasone and betamethasone effects on fetal Doppler flow velocity waveforms Remigiusz Urbana,*, Adam Lemancewicza, Jerzy Przepies´c´a, Jan Urbana, Małgorzata Kre˛towskab a
Department of Perinatology, Medical Academy of Bialystok, University Hospital, Sklodowska-Curie 24a, 15-276 Bialystok, Poland b Technical University, Bialystok, Poland
Received 14 June 2004; received in revised form 4 September 2004; accepted 23 September 2004
Abstract Objective: To compare the effects of antenatal administration of dexamethasone and betamethasone, used in two different regimens, on fetal Doppler flow velocities. Study design: Sixty-seven women at risk for preterm delivery received course of corticosteroids by means of a computer-generated randomization table. The Doppler examination of the pulsatility index (PI) of the umbilical artery (UA), the middle cerebral artery (MCA) and the middle cerebral artery/umbilical artery PI ratio (MCA PI/UA PI) were performed before treatment, 24 and 72 h after the first dose of corticosteroids. The SAS system was used to perform statistical analysis. Results: No significant change was observed in UA PI through dexamethasone therapy. In MCA there was a significant decrease in PI at 72 h (2 0.43 before and 1.68 0.31 after, p = 0.0001). Similarly a significant decrease in MCA PI/UA PI ratio was noted (2.09 0.51 before and 1.83 0.4 after, p = 0.0137). No significant changes were observed in UA PI, MCA PI and MCA PI/UA PI ratio during betamethasone treatment. Conclusions: Our results indicate significant decrease in fetal middle cerebral artery impedance at 72 h after maternal administration of the first dose of dexamethasone. Effects of dexamethasone on fetal brain warrants further research. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Dexamethasone; Betamethasone; Antenatal corticosteroids; Doppler velocimetry
1. Introduction The use of antenatal corticosteroids for the prevention of neonatal respiratory distress syndrome (RDS) stems from the animal work by Liggins and Howie [1]. Since then, 15 additional prospective randomized controls trials have been performed. Crowley [2] conducted a meta-analysis of these trials confirming that maternal steroid therapy significantly decreased the incidence and severity of RDS. Neonatal mortality was also reduced, as was the incidence of intraventricular hemorrhage and necrotizing enterocolitis.
* Corresponding author. Tel.: +48857468662; fax: +48857468662. E-mail address: [email protected] (R. Urban).
Previous studies have shown that maternal management of synthetic corticosteroids can cause a transient reduction in fetal heart rate (FHR) variability and can also alter biophysical profile parameters [3–7]. Doppler examination is another important tool to assess fetal well being. In fact, conflicting results concerning the effects of exogenous corticosteroids on fetal hemodynamics have been reported. Cohlen et al. [8] found, following antenatal betamethasone therapy, no significant change in the pulsatility index (PI) of any of the fetal vessels. Senat and Ville [7] recorded no significant effects of maternal steroids on Doppler flow velocity measurements in intrauterine growth retardation fetuses (IUGR). Chitrit et al. [9] observed a transient, significant and unexplained decrease in fetal middle cerebral artery (MCA) impedance on the fourth day
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.09.009
R. Urban et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 170–174
following maternal dexamethasone administration. Deren et al. [10] and Rotmensch et al. [11] in different investigations, demonstrated that betamethasone administration can cause a significant but transient, suppression of fetal breathing and body movements, however the middle cerebral and umbilical artery (UA) Doppler indices were found to be unaffected. Piazze et al. [12] found that betamethasone treatment is associated with significant reduction of the middle cerebral pulsatility index, especially at gestation before 32 weeks. The purpose of present study was to compare the effects of antenatal administration of dexamethasone and betamethasone, used in two different regimens, on fetal Doppler flow velocity waveforms in pregnancies with normal fetoplacental vascular resistance.
2. Materials and methods The study was performed in the Department of Perinatology, Medical Academy of Bialystok, Poland. This investigation received approval from University Ethic Committee. Sixty-seven women with singleton pregnancies were approached for participation, and informed consent was obtained. At the time of initial scanning, all pregnancies had umbilical artery flow velocity waveforms values between the 5th and the 95th centile, consistent with reference limits as published by Arduini and Rizzo [13]. There were no infants with major structural malformations or abnormal karyotype. Gestational age was calculated according to the date of last menstrual period and confirmed by first trimester ultrasound. All patients were considered at risk for preterm delivery by medical indication (preterm contractions of the uterus, preterm premature rupture of the membranes, cervical length less 20 mm, placenta praevia) before 34 weeks and received course of corticosteroids. Two different corticosteroid regimens were used: (1) four intramuscular injections of 6 mg dexamethasone (Dexaven, Jelfa, Poland) were given 12 h apart and (2) two intramuscular injections of 12 mg betamethasone (Diprophos, Schering-Plough, Belgium) were given 24 h apart, accordingly to National Institutes of Health (NIH) recommendations [14]. Subjects were assigned to dexamethasone or betamethasone by means of a computer-generated randomization table, and their allocation was placed in consecutively numbered and sealed opaque envelopes. Tocolytic agent, used to stop the preterm contractions of the uterus, was introduced before the first Doppler examination and discontinued after the last evaluation. Fenoterol (Partusisten, Boehringer Ingelheim, Germany) was administered via infusion pump. The initial infusion was 0.5–1 mg/min, with the rate increased when necessary every 10–15 min to maximum of 3.0 mg/min. The Doppler examination included the assessment of the pulsatility index of the umbilical artery, the fetal middle cerebral artery and the middle cerebral artery/umbilical artery PI ratio (MCA PI/UA PI). The measurements of color
171
Doppler flow were performed in all patients before treatment, 24 and 72 h after the first dose of dexamethasone or betamethasone with Toshiba SSH 140 A/G with a 3.75 MHz convex probe. The spatial peak temporal average power did not exceed 87 mW/cm2 and the Doppler angle of insonation was less than 468. The measurements were taken between the contractions during fetal quiescence. The women rested in a semi-recumbent position throughout the Doppler examination. The umbilical artery was examined on the free umbilical loop and the fetal middle cerebral artery about 1 cm distal to its origin from the internal carotid artery. For each artery, the image was frozen when three or more consecutive similar waveforms of good quality were obtained. The PI was calculated by averaging the first two pulsatility indexes from two consecutive velocity waveforms. The Doppler examinations were performed by two of the authors (UR and LA) and each subject was evaluated always by the same operator. Intra- and interobserver variation was calculated as a coefficient of variation (standard deviation/mean 100%). The intraobserver coefficients of variation, for measurements in UA and MCA were less than 4% and similar for the observers (UR and LA). To asses the interobserver differences the repeated measurements of Doppler indexes were performed by both operators in 31 pregnancies, before 34 weeks of gestation, without medical indication for antenatal corticosteroids treatment. The interobserver coefficients of variations were 5.6 and 6.3% for measurements in UA and MCA, respectively. In both treatment groups the same clinical monitoring routine was followed. Continuous FHR and uterine activity monitoring was performed in all patients using system Sonicaid 8002 (Oxford Instruments Plc. Medical Systems Division) before, during and after the course of steroids. FHR patterns were classified in the manner described by Kubli et al. [15]. Abnormal fetal heart rate patterns were defined as the presence of fetal tachycardia or bradycardia, late decelerations, or moderate to severe variable decelerations of fetal heart rate. The statistical analysis was performed using SAS System Release 6.12. Data were analyzed with Student’s unpaired ttest (maternal demographic data, neonatal outcome) and Fisher’s exact test (abnormal fetal heart rate patterns). To compare mean values of UA PI, MCA PI and MCA PI/UA PI coefficients before treatment, and 24 and 72 h after the first dose of dexamethasone or betamethasone Student’s paired ttest was applied. p-values less than 0.05 were considered statistically significant. The data are expressed as mean standard deviation. An abbreviation, NS means no significant differences.
3. Results There were 67 patients assigned to receive either dexamethasone (n = 34) or betamethasone (n = 33). Mean gestational age and S.E.M. at dexamethasone and betha-
172
R. Urban et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 170–174
Table 1 Umbilical (UA), fetal middle cerebral (MCA) blood velocity values and number of abnormal fetal heart rate (FHR) patterns before treatment, 24 and 72 h after the first dose of dexamethasone
UA PI MCA PI MCA PI/UA PI Abnormal FHR patterns (%) *
Before treatment
24 h after first dose
Significance (p)
72 h after first dose
Significance (p)
0.98 0.17 2 0.43 2.09 0.51 0
0.94 0.1 1.84 0.34 2.04 0.46 6 (17.6%)
NS NS NS NS
0.93 0.13 1.68 0.31 1.83 0.4 4 (11.8%)
NS 0.0001* 0.0137* NS
Statistically significant differences at 0.05 significance level.
metasone administration was 31.5 0.3 and 31.4 0.5 weeks. Mean maternal age and S.E.M. was 29.7 1.1 and 27.1 0.9 years. There were no statistically significant differences between numbers of nulliparous (12 versus 10) and multiparous (22 versus 23) in both groups. Tocolytic therapy was used in 18 subjects (53%) who received dexamethasone and in 16 (48.5%) given betamethasone. Observations regarding neonatal outcome, including: gestational age at delivery (37.7 0.49 weeks versus 36.3 0.66 weeks), neonatal weight (3038 144 g versus 3035 153 g), Apgar score in 1 min (8.4 0.32 versus 8.0 0.45), Apgar score in 5 min (9.5 0.19 versus 9.3 0.3), umbilical cord artery pH (7.27 0.02 versus 7.26 0.02) and base deficit (4.16 0.9 versus 4.6 0.8) were compared in dexamethasone and betamethasone groups, respectively and presented at mean S.E.M. There were no statistically significant differences. Umbilical and middle cerebral blood velocity values and number of abnormal fetal heart rate patterns before treatment, and 24 and 72 h after the first dose of dexamethasone are shown in Table 1. Compared with mean value at initial presentation no significant changes were observed in UA PI and number of abnormal FHR patterns. In middle cerebral artery, there was a significant decrease in PI at 72 h (2 0.43 before and 1.68 0.31 after, p = 0.0001). Similarly, compared with pretreatment mean value, a significant decrease in MCA PI/UA PI ratio was noted at 72 h after the administration of first dose of dexamethasone (2.09 0.51 before and 1.83 0.4 after, p = 0.0137). The changes are presented graphically on Figs. 1 and 2. A separate analyzes of MCA PI before treatment, and 24 and 72 h after the first dose of dexamethasone were made for
Fig. 1. Fetal middle cerebral artery pulsatility index (MCA PI) values before treatment, (0), 24 and 72 h after the first dose of dexamethasone.
subgroups receiving (n = 18) and not receiving (n = 16) tocolysis. Compared with mean value at initial presentation, there were significant decreases in MCA PI at 72 h in both subgroups (2.04 0.46 before and 1.73 0.33 after, p = 0.013 and 1.96 0.39 before and 1.62 0.27 after, p = 0.0045 in a subgroups receiving and not receiving tocolytic, respectively). Umbilical and middle cerebral blood velocity values and number of abnormal fetal heart rate patterns before treatment, and 24 and 72 h after the first dose of betamethasone are shown in Table 2. Compared with mean values at initial presentation no significant changes were observed in UA PI, MCA PI and MCA PI/UA PI ratio and number of abnormal FHR patterns.
4. Discussion The commonly utilized corticosteroids for enhancement of fetal maturity are dexamethasone and betamethasone. These two steroids have been identified as the most appropriate for antenatal use as they readily cross the placenta and have long half-lives and limited mineralocorticoid activity. In the present study, we have observed that in pregnancies with normal umbilical artery velocimetry, middle cerebral artery PI decreased significantly 72 h following the first dose of dexamethasone. Moreover, compared with pretreatment mean value, a significant decrease in the middle cerebral artery/umbilical artery PI ratio was noted at 72 h after the administration of first dose of dexamethasone. The changes
Fig. 2. The middle cerebral artery/umbilical artery P1 ratio (MCA PI/UA PI) values before treatment, (0), 24 and 72 h after the first dose of dexamethasone.
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Table 2 Umbilical (UA), fetal middle cerebral (MCA) blood velocity values and number of abnormal fetal heart rate (FHR) patterns before treatment, 24 and 72 h after the first dose of betamethasone
UA PI MCA PI MCA PI/UA PI Abnormal FHR patterns (%)
Before treatment
24 h after first dose
Significance (p)
72 h after first dose
Significance (p)
0.97 0.16 1.93 0.41 2.04 0.51 0
0.92 0.015 1.74 0.29 1.97 0.64 7 (21.2%)
NS NS NS NS
0.92 0.15 1.79 0.32 2.01 0.53 3 (9.1%)
NS NS NS NS
* Statistically significant differences at 0.05 significance level.
in MCA PI were also significant in subgroups receiving and not receiving tocolysis. Since tocolytic agent was introduced before the first Doppler examination and discontinued after the last evaluation, it should not have influenced the changes during steroid therapy. These findings are in agreement with data, published by Chitrit et al. [9]. They observed in healthy fetuses a transient and significant decrease in fetal MCA PI and an increase in UA PI/ MCA PI ratio on the fourth day after maternal dexamethasone administration. Senat and Ville [7] examined the effect of steroids on blood flow waveforms in intrauterine growth retardation fetuses and found no significant changes of PI values in the different vessels during the dexamethasone course. PI recorded from the umbilical arteries, descending aorta and middle cerebral artery were similar before, 24–48 h and 4–7 days after first injection were given to the mother. However, the MCA PI showed a trend to decrease within the course and after the treatment was stopped. The trend might be explained by either the physiological decrease in resistance in the fetal brain with gestation that would be expected to be even more marked in IUGR fetuses, or the early sign of redistribution of the blood flow. Decrease in MCA PI may be caused by a direct effect of corticosteroids on the fetal brain. Cerebral areas where corticosteroid receptors are present, in particular a number of brainstem nuclei, are part of the presumptive sleep center in the pons, and are thought to control motor activity of the fetus in the third trimester [16]. Vasomotor factors are also stimulated by corticosteroid administration. Experimental studies on fetal sheep have shown that steroids may cause considerable changes in fetal blood pressure, heart rate and blood volume [17]. It has been stated that maternal administration of corticosteroids up-regulates placental expression and secretion of corticotrophin-releasing hormone (CRH) [18,19]. Recent investigations have shown that CRH causes vasodilatation via induction of nitric oxide synthase in human placental and fetal circulations [20,21]. It is therefore, possible that such mechanism may be operating in the regulation of the fetal cerebral blood flow. In our study the numbers of abnormal FHR patterns at 24 and 72 h after the first dose of steroids were similar in dexamethasone and betamethasone groups. Our data show no significant changes in umbilical artery impedance during and after the course of steroids administration. These results, obtained from UA are consistent with all previous studies
[3,7–12] except one. Wallace and Baker [22] reported an association between betamethasone treatment and decreased placental vascular resistance as reflected by waveforms obtained from umbilical artery. Subsequently, the different impact of corticosteroids in UA flow velocity waveforms in their study may be due to fetoplacental dysfunction observed in those pregnancies before treatment. Compared with the mean values at initial presentation, there were any significant changes in MCA PI and MCA PI/ UA PI ratio at 24 and 72 h after the first dose of betamethasone. Ballard and Ballard [23] analyzed the pharmacokinetics of dexamethasone and betamethasone and found that the two recommended regimens should produce only minor differences in the circulating level of glucocorticoid activity in the treated fetus, with lower peak levels for dexamethasone but a somewhat longer time of elevated activity. This may explain that the significant decrease in MCA PI and MCA PI/ UA PI was observed in our study only after dexamethasone administration. There is no evidence that these effects on blood flow are harmful to the fetus, however more concerning are data suggesting a neurotoxic effect of dexamethasone [24]. Our results indicate significant decrease in fetal middle cerebral artery impedance at 72 h after maternal administration of the first dose of dexamethasone. No significant changes were observed in blood velocity values during betamethasone treatment. Effects of dexamethasone on fetal brain warrants further research.
Acknowledgment The study compares the effects of corticosteroids on fetal Doppler flow velocity, observing significant decrease in middle cerebral artery impedance at 72 h after the first dose of dexamethasone.
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