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 Przepieśća,
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 Previous studies have shown that maternal management

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: urbanrem@amb.edu.pl (R. Urban).
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 dex-
amethasone 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 (Dipro-
phos, Schering-Plough, Belgium) were given 24 h apart,
accordingly to National Institutes of Health (NIH) recom-
mendations [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 intraob-
server 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 t-
test (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 t-
test 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
Before treatment 24 h after first dose
UA PI 0.98
0.17 0.94
0.1
MCA PI 2
0.43 1.84
0.34
MCA PI/UA PI 2.09
0.51 2.04
0.46
Abnormal FHR patterns (%) 0 6 (17.6%)
*
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: gesta-
tional 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 beta-
methasone 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.
Significance (p) 72 h after first dose Significance (p)
NS 0.93
0.13 NS
NS 1.68
0.31 0.0001*
NS 1.83
0.4 0.0137*
NS 4 (11.8%) NS
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 mineralo-
corticoid 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
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
Before treatment 24 h after first dose
UA PI 0.97
0.16 0.92
0.015
MCA PI 1.93
0.41 1.74
0.29
MCA PI/UA PI 2.04
0.51 1.97
0.64
Abnormal FHR patterns (%) 0 7 (21.2%)
* 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] exam-
ined 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 hor-
mone (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
173
Significance (p) 72 h after first dose Significance (p)
NS 0.92
0.15 NS
NS 1.79
0.32 NS
NS 2.01
0.53 NS
NS 3 (9.1%) NS
[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 gluco-
corticoid 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 adminis-
tration 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 glucocorti-
coid 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: pri-
mary sources Cochrane Pregnancy and Childbirth Group Trials Reg-
ister 2000 (1).
174 R. Urban et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 120 (2005) 170–174
[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 mat-
ernal 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 Do-
ppler 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 beta-
methasone 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 corticotrophin-
releasing 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 circula-
tion: involvement of the nitric oxide-cyclic guanosine 30 ,50 -monopho-
sphate-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 adminis-
tration 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.