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Effects of vaginal progesterone for maintenance tocolysis on uterine

electrical activity: Effects of progesterone on uterine EMG

Article  in  Journal of Obstetrics and Gynaecology Research · January 2018

DOI: 10.1111/jog.13545

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doi:10.1111/jog.13545 J. Obstet. Gynaecol. Res. 2018

Effects of vaginal progesterone for maintenance tocolysis

on uterine electrical activity

Miha Lucovnik1 , Andreja Trojner Bregar1, Lea Bombac1, Ksenija Gersak1 and
Robert E. Garfield2
1
Department of Perinatology, Division of Obstetrics and Gynecology, University Medical Center Ljubljana, Ljubljana, Slovenia;
and 2Department of Obstetrics, Guangzhou Women and Children’s Medical Center, Guangzhou, China

Abstract
Aim: The effectiveness of vaginal progesterone for maintenance tocolysis after arrested preterm labor
remains controversial. Myometrial contractility can be assessed objectively and non-invasively after proges-
terone treatment by monitoring uterine electromyography (EMG). We examined the effects of vaginal pro-
gesterone on uterine EMG after successful acute tocolysis.
Methods: This was a randomized, double-blind, single-center study performed between 2012 and 2015.
Thirty women who experienced preterm labor between 24 0/7 and 33 6/7 weeks were randomly allocated
to groups administered either 400 mg vaginal progesterone or a placebo 48 h after acute tocolysis. EMG
measurements were taken prior to and 1 h and 2 h following treatment. Mann–Whitney U tests were used
to compare EMG power density spectrum peak frequency and peak amplitude, propagation velocity of
EMG signals, and duration and number of EMG bursts in 30 min recordings between the groups (P < 0.05).
Results: EMG propagation velocity was higher in patients receiving the placebo compared to those treated
with progesterone at 1 h (27.83  10.66 vs 15.60  2.94 cm/s) and 2 h (26.97  13.39 vs 15.12  2.58 cm/s)
following treatment (P = 0.001). PDS peak frequencies were higher in the placebo compared to the progester-
one group at 2 h following treatment (0.54  0.11 vs 0.44  0.06 Hz; P = 0.003).
Conclusions: Treatment of 400 mg of vaginal micronized progesterone as maintenance tocolysis significantly
reduces the propagation velocity of electrical signals within the myometrium and is associated with a shift
toward lower uterine electrical signal frequencies.
Key words: electrohysterography, preterm birth, progesterone, tocolysis, uterine electromyography.

Introduction permit transport of patients to centers with neonatal

Preterm birth remains the greatest unsolved obstetrical
problem. Up to 75% of perinatal mortality and half of
all childhood neurodevelopmental disabilities are
attributed to prematurity.1,2 Approximately 50% of all
preterm neonates are born after spontaneous preterm
labor.3 Once preterm labor is established, acute (pri-
mary) tocolysis is often used to delay delivery in order
to administer antenatal corticosteroids for lung matu-
ration, magnesium sulfate for neuroprotection and to
intensive care units.4,5 However, none of the currently
available treatments for preterm labor can sufficiently
prolong pregnancy to allow further intrauterine
growth and maturation of the fetus. After successful
primary tocolysis, several maintenance tocolytic
agents have been studied, but none have proven bene-
ficial. Compared to a placebo, maintenance tocolysis
with oral betamimetics,6 terbutaline pump,7 calcium
channel blockers,8–10 cyclooxygenase inhibitors,11–13
magnesium sulfate14 and oxytocin receptor antagonist

Received: April 26 2017.

Accepted: October 1 2017.
Correspondence: Assistant Professor Miha Lucovnik, Department of Perinatology, Division of Obstetrics and Gynecology, University
Medical Centre Ljubljana, 4 Slajmerjeva, 1000 Ljubljana, Slovenia. Email: miha.lucovnik@kclj.si

© 2018 Japan Society of Obstetrics and Gynecology 1

M. Lucovnik et al.
atosiban15 have not been proven to prevent preterm
birth or improve neonatal outcomes.
The importance of progesterone for maintaining
pregnancy has been established for more than
80 years, since the classic work of Allen and Corner
and Csapo.16,17 In recent years, large clinical trials
have found that vaginal progesterone can prevent
preterm birth in women with a mid-trimester short
cervix.18 Nevertheless, its role as a maintenance
tocolytic agent after arrested preterm labor remains
controversial. A meta-analysis of five small random-
ized trials showed that vaginal progesterone admin-
istered as maintenance tocolysis was associated
with a reduction in preterm birth and significant
prolongation of pregnancy.19 On the other hand,
two large randomized trials of vaginal progesterone
administered as a maintenance tocolytic agent in
women experiencing preterm labor showed no
reduction in preterm birth rate, either as an addi-
tional agent with primary tocolysis or after success-
ful primary tocolysis.20,21
Experimental data suggest that progesterone exerts
control on both cervical ripening and myometrial
contractility;22,23 however, it is not clear,which
of these two mechanisms is clinically important for
preventing preterm delivery with progesterone treat-
ments. Myometrial contractility can be objectively
and non-invasively assessed in vivo by monitoring
uterine electromyography (EMG), as uterine contrac-
tions are the result of the electrical activity generated
and propagated in the myometrium. It is therefore
possible to determine the effect of maintenance toco-
lysis with vaginal progesterone on uterine activity by
monitoring uterine EMG.
Our study objective was to examine the effects of
vaginal progesterone on uterine EMG activity after an
episode of preterm labor that responded to tocolytic
treatment.
Methods
This randomized, double blind, placebo-controlled
study was performed at a single tertiary perinatal cen-
ter from March 2012 to March 2015. The trial was reg-
istered at www.clinicaltrials.gov (NCT01523483). The
National Medical Ethics Committee approved the
study (reference no.: 137/02/10, March 24, 2010). The
data in the present submission were collected as per
the protocol of this registered trial; however, we can-
not guarantee compliance with treatments initiated at
2 © 2018 Japan Society of Obstetrics and Gynecology
our center after discharge from the hospital. There-
fore, we analyzed and report only data on prespeci-
fied secondary outcomes of the trial, that is, data on
uterine EMG measurements after progesterone versus
placebo treatment while the patients were still
hospitalized.
Patients presenting with signs and symptoms of pre-
term labor at gestational age 24 0/7 to 33 6/7 weeks
were admitted and administered the standard treat-
ment for preterm labor, that is, tocolysis (atosiban or
magnesium sulfate as per the attending physician’s
preference) for 48 h and antenatal steroids. Calculation
of gestational age was based on the last menstrual
period or when it differed by ≥ 7 days from the ultraso-
nographic estimation (calculated by crown rump
length measured within the first trimester), on ultra-
sound. Preterm labor was defined as regular phasic
uterine contractions with a minimum of four contrac-
tions in 30 min assessed by tocodynamometry (TOCO)
and a cervical length of ≤ 25 mm assessed by transva-
ginal ultrasound. Patients with preterm premature rup-
ture of membranes were excluded from the study, as
were those with suspected chorioamnionitis. Patients
with medical conditions that contraindicated tocolysis,
such as non-reassuring fetal heart tracings, were also
excluded. Women who remained undelivered for 48 h
and fulfilled the inclusion criteria were then offered
entrance into the study. All women provided written
informed consent for study participation.
After written informed consent was obtained, an
initial 30 min uterine EMG measurement was per-
formed. Patients were then randomized into two
groups by the attending obstetrician. They received
either two micronized progesterone capsules
(Utrogestan 200 mg, i.e. 400 mg of micronized pro-
gesterone in sunflower oil) or two placebo capsules
identical in appearance, placed into the posterior vagi-
nal fornix. Randomization was performed in a 1:1
ratio using a computer generated randomization
sequence (PASW Statistics, version 18). The randomi-
zation codes and preparations (Utrogestan and pla-
cebo capsules) were kept at the pharmacy
department. Both the active drug and placebo were
stored in boxes with the same appearance and weight
(clinicians and women were not aware of the type of
medication administered). Boxes were labeled by cor-
responding study numbers.
In both arms of the study, EMG measurements
were repeated 1 h and 2 h following the initial admin-
istration of the study drug or placebo. The EMG
methods used in this study are the same as those used

previously in other studies (Fig. 1).24 Researchers per-
forming EMG measurements and outcome assessment
were blinded to group assignment.
Prior to measurement of contractile activity, Ag2Cl
adhesive electrodes were placed upon the abdominal
surface vertically along the midline, with two elec-
trodes located above and two below the navel. The
electrodes remained on the patient for 10 min, and
uterine electrical activity was then measured for
30 min. Analog signals were then digitally filtered to
yield a final band-pass of 0.34–1.00 Hz, and sampled
at 100 Hz. Patients were asked to lie still to avoid dis-
turbing any of the probes or wires.
EMG tracings were analyzed using a power density
spectrum (PDS) technique to determine the PDS peak
frequency and amplitude within ‘bursts’ of EMG
Figure 1 (a) Measurement of uterine electromyography
(EMG) was accomplished using the SureCALL Labor
Monitor, which includes electrodes; patient lead wires
and cables; an isolated patient-safe amplifier and elec-
trical filter system; and a computer and monitor for
storage, analysis and display of uterine EMG activity.
(b) Electrode placement on the abdominal surface of
the patient to perform uterine EMG measurement.
© 2018 Japan Society of Obstetrics and Gynecology
Effects of progesterone on uterine EMG
activity. Propagation velocity (PV) of uterine EMG
signals was determined from the time interval
between signal arrival at adjacent electrodes. The
duration and number of bursts within the 30 min
recording were also analyzed. EMG parameters were
chosen from previous publications (the definition of
the parameters, as well as the rationale for their use,
can be found in these publications).24 In brief, several
possible EMG diagnostic variables have been
described over the past decades. ‘Timing related’
EMG parameters (i.e. related to the duration of EMG
signal events), such as the duration and number of
EMG bursts analyzed in the present study, seem to
have the least value in the diagnosis of true labor.
Burst duration and frequency are the electrical equiv-
alent of the duration and frequency of contractions,
which are the only properties of contractions that can
be evaluated by TOCO. The poor predictive values of
these EMG parameters are not surprising because
TOCO has been proven ineffective for monitoring
uterine activity to identify patients in preterm labor.24
‘Amplitude related’ (i.e. related to the intensity of
EMG-signal events) EMG parameters, such as PDS
peak amplitude, may represent the uterine EMG sig-
nal power or EMG signal energy. Their major limita-
tion is the fact that attenuation of myometrial signals
occurs more for some patients and less for others,
depending on a variance in subcutaneous tissues, and
a variance in conductivity at the skin-electrode inter-
face. These limitations make amplitude related EMG
parameters interesting but perhaps less reliable in the
prediction of true labor. ‘Frequency related’ EMG
parameters (i.e. related to the rate of change of EMG
signal events), include PDS peak frequency and are
one of the most predictive EMG parameters in both
human and animal studies.24 Shifts to higher uterine
electrical signal peak frequencies occur during transi-
tion from a non-labor state to both term and preterm
labor states.24 PDS peak frequency also increases as
the measurement-to-delivery interval decreases.24
Finally, as the PV of electrical events in the myome-
trium is increased at delivery when gap junctions are
increased, the PV of uterine EMG signals has also
been shown to increase as delivery approaches.
Recent studies suggest that EMG PV may predict
term and preterm delivery more reliably than any
other EMG or clinically used parameter investigated
so far.24–26
Sample size calculations using prior studies com-
paring uterine EMG in patients in labor versus those
not in labor give an expected difference in means of
3
M. Lucovnik et al.
the EMG PDS peak frequency of 0.51–0.40 = 0.11 and
standard deviation of 0.10.24 Thus, a minimum sam-
ple size of 14 per group was required to discern any
differences between the groups and was calculated
using a desired power of 0.80 and an alpha of 0.05.
Student’s t or Mann–Whitney U tests (when appro-
priate because of non-normal distribution of vari-
ables) were used to compare EMG parameters (PDS
peak frequency, PDS peak amplitude, PV, duration
and number of bursts in the recording) between the
two study groups (progesterone vs. placebo) prior to
treatment as well as at 1 h and 2 h following treat-
ment. The clinical characteristics of patients in each
group were compared using Student’s t, Mann–
Whitney U or chi-square tests as appropriate. P < 0.05
was considered significant. SPSS version 21.0 was used
for statistical analysis.
Results
Sixty-three women hospitalized for preterm labor
were assessed for eligibility during the study period.
Thirty-three were not included in the study: five who
declined to participate and 28 because they received
vaginal progesterone within 48 h of commencing
acute tocolysis. In total, 30 patients were included and
randomly allocated to progesterone (n = 15) or pla-
cebo (n = 15) groups. None of the women were lost to
follow-up (Fig. 2). Baseline characteristics of the
women included in the two groups were comparable
(Table 1). The participants had a median age of
32 years (range 23–39) and a median gestational age
at study entry of 27 5/7 weeks (range 24 3/7–33 5/7).
There were 19 (63%) nulliparous women, two (7%)
had a history of previous spontaneous preterm birth
and nine (30%) reported tobacco smoking during
pregnancy. We included seven (23%) women preg-
nant with twins who were equally distributed
between the groups. Transvaginal cervical length was
measured in all patients. Cervical length did not differ
significantly between the two groups (median 16 mm
in the progesterone, median 15 cm in the placebo
group; P = 0.55). Three patients (one in the progester-
one and two in the placebo group) were treated with
atosiban and 27 with magnesium sulfate. The two
study groups did not differ significantly in terms of
primary tocolytic agent used (P = 0.57) (Table 1).
Tables 2–4 present EMG parameters in the proges-
terone versus placebo groups before treatment and
1 h and 2 h following treatment, respectively. EMG
4 © 2018 Japan Society of Obstetrics and Gynecology
PV was significantly higher in patients receiving the
placebo compared to those treated with progesterone
at 1 h and 2 h following treatment (P = 0.001) (Fig. 3).
PDS peak frequencies were significantly higher in
patients receiving the placebo compared to those trea-
ted with progesterone at 2 h following treatment
(P = 0.003), but not 1 h post treatment (P = 0.62)
(Fig. 4). There were no significant differences in other
EMG parameters between the groups.
Discussion
In women with arrested preterm labor, treatment
with 400 mg of vaginal micronized progesterone as
maintenance tocolysis significantly reduced PV of
electrical signals within the myometrium and was
associated with a shift toward lower uterine electrical
signal frequencies.
Our findings are consistent with the results of
numerous previously published studies, which indi-
cated that progesterone inhibits myometrial activity
by several mechanisms. It suppresses a number of
genes that are essential for effective uterine contrac-
tions, including genes for the gap junction protein
connexin, calcium channels and oxytocin receptors.25
It also upregulates relaxation mechanisms, such as the
generation and action of cyclic adenosine monopho-
sphate and cyclic guanosine monophosphate.25 In
addition, progesterone acts by functionally opposing
estrogen, which increases myometrial contractility.25
Animal uterine EMG studies have demonstrated that
treatment with onapristone (ZK-98299), a pure anti-
progestin, induces preterm delivery and increases
uterine EMG activity in rats.26 Progesterone, but not
17-alpha-hydroxyprogesterone caproate, also sup-
presses contractility of human myometrium in vitro.23
Several randomized trials have assessed the effec-
tiveness of vaginal progesterone on prolongation of
pregnancy and reduction of prematurity in women
with preterm labor after successful acute tocolysis.
Borna and Sahabi showed that treatment with 400 mg
of vaginal progesterone was effective in prolonging
gestation after an episode of preterm labor.27 Lotfali-
zadeh et al. evaluated the use of 400 mg of vaginal
progesterone versus no treatment after arrested pre-
term labor in women with a history of previous pre-
term birth, and showed a significant reduction in
recurrent preterm delivery.28 Other similar studies
have used a lower dose of vaginal progesterone
(i.e. 200 mg daily). Arikan et al., Sharami et al. and

Figure 2 Randomization, treatment and follow-up of participants.
Areia et al. all reported significant prolongation of
pregnancy with this dose of progesterone.29–31 How-
ever, the largest study to date of the use of vaginal
progesterone in women with preterm labor showed
no reduction in preterm birth with 200 mg of vaginal
progesterone used with acute tocolysis and continued
after arrested preterm labor.20 Similarly, a recently
published placebo-controlled trial by Palacio et al. also
found no reduction in preterm delivery rate with
maintenance treatment of 200 mg vaginal progester-
one daily in women discharged home after an episode
of arrested preterm labor.21 Both trials even showed
trends toward earlier birth and shorter latency in the
© 2018 Japan Society of Obstetrics and Gynecology
Effects of progesterone on uterine EMG
progesterone group, contradicting the results of the
meta-analysis performed by Suhag et al., which was
largely informed by smaller, often poor quality open-
label studies.19 Use of vaginal progesterone as a main-
tenance tocolytic agent thus remains controversial.
There is also controversy over the mechanisms by
which progesterone could prolong pregnancy after an
episode of preterm labor. Our study results suggest
that inhibition of myometrial contractility could be
one such mechanism.
The main limitation of this study is that we were
only able to provide data on the secondary outcome
of the registered randomized trial. The study does
5
M. Lucovnik et al.

Table 1 Clinical background characteristics of participants

Characteristic Progesterone (n = 15) Placebo (n = 15) P
Maternal age (years) 31 (27–38) 32 (23–39) 0.59
Nulliparity 8 11 0.86
History of previous preterm birth 1 1 0.84
Twin gestation 4 3 0.40
Smoking during pregnancy 4 5 0.94
Gestational age at entry (weeks) 29 1/7 (24 4/7–33 5/7) 27 1/7 (24 3/7–31 0/7) 0.28
Cervical length (mm) 16 (11–25) 15 (5–25) 0.55
Number of contractions on TOCO before treatments 2 (1–3) 2 (1–3) 0.68
Treated with atosiban 1 2 0.57
Treated with magnesium sulfate 14 13 0.57
Delivery < 37 weeks 10 8 0.57
Delivery < 34 weeks 4 3 0.75
Time to delivery (days) 28 (1–94) 47 (1–112) 0.31
Data are median (range) and n. P calculated by Mann–Whitney U or chi square test. TOCO, tocodynamometry.

Table 2 Comparison of uterine EMG parameters between progesterone and placebo groups before treatment
EMG parameter Progesterone Placebo P
(n = 15) (n = 15)
PDS peak frequency 0.56  0.07 Hz 0.57  0.08 Hz 0.98
PDS peak amplitude 6.99  6.70 μV2 5.93  2.85 μV2 0.68
Propagation velocity 30.93  13.36 cm/s 33.94  21.91 cm/s 0.90
Mean burst duration 26.62  3.36 s 28.38  2.36 s 0.17
Number of bursts in 30 min recording 3.15  1.52 4.12  1.58 0.08
EMG, electromyography; PDS, power density spectrum.

Table 3 Comparison of uterine EMG parameters between progesterone and placebo groups at 1 h following treatment
EMG parameter Progesterone Placebo P
(n = 15) (n = 15)
PDS peak frequency 0.55  0.09 Hz 0.53  0.09 Hz 0.62
PDS peak amplitude 6.68  3.11 μV2 5.16  3.14 μV2 0.13
Propagation velocity* 15.60  2.94 cm/s 27.83  10.66 cm/s 0.001
Mean burst duration 28.54  8.81 s 27.23  3.04 s 0.61
Number of bursts in 30 min recording 3.08  0.95 3.18  1.59 0.80
*Statistical significance (P < 0.05). EMG, electromyography; PDS, power density spectrum.

Table 4 Comparison of uterine EMG parameters between progesterone and placebo groups at 2 h following treatment
EMG parameter Progesterone Placebo P
(n = 15) (n = 15)
PDS peak frequency* 0.44  0.06 Hz 0.54  0.11 Hz 0.003
PDS peak amplitude 6.54  2.50 μV2 4.94  3.06 μV2 0.08
Propagation velocity* 15.12  2.58 cm/s 26.97  13.39 cm/s 0.001
Mean burst duration 27.85  3.63 s 26.59  3.37 s 0.37
Number of bursts in 30 min recording 2.77  1.24 3.06  1.52 0.59
*Statistical significance (P < 0.05). EMG, electromyography; PDS, power density spectrum.

not, therefore, answer the question of potential preg-
nancy prolongation with progesterone maintenance
tocolysis. In addition, we only evaluated a short
period (i.e. 2 h) following progesterone treatment,
which provides limited evidence of the effects of
progesterone as a maintenance tocolytic agent. Never-
theless, our study provides important information on
increased uterine quiescence with progesterone ther-
apy in patients presenting with threatened preterm
birth. However, it is not possible to draw any

6 © 2018 Japan Society of Obstetrics and Gynecology


Figure 3 Comparison of uterine electromyography
propagation velocity values in the progesterone and
placebo groups. Propagation velocity was higher in
patients receiving placebo compared to those treated
with progesterone at 1 and 2 h after treatment
(P = 0.001). ( ) Before treatment; ( ) 1 h after treat-
ment, and ( ) 2 h after treatment.
definitive conclusion on the effects of progesterone
treatment on prolongation of pregnancy or improve-
ment in neonatal outcomes from our results because
of the small sample size. Although small, the number
of participants was chosen based on a calculation of
the sample size required to answer the study’s main
question: Does maintenance tocolysis with progester-
one significantly affect uterine EMG activity? Another
weakness of the study is the inclusion of twin preg-
nancies. We chose to include these pregnancies
because of their important contribution to overall pre-
maturity rates.32 The question whether vaginal pro-
gesterone could also exert an inhibitory effect on
myometrial activity in twin pregnancies, in our opin-
ion, is of great clinical importance.
Extensive studies have been performed in the last
decades demonstrating that uterine EMG measure-
ment has similar effectiveness for detecting uterine
contractions as TOCO, and even as intrauterine pres-
sure catheter.24 In addition, many studies have shown
that different uterine EMG parameters yield valuable
information about electrical coupling and excitability
of myometrial cells required for labor at term and
preterm.24,33–35 Our study results suggest that apart
from being an accurate diagnostic method, uterine
© 2018 Japan Society of Obstetrics and Gynecology
Effects of progesterone on uterine EMG
Figure 4 Comparison of uterine electromyography
power density spectrum (PDS) peak frequency values
in the progesterone and placebo groups. PDS peak
frequencies were higher in the placebo compared to
the progesterone group at 2 h after treatment
(P = 0.003). ( ) Before treatment; ( ) 1 h after treat-
ment, and ( ) 2 h after treatment.
EMG could allow assessment of different obstetrical
interventions to better understand their effects and
potential benefits.
In conclusion, treatment with 400 mg of vaginal
micronized progesterone as maintenance tocolysis sig-
nificantly reduces the propagation velocity of electri-
cal signals within the myometrium and is associated
with a shift toward lower uterine electrical signal
frequencies.
Acknowledgments
The authors would like to thank prof. Ziva Novak
Antolic, MD, PhD, for her help with formulating the
initial research agenda and for her support with uter-
ine EMG studies.
Disclosure
Besins Laboratory (Besins Healthcare, Bangkok,
Thailand) produced and supplied the study drugs
(Utrogestan and placebo) free of charge. Besins
Healthcare did not participate in the study design,
7
M. Lucovnik et al.
data analysis, data interpretation or writing of the
manuscript.
The authors have no financial interest in the tech-
nology or drugs used in the study and therefore have
no conflict of interest to declare.
Author contributions
All authors have read and approved the final version
of the manuscript.
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