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J Matern Fetal Neonatal Med, Early Online: 15
! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1018171

ORIGINAL ARTICLE

Tocolysis in women with advanced preterm labor: a secondary analysis

of a randomized clinical trial

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Chad K. Klauser1, Christian M. Briery2, Ann R. Tucker3, Rick W. Martin3, Everett F. Magann4, Suneet P. Chauhan5, and
John C. Morrison3
1

Departments of Obstetrics and Gynecology, The Mount Sinai Medical Center, New York City, NY, USA, 2Departments of Obstetrics and Gynecology,
Regional Perinatal Group, Shreveport, LA, USA, 3Departments of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS,
USA, 4Departments of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA, and 5Departments of Obstetrics
and Gynecology, Lyndon B. Johnson General Hospital, Houston, TX, USA
Abstract

Keywords

Objective: To compare the efficacy of tocolytic treatment with indomethacin (I), magnesium
sulfate (M) and nifedipine (N) for acute tocolysis in women with advanced cervical dilation
(46 cm).
Methods: A single center, randomized trial was carried out involving patients in preterm labor
(cervix 16 cm). Secondary analysis of women with advanced cervical dilation (cervix 46 cm)
at 2432 weeks gestation who received intravenous M, oral N or I suppositories comprised this
study population.
Results: Over 38 months, 92 women with advanced cervical dilation were randomized to one
tocoloytic type. Days gained in utero (11.7) and percent remaining undelivered at 48 h (60.8%),
72 h (53.1%) and 47 days (38.3%) were similar regardless of tocolytic employed (p 0.923,
0.968, 0.791, 0.802, respectively). Likewise, gestational age at delivery (30.7 3.2) was similar
between groups (p 0.771). Finally, neonatal statistics were not different when stratified by
tocolytic treatment.
Conclusion: There were no statistical differences between tocolytics in treating women with
advanced cervical dilation. All offered significant days gained in utero after therapy, a high
percentage remaining undelivered after 48 or 72 h and after 7 days. It would appear from data
that there may be advantages to tocolytic treatment even in women with advanced cervical
dilation.

Advanced cervical dilation, maternalfetal

medicine, pregnancy, preterm labor,
tocolytic treatment

Introduction
In spite of all the advances in perinatal medicine, preterm
delivery continues to be the leading serious complication of
pregnancy, affecting as many as 10% of all gestations and
accounting for the vast majority of perinatal morbidity and
mortality [1]. Preterm labor with or without early rupture of
the membranes is responsible for up to 70% of the cases of
preterm delivery [2]. Several tocolytic drugs (such as
magnesium sulfate, terbutaline, nifedipine, indomethacin)
have been demonstrated to postpone delivery for several
days or up to a week following acute preterm labor but their
success is inversely related to cervical dilation when tocolysis
is begun [3].
The success rate of tocolytic treatment when the cervix is
dilated to 3 cm is assumed to be very poor [4]. Indeed, many
practitioners choose not to administer tocolytic drugs in such

Address for correspondence: Everett F. Magann, MD, Department of

Obstetrics & Gynecology, UAMS, 4301 W. Markham St. Slot # 518,
Little Rock, AR 72205-7199, USA. Tel: +1 501 686 8345. Fax: +1 501
526 7820. E-mail: efmagann@uams.edu

History
Received 24 November 2014
Revised 4 February 2015
Accepted 9 February 2015
Published online 9 March 2015

cases due to the presumed high failure rate [5]. For example,
Cordero et al. [6] found that the primary reason women in
preterm labor were not appropriately referred to tertiary
centers was advanced cervical dilation. While the literature on
this subject is sparse, a few studies over the past decades have
shown significant prolongation of pregnancy for 23 days or
even 47 days [35,7].
The purpose of this study was to compare intravenous
magnesium sulfate, rectal indomethacin and oral nifedipine in
a group of women with advanced cervical dilation to assess
the efficacy of such treatment in these patients.

Materials and methods

This randomized clinical trial was approved by the
Institutional Review Board (#0249), registered as a clinical
trial (NCT 00811057) and conducted according to CONSORT
guidelines. The overall trial regarding tocolytic efficiency and
side effects have been published by Klauser et al. [8]. The
current study, which was a prespecified secondary analysis,
includes women who, at study entry, had a cervical dilation of
46 cm. The methods have been described in detail previously

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C. K. Klauser et al.

but in this assessment women between 24 and 32 weeks

gestation (singleton or twin) who had acute preterm labor
(cervical dilation of 4 cm or 6 cm plus contractions
5 min apart) with intact membranes and a vertex presentation were eligible for participation. Exclusion criteria
included serious maternal/fetal/placental abnormalities (preeclampsia, diabetes, fetal anomalies, previa, abruption), any
infection requiring antibiotics, or unwillingness/inability to
give consent. Consecutive patients meeting the study criteria
and willing to give informed consent were offered randomization. After signing the informed consent form a disinterested third party (pharmacy service) was notified and they
selected, in sequence, an opaque envelope containing a card
generated from a random number table. The patients were
assigned to one of three groups: intravenous magnesium
sulfate, indomethacin suppositories or oral nifedipine capsules. The appropriate medications were marked with a
unique study number for each patient and sent to the labor and
delivery suite. Magnesium was administered as a 6 g intravenous load over 20 min followed by 4 g per hour (up to 6 g
per hour maximum [9]) until labor was arrested as judged by
the attending physician. Women who received nifedipine were
given a loading dose of 30 mg orally (10 mg 15 min  3)
followed by 30 mg every 46 h until cessation of labor as
described above. Indomethacin was given as 100 mg rectal
suppository, which could be repeated once, two hours after
the initial dose, if contractions continued. This treatment was
followed by 50 mg of oral indomethacin every 6 h until labor
ceased as noted for the other two groups. Indomethacin
therapy was only used for 48 h as a total treatment cycle. Due
to different routes of administration and appearance of the
study medication, caregivers could not be blinded to drug
allocation.
Regardless of group assignment, fetal heart rate and
uterine contractions were monitored until effective uterine
activity had ceased and then they were kept on the high risk
floor for 12 days before discharge. All patients received a
full course of corticosteroids for lung maturation, but none
received antibiotics. Demographic characteristics, such as
age, race gravidity, parity and the number of prior preterm
births were recorded as were the initial cervical exam and
gestational age at randomization. The primary outcomes
selected before study initiation were the number of patients in
each group who remained undelivered after 72 h and 47 days
post-treatment. Secondary outcomes included gestational age
Figure 1. Patient allocation for this study.

J Matern Fetal Neonatal Med, Early Online: 15

at delivery (530 weeks and 53034 weeks), as well as total

days gained in utero. Also, neonatal statistics of birthweight,
Apgar score at 5 min, cord pH, selected newborn morbidity
and total hospital days were recorded in each group.
A prospective sample size calculation indicated 40 patients
in each arm would be needed (assuming 90% of patients
would deliver within 7 days) to demonstrate a 25% reduction
in the rate of delivery within one week. The original clinical
trial was stopped when 276 total pregnancies were enrolled
(without knowing cervical dilation or any other data). This
was the pre-study statistical sample size to offer 300 neonates
for assessment of neonatal morbidity, which was required to
show a difference between tocolytic treatments (previously
published) [10]. When the overall data set were interrogated,
there were only 92 patients enrolled, who in the prespecified
secondary analysis had advanced cervical dilation (instead of
the required 120). An attempt was made to restart the trial but
this was not successful. Statistical analysis was carried out
using Chi-square test on categorical data, while continuous
data were examined by ANOVA if normally distributed. If the
data were not normally distributed, the KruskalWallis one
way analysis of variance on ranks test was used.

Results
In this study, 276 subjects were randomized and 87 received
indomethacin while 85 were treated with magnesium sulfate
and 104 were tocolized with nifedipine over a 38 month
period (Figure 1). Of these, 32 receiving indomethacin (37
infants), 33 treated with magnesium sulfate (36 infants) and
27 who received the tocolytic nifedipine (32 infants) were
4 cm to 6 cm and comprised this study population. As
shown in Table 1, the demographics of age, race, gravidity
and parity as well as women having had a prior preterm
delivery were not different between the three groups.
Similarly, the cervical dilation on admission was similar
between the three groups (p 0.521), as was the gestational
age (all 2829 weeks) at randomization (p 0.129).
Table 2 shows the various obstetric factors. All deliveries
were due to spontaneous labor and none were indicated for
maternal/fetal complications. The gestational age at delivery
(30.7 3.2 weeks) was similar between groups (p 0.771).
Magnesium had more births in the 3034 week group,
whereas indomethacin was associated with more women
delivering at 530 weeks but neither was statistically

Tocolysis in Women with Advanced PTL

DOI: 10.3109/14767058.2015.1018171

Table 1. Maternal demographics.

n 92

Indomethacin
32

MgSO4
33

Nifedipine
27

p value

Age (yrs)
Race (AA/C/H)*
Gravity
Parity
Prior preterm birth
Cervical exam (cm) at randomization
Gestational age at entry weeks

23.1 5.3
27/3/2
2.3 1.2
0.9 1.1
7 (21.8%)
4.3 0.6
28.2 2.4

22.7 4.7
30/3/0
2.7 1.9
1.3 1.5
12 (36.4%)
4.3 0.5
29.3 2.1

23.6 4.1
24/3/0
2.8 1.3
1.2 1.3
8 (29.6%)
4.3 0.5
28.1 2.4

0.483
0.419
0.374
0.173
0.439
0.521
0.129

*African American/Caucasian/Hispanic.

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Table 2. Obstetric factors.

n 92
GA at del
3034 weeks
530 weeks
Days gained
448 h
472 h
47 days

Indomethacin
32

MgSO4
33

Nifedipine
27

p value

30.3 3.6
11
21

30.8 2.9
17
16

30.1 3.1
11
16

0.771
0.368
0.296

15.7 20.6
20 (62.5%)
17 (53.1%)
14 (43.7%)

9.9 13.1
20 (60.6%)
15 (45.4%)
12 (36.4%)

9.5 10.9
16 (59.3%)
15 (55.5%)
10 (37.0%)

0.923
0.968
0.791
0.802

MgSO4
36

Nifedipine
32

p value

Table 3. Neonatal statistics.

n 104

Indomethacin
37

Birth weight (g) 1585.7 693.2 1643.3 595.7 1496.0 513.9 0.696
APGAR 5
8.4 1.6
8.6 1.3
8.8 0.5
0.760
Cord pH
7.31 0.06
7.30 0.06
7.29 0.06 0.705
Neonatal morbidity
RDS
22
PDA
6
Sepsis
5
NEC
4
IVH
1
Total hosp. days 37.3 25.2

16
5
4
0
4
30.5 19.6

12
4
3
1
3
40.5 36.7

0.180
0.908
0.866
0.087
0.348
0.683

significant. Paradoxically, more days were gained in utero

with indomethacin (15.7 20.6 days) compared to magnesium sulfate (9.9 13.1) and nifedipine (9.5 10.9 days) but
the difference did not achieve statistical significance
(p 0.923). Table 2 also demonstrates that 460% of patients
gained 448 h and 450% extended gestation by 472 h which
was similar between groups (p 0.968, 0.791). In women
gaining 47 days there was no statistically significant difference when stratified by tocolytic treatment with success
ranging from 36% to 44% (p 0.802).
Neonatal statistics showed no difference between the three
groups (Table 3). Birthweight was heavier in the magnesium
sulfate group but this was not statistically significant
(p 0.696). The APGAR score at 5 min as well as the cord
pH and neonatal morbidity between the three groups was
similar. Table 3 also shows that the neonatal hospital days
were not different when ordered by the type of tocolytic drug
given to the mother (p 0.683).

Discussion
There is a dearth of studies about acute preterm labor
and advanced cervical dilation treated with tocolytic drugs.

We could only find four pier-reviewed cohort studies in the

past three decades (19752005) which directly addressed this
topic [35,7]. It appears that there may be a bias toward not
using tocolysis when the cervix is 434 cm. Lewis et al. [4]
conducted a retrospective study in 44 women with preterm
labor who were presented with a cervical dilation of 35 cm.
At the discretion of the attending physician, magnesium
sulfate or magnesium plus indomethacin tocolysis was used.
There was a longer duration of successful tocolysis when the
combination of magnesium sulfate and indomethacin was
used (368.3 h) versus magnesium sulfate alone (70.9 h). There
was no difference between the two groups with delayed
delivery for448 h (17/21, 80%) versus 12/23, (52%, p 0.09)
perhaps due to a small number of patients. However,
pregnancy prolongation was 15.4 days in the combined
therapy group versus only 2.9 days in the magnesium alone
group (p 0.001). The authors concluded that the combination of magnesium sulfate and indomethacin was safe and
effective in women with advanced cervical dilation and the
use of both drugs achieved greater pregnancy prolongation
compared to magnesium sulfate alone.
de Veciana et al. [5] completed a retrospective chart review
of 73 patients in preterm labor who presented 3.5 cm
dilated. Because of advanced cervical dilation (5.3 1.8 cm),
one group (n 29) received no tocolysis based on individual
physician preference. The other group of 44 women
(4.0 0.5 cm, p NS) received magnesium sulfate and 13
of these also received indomethacin. They found that 37% of
the patients treated with any tocolytic versus only 10% of
untreated women had a delay in delivery of more than 48 h
(p 0.002). In addition, more of those treated with a tocolytic
received maternal steroids (65% versus 0, p 0.05), than
women who were untreated. More importantly, treated
subjects had a lower incidence of severe neonatal respiratory
distress syndrome compared to the group who did not receive
tocolysis (p 0.04; RR 0.047 [CI, 0.2, 1.0]). These authors
stated that there were neonatal benefits of tocolysis in women
who had advanced cervical dilation, particularly in those who
were 530 weeks.
More recently, Amon et al. [3] published a large study
spanning three years, involving women in preterm labor who
had a cervical dilation of 3 cm. Two-hundred and fiftyseven subjects were treated with magnesium sulfate, and
delivery was delayed at 448 h in 60% of the cases. Overall,
21% remained undelivered after 1 week and, using trend
analysis, there was a highly significant inverse relationship
between cervical dilation at admission and delay of delivery
(p 0.001). However, even when dilated to 6 cm or more 19%

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C. K. Klauser et al.

gained at least 48 h. Finally, Psomiadis and Goldkrand [7]

investigated the effectiveness of tocolysis in women who
presented with advanced cervical dilation (3 cm). They
studied 249 pregnancies in preterm labor between at 23and 36
weeks gestation. They compared the control group (A)
consisting of 117 women who were 53 cm versus the study
group (B) consisting of 132 patients who were 3 cm.
In group A, 75% achieved 72 h of pregnancy prolongation
compared to 50% of the women with advanced cervical
dilation. Although as expected, there was more neonatal
morbidity in the advanced cervical dilation group due to
differences in latency (group A: 24.6 20.8 days versus study
group B: 9.4 11.1 days), they felt that prolongation of
pregnancy in those with advanced cervical dilation had a
beneficial effect on neonatal outcome.
There are two primary findings of the current study. First,
in women with advanced cervical dilation, any of the three
currently used tocolytics (indomethacin, magnesium sulfate
or nifedipine) appears equally effective in stopping preterm
labor and extending gestation for a significant period of time.
There were no obstetric factors which differed by tocolytic
treatment. Secondly, women gained 11.7 14 days in utero
from the time of presentation. Additionally 60.8% extended
gestation 448 h, 51.3% gained 472 h with nearly 40%
prolonging pregnancy by a week or more after treatment,
comparable to previous studies [35,7]. In addition, regardless of which tocolytic agent was used there was no difference
in birth weight, Apgar scores, cord ph, neonatal hospital days
or neonatal morbidity between the three groups in women
with advanced cervical dilation (similar to our overall
findings) [10].
However, there may be indirect neonatal benefits. For
example, it is known that only a 48 h prolongation of
pregnancy is associated with improved neonatal salvage
rates, particular in those with lower birth weights [11]. In our
study, like Amon et al. [3], 460% of patients gained 48 h.
Cooper et al. [11] also showed that extension of pregnancy47
days was also associated with increased neonatal survival in
any pregnancy 537 weeks [11]. Our data, like Psomiadis and
Goldkarnd [7], show that over 50% gained 472 h even with
advanced cervical dilation. This is important as patients with
advanced cervical dilation are often not given corticosteroids
since providers assume delivery will ensue within a matter of
hours [5,7]. In the four retrospective studies [35,7], as well
as the current prospective investigation, the vast majority of
women received a full course of steroids to enhance fetal lung
maturity. The National Institution of Health demonstrated
years ago that a course of steroids significantly improved
neonatal outcome [12]. The majority of women with
advanced cervical dilation treated with tocolysis can be
transferred in utero to higher levels of care when appropriate.
This is important as transfer in utero (rather than after birth) is
estimated to allow neonatal survival equivalent to at least one
extra week of gestation [13].
The principal strength of our study is that it is a
prespecified secondary analysis of women with advanced
cervical dilation in a randomized clinical trial of subjects with
preterm labor that specifically examined the issue of tocolysis
using several first line drugs. There are several weaknesses in
the study that need to be acknowledged. First, we did not have

J Matern Fetal Neonatal Med, Early Online: 15

a control group of women who were not treated with tocolytic

drugs, as the IRB would not approve such a comparator.
However, the untreated control group in the study by de
Veciana et al. [5] showed that only 10% gained 48 h compared
to 37% of treated women and 60% in our study where
tocolysis was used. On this basis it seems unlikely that the
lack of an untreated control group biased our results.
Secondly, since preterm labor in singletons may have a
different initiator of contractions as well as tocolytic response
compared to twin gestations, perhaps our inclusion of multifetal pregnancies could be a source of bias. However, when
we analyzed our twin versus singleton gestations separately,
there was no difference in days gained or in time the
pregnancy was prolonged (472 h or 47days) as stratified by
tocolytic treatment. Therefore, we feel it is unlikely that
inclusion of twin pregnancies biased our results. Lastly, we
did not enroll enough patients to meet our power calculations
of 120 subjects. As noted in the Methods section, this was due
to completion of the overall study when the enrollment
requirement was reached. However, since we did recruit 76%
of our sample size, using the same calculation, we could
detect a 20% (rather than a 25%) difference in deliveries
occurring within one week. Also given our outcomes data, it
would take over 1000 enrolled patients to show a difference
between tocolytic treatments. Therefore, we feel that enrollment of 76% of our expected population is unlikely to have
biased our results.
In conclusion, patients who were present with advanced
cervical dilation in preterm labor, regardless of which
tocolytic is used, demonstrate a pregnancy prolongation of
48 h in 460% and 472 h in over 50% of our subjects, which
would allow for a complete course of steroids and transfer to a
higher level of care, when appropriate. There was significant
time gained in utero (11.7 days), and approximately 40% of
women gained greater than one week, therefore, providing
possible neonatal benefit as noted in several studies
[5,7,11,13]. However, confirmation of improvement in neonatal morbidity versus those who received no therapy will
require further research.

Declaration of interest
The authors report no conflicts of interest. The
authors alone are responsible for the content and writing of
this article.

References
1. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for
2011. Natl Vital Stat Rep 2013;62:190.
2. Morrison JC, Elliott JP, Jones S. Uterine contraction monitoring,
maintenance tocolysis, and preterm birth. In: Morrison JC, ed.
Preterm birth mother and child. Croatla, Rijeka: InTech;
2012:20212.
3. Amon E, Midkiff C, Winn H, et al. Tocolysis with advanced
cervical dilation. Obstet Gynecol 2000;95:35862.
4. Lewis DF, Grimshaw A, Brooks GG, et al. A comparison of
magnesium sulfate and indomethacin to magnesium sulfate only for
tocolysis in preterm labor with advanced cervical dilation. South
Med J 1995;88:73740.
5. de Veciana M, Porto M, Major CA, Barke JI. Tocolysis in advanced
preterm labor: impact on neonatal outcome. Am J Perinatol 1995;
12:2948.

DOI: 10.3109/14767058.2015.1018171

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/10/15
For personal use only.

6. Cordero L, Schurman S, Zuspan FP. Appropriateness of antenatal

referrals to a regional perinatal center. J Perinatol 1989;9:3842.
7. Psomiadis N, Goldkrand J. Efficacy of aggressive tocolysis for
preterm labor with advanced cervical dilation. J Matern Fetal
Neonatal Med 2005;18:4752.
8. Klauser CK, Briery CM, Martin RW, et al. A comparison of three
tocolytics for preterm labor: a randomized clinical trial. J Matern
Fetal Neonatal Med 2014;27:8016.
9. Terrone DA, Rinehart BK, Kimmel ES, et al. A prospective,
randomized, controlled trial of high and low maintenance doses of
magnesium sulfate for acute tocolysis. Am J Obstet Gynecol 2000;
182:147782.

Tocolysis in Women with Advanced PTL

10. Klauser CK, Briery CM, Keiser SD, et al. Effect of antenatal
tocolysis on neonatal outcomes. J Matern Fetal Neonatal Med 2012;
25:277881.
11. Cooper RL, Goldenberg RL, Creasy RK, et al. A multicenter study
of preterm birth weight and gestational age-specific neonatal
mortality. Am J Obstet Gynecol 1993;168:7884.
12. National Institutes of Health Consensus Development Conference
Statement. Effect of corticosteroids for fetal maturation on perinatal
outcomes, February 28March 2, 1994. Am J Obstet Gynecol 1995;
173:24652.
13. Keirse MJ. New perspectives for the effective treatment of preterm
labor. AM J Obstet Gynecol 1995;173:61828.