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Tocolysis in women with preterm labor between 32 0/7
and 34 6/7 weeks of gestation: A randomized controlled
pilot study
Helen Y. How, MD, Leila Zafaranchi, MD, Caroline L. Stella, MD, Katherine Recht, MS,
Rose A. Maxwell, PhD, Baha M. Sibai, MD, Joseph A. Spinnato, MD
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Cincinnati,
Cincinnati, OH
Received for publication December 7, 2005; revised February 21, 2006; accepted February 23, 2006
KEY WORDS
Preterm labor
Magnesium sulfate
Nifedipine
Tocolysis
Objective: The purpose of this study was to determine whether intravenous magnesium sulfate
(MgSO
4
) followed by oral nifidepine tocolysis in women with preterm labor between 32 0/7
and 34 6/7 weeks’ gestation reduces neonatal hospital stay.
Study design: Fifty-four women between 32 0/7 and 34 6/7 weeks with preterm labor were ran-
domized to receive either MgSO
4
and oral nifidepine (n = 24) or no tocolysis (n = 30). All
women received betamethasone and prophylactic antibiotics. The primary outcome was total
neonatal hospital stay. Data were analyzed using Chi-square and Mann Whitney U test.
Results: The 2 groups had similar mean cervical dilation and gestational age at enrollment. There
were no statistically significant differences in total neonatal hospital stay (5.8 G7.2 days; median
of 3 days in the no tocolysis vs. 7.5 G8.6 days; median of 3 days in the tocolysis group), rate of
preterm delivery (57% vs. 75%) or need for oxygen supplementation (7% vs. 21%, p !0.23).
The neonatal complications were similar in each group.
Conclusion: Tocolysis after 32 weeks gestation does not reduce neonatal hospital stay.
Ó2006 Mosby, Inc. All rights reserved.
Preterm birth is the leading cause of infant morbidity
and mortality and it accounts for 35% of all health care
spending on infants.
1
Preterm birth affects about 12.3%
of births in the USA
2
and of these 40-50% have been at-
tributed to preterm labor.
2-4
The use of tocolytic therapy
in an attempt to reduce preterm delivery has not reduced
the overall preterm birth rate. Furthermore, there are no
established guidelines regarding the upper limits of ges-
tational age beyond which tocolysis is not indicated,
with recommendations ranging from 32 to 36 completed
weeks.
5
The goals of tocolytic therapy in women with
preterm labor are 1) to allow maternal transport to a
tertiary care center, 2) to prolong pregnancy for at least
48 hours to optimize the beneficial effect of steroids for
fetal lung maturation and 3) to prolong pregnancy in an
attempt to improve perinatal outcomes. It is well estab-
lished that tocolytic therapy can prolong pregnancy for
at least 48 hours.
6
Beyond this benefit, there is little
evidence that prolonged tocolytic therapy improves
Presented at the 26th Annual Meeting of the Society for Maternal
Fetal Medicine, Miami, FL, January 30-February 4, 2006.
Reprints not available from the authors.
0002-9378/$ - see front matter Ó2006 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2006.02.030
American Journal of Obstetrics and Gynecology (2006) 194, 976–81
www.ajog.org
perinatal outcomes at any gestational age (GA).
5,7
De-
spite this, tocolysis beyond 48 hours is commonly
prescribed.
Magnesium sulfate (MgSO
4
) is the tocolytic drug of
choice in many centers.
5,7
The use of oral nifedipine,
as maintenance tocolytic therapy after the initial episode
of preterm labor, has been shown to provide sympto-
matic relief and decrease the number of triage visits,
and is common practice among many obstetricians.
8
How-
ever, Sanchez-Ramos et al,
7
in a recent meta-analysis
reported that the use of oral nifedipine did not improve
maternal or neonatal outcomes. We conducted a ran-
domized controlled trial to determine if aggressive tocol-
ysis with MgSO
4
followed by maintenance therapy with
oral nifedipine, in women with preterm labor at 32 0/7
weeks to 34 6/7 weeks, will reduce the total neonatal
length of hospital stay.
Material and methods
This trial was performed at the University Hospital,
Cincinnati, Ohio between August 2002 and July 2005.
Pregnant women with singleton gestation, who were in
preterm labor between gestational age of 32 0/7 and 34
6/7 weeks with intact amniotic membranes, a diagnosis
of preterm labor and a cervical dilation of %4 cm were
considered for the study. Preterm labor (PTL) was
defined as progressive cervical dilation or effacement
associated with regular uterine contractions (R6/hr). At
our institution, fetal fibronectin (FFN) and/or cervical
length evaluation by ultrasound are not used for
confirming the diagnosis of preterm labor. In addition,
amniocentesis to assess lung maturity or infection is not
routinely performed for women in PTL. Exclusion
criteria were: cervical dilation O4 cm, multifetal gesta-
tion, obstetrical contraindications to tocolysis (known
fetal anomalies, suspect chorioamnionitis, non-reassuring
fetal heart tracings, preeclampsia, placenta previa and
bleeding or abruptio placenta), preterm premature rup-
ture of membranes, known HIV, and refusal to partic-
ipate. Institutional review board approval was obtained
before initiation of patient enrollment. After informed
consent was obtained, patients were randomly assigned
to receive either tocolysis or no tocolysis. Random
assignments were made by picking sealed, opaque,
sequentially numbered envelopes using a computer-
generated random number.
Women assigned to tocolysis received MgSO
4
6gmIV
load over 30 minutes followed by 2-5 g/hr of maintenance
MgSO
4
IV to achieve uterine quiescence (!6 contrac-
tions/hr). All women received a course of 2 doses of beta-
methasone 12 mg IM 24 hrs apart and prophylactic
antibiotics for GBS prophylaxis. After 24 hrs and follow-
ing the administration of the second dose of betametha-
sone, if patients remained without contractions, they
were given nifedipine 10-20 mg orally every 4-6 hrs until
36 6/7 weeks or delivery. If these women started contract-
ing again, after initial therapy and before 35 0/7 weeks;
MgSO
4
tocolysis was reinstituted as described. Women
assigned to no tocolysis (control group) only received
betamethasone and prophylactic antibiotics, no tocolytic
agents were allowed in these women.
Women who received IV MgSO
4
for less than 6 hours
prior to transfer from referring hospitals were eligible
for randomization. All women were instructed on signs
and symptoms of preterm labor and had weekly follow
up with their primary physician. Data regarding pa-
tient’s age, race, parity, risk factors, gestational age,
and cervical exam were recorded from the charts. Mater-
nal and neonatal outcomes were collected after delivery.
Data Analysis and Sample Size
The primary outcome of the trial was the total length of
neonatal hospital stay. The secondary outcomes were rate
of preterm delivery (!37 weeks), rate of neonatal inten-
sive care unit (NICU) and transitional neonatal care unit
(TCN) admissions, % of neonates requiring oxygen
supplementation (continuous positive airway pressure
(CPAP) or oxygen tent), neonatal death, % of neonates
with hyperbilirubinemia and feeding issues, respiratory
distress syndrome (RDS), intraventricular hemorrhage
(IVH) and necrotizing enterocolitis (NEC). In order to
justify administration of IV MgSO
4
in these women with
PTL between 32 and 34 completed weeks, we considered
40% reduction in neonatal length of stay as clinically
significant. Prior to our sample size calculation, we were
informed by our Neonatologist that the average length
of neonatal stay of infants between 32 and 34 completed
weeks at our institution is 15 G7 days. Twenty eight
patients per group were needed to detect a 40% differ-
ence in the total neonatal length of hospital stay with
a= 0.05 (2 tailed and power = 80%). Statistical analysis
was by intention to treat and the data from all randomized
women were included in the analysis. Data analysis in-
cluded Mann Whitney U test for continuous variables
and Chi-square or Fisher exact test for categorical varia-
bles. A p value of !0.05 was considered significant.
Results
A total of 54 women were enrolled; 30 were randomized
to the control group (no tocolysis) and 24 were ran-
domized to the treatment group (IV and oral tocolysis).
There were 2 (7%) women in the no tocolysis group and
4 (17%) women in the tocolysis group who were
maternal transfers from other institutions. Table I
reports the baseline characteristics for the women at
randomization. There were no statistically significant
differences with regard to maternal demographics,
mean cervical dilation and mean gestational age at
enrollment between the 2 groups. Table II summarizes
How et al 977
the latency period according to cervical dilation at en-
rollment and Table III shows the frequency distribution
of cervical dilation by cm and % effacement at enroll-
ment in each group. One (3%) woman in the no tocoly-
sis group and 3 (12%) women in the tocolysis group
had a diagnosis of gestational diabetes. Twenty-five
(85%) women in the no tocolytic group and 19 (79%)
women in the tocolysis group were discharged home
undelivered after randomization. Three (10%) women
in the no tocolysis group and 1 (4%) woman in the
tocolysis group were delivered at one of our affiliated
hospitals, allowing us to obtain both maternal and neo-
natal outcome data. Table IV reports the neonatal out-
come. The primary outcome, total length of neonatal
hospital stay, was not significantly different between
the two groups (5.8 G7.2 days in the no tocolysis group
and 7.5 G8.6 days in the tocolysis group). The median
total neonatal hospital stay for both groups was 3 days
(range, 1-26 and 1-27, for no tocolysis group and tocol-
ysis group, respectively). The main reason for prolonged
neonatal stay for the majority of infants in both groups
was feeding issues; 4 (13%) neonates in the no tocolysis
group and 5 (21%) neonates in the tocolysis group
stayed for more than 2 weeks whereas 1 (3%) neonates
in the no tocolysis group and 1 (4%) neonate in the
tocolysis group stayed for more than a week but less
than 2 weeks. In addition, there were no significant
differences regarding the rate of preterm delivery and
neonatal complications between the 2 groups. Thirteen
(43%) women in the no tocolysis group and 6 (25%)
women in the no tocolysis group delivered at term.
One patient in each group were delivered for non-
reassuring fetal heart tracing. All other women delivered
due to PTL or PPROM.
There were no cases of neonatal death, RDS, IVH or
NEC in either group. Oxygen supplementation was
required in the form of CPAP at delivery in 2 (7%)
neonates in the no tocolysis group and 5 (21%) neonates
in the tocolysis group (p !0.23). The maximum
duration on CPAP was 14 hours. Of the 5 neonates in
the tocolysis group who required oxygen supplementa-
tion, only 1 neonate required oxygen tent for 23 hours,
this neonate was delivered at 35 weeks; he stayed in the
NICU for 22 days and was treated with antibiotics for
probable sepsis due to findings of bandemia and throm-
bocytopenia. Hyperbilirubinemia was diagnosed in 3
(10%) neonates in the no tocolysis group and 7 (29%)
neonates in the tocolysis group (p !0.09).
Table V reports maternal outcome for the 2 study
groups. There were no significant differences regarding
any of the maternal outcome. There were no cases of
adverse maternal outcome related to tocolytics.
Table I Maternal demographics
Characteristics No tocolysis (n = 30) Tocolysis (n = 24) Pvalue
Maternal age (y) 22.0 G5.0 21.6 G3.5 NS
20.5 (14-32) 21.0 (16-30)
Race
White n (%) 9 (30) 10 (42) NS
1st pregnancy n (%) 7 (23) 8 (33) NS
Previous preterm delivery n (%) 10/23 (44) 7/16 (44) NS
Gestational age at enrollment (wk) 33.1 G0.8 33.1 G0.8 NS
33.2 (32.0-34.5) 33.3 (32.0-34.5)
Cervical dilation at enrollment (cm) 2.8 G1.1 2.7 G0.9 NS
3 (1-4) 3 (1-4)
Data are presented as mean GSD, median (range) unless otherwise noted.
Table II Latency period according to cervical dilation at
enrollment
Delivery
Dilation
%1
wk
1-2
wk
2-3
wk
O3
wk Mean (d) Median (d)
No tocolysis
3 cm (n = 13) 2 2 0 9 25.0 26.0
4 cm (n = 7) 2 1 2 2 16.0 19.0
Tocolysis
3 cm (n = 13) 2 2 4 1 16.6 16.0
4 cm (n = 7) 1 0 1 2 17.2 21.0
Table III Frequency distribution of cervical dilation by
centimeter and % effacement at enrollment in each group
Dilation (cm) No tocolysis n (%) Tocolysis n (%)
!2 5 (17) 3 (13)
2-2.9 5 (17) 8 (33)
3-4 20 (67) 13 (54)
Median dilation (cm) 3 3
Effacement (%) No tocolysis n (%) Tocolysis n (%)
0-25 1 (3) 0
50-75 23 (77) 18 (75)
80-100 6 (20) 6 (25)
Median effacement 70% 55%
Mean effacement 66% 63%
978 How et al
Comments
Principal Findings of the Study
In this prospective, randomized clinical trial we evalu-
ated the efficacy of aggressive tocolysis with IV MgSO
4
followed by maintenance oral nifedipine in women
determined to be in preterm labor between 32 0/7 and
34 6/7 weeks gestational age. Our results indicate that
aggressive tocolysis does not improve neonatal outcome
as measured by the total length of neonatal hospital
stay. In addition, we found that neonatal morbidity is
minimal at this gestational age following administration
of steroids irrespective of the use of tocolytic agents.
Clinical Implications of the Study
Several studies suggest that acute tocolytic therapy does
not prevent preterm birth or significantly reduce gesta-
tional age dependent morbidity when given for women
in preterm labor.
6
In general, data from randomized
trials suggest that tocolytic agents prolong pregnancy
up to 48 hours,
6
thus treatment is being given on the
basis that tocolysis will prevent delivery in the first 24
to 48 hours to optimize the effect of steroids. However,
most studies are plagued by a variety of confounding
variables, such as lack of progressive cervical change
before randomization,
9-18
inclusion of women with pre-
term rupture of membranes,
11,14,16
large range of gesta-
tional age (20 to 36 weeks’ gestation) at enrollment,
5,7
the inclusion of near term deliveries between 35 and
36 weeks’ gestation with little risk for significant infant
morbidity and mortality,
9-18
and inadequate power to
assess infant morbidity and mortality.
9-11,13,15-18
Parenteral magnesium sulfate is the most commonly
utilized tocolytic agent in the treatment of preterm labor
in North America. A recently published meta-analysis
by Crowther et al
19
revealed no evidence of clinically
important tocolytic effect for MgSO
4
and concluded
that treatment with MgSO
4
does not substantially in-
crease the proportion of women delivering within 48
hours (RR 0.85, 95% C.I. 0.58-1.25, 11 trials, 881
women), and it does not substantially reduce infant
morbidity.
The critical importance of preterm birth is its rela-
tionship to infant morbidity and mortality. The majority
of perinatal mortality is directly related to complications
of prematurity. Long term sequelae, including cerebral
palsy, blindness, deafness, and chronic lung disease are
Table IV Primary and other secondary neonatal outcome
Characteristics No tocolysis (n = 30) Tocolysis (n = 24) Pvalue
Total neonatal stay (d) 5.8 G7.2 7.5 G8.6 NS
3.0 (1-26) 3.0 (1-27)
Length of NICU stay (d) 3.8 G8.1 4.9 G8.4 NS
0 (0-26) 0 (0-26)
Length of TCN stay (d) 0.3 G0.8 1.1 G5.5 NS
0 (0-3) 0 (0-27)
Delivered with 48 n (%) 5 (17) 3 (13) NS
Delivered !7 days n (%) 7 (23) 7 (29) NS
!37 weeks n (%) 17 (57) 18 (75) NS
Birth weight (g) 2794 G601 2507 G431 NS
2755 (1853-4058) 2514 (1700-3494)
Data are presented as mean GSD, median (range) unless otherwise noted.
Table V Maternal outcome
Characteristics No tocolysis (n = 30) Tocolysis (n = 24) Pvalue
Gestational age at delivery (wk) 36.5 G2.2 35.7 G1.8 NS
36.5 (32.6-40.1) 35.5 (33.0-40.1)
Latency (d) 23.9 G15.9 17.8G12.0 NS
25.5 (0-52) 18.5 (1-47)
Total no. of maternal
hospital days
5.3 G5.3 7.8 G4.4 NS
4 (2-31) 7 (2-22)
Recurrent preterm
contractions n (%)
14 (48) 15 (65) NS
Require readmission n (%) 11 (37) 12 (50) NS
C-section n (%) 4 (13) 4 (17) NS
Data are presented as mean GSD, median (range) unless otherwise noted.
How et al 979
directly linked to preterm birth, particularly in infants
born before 32 weeks gestation or under 1500 grams.
20,21
Although survival is almost 100% and perinatal morbid-
ity is less common (!5-10%) with preterm birth after 32
weeks of gestation, some of these neonates will require
prolonged hospitalization due to acute complications in-
cluding transient tachypnea of the newborn, hyperbiliru-
binemia, temperature instability, apnea and bradycardia
of prematurity and poor feeding.
22,23
Strengths and Weaknesses of the Study
One major strength of this study is limiting the sample of
women to those with preterm labor between 32 to 34 6/7
weeks’ gestation. A large proportion of women present-
ing with preterm labor fall into this gestational age
range.
5,7
Other studies have used much larger ranges for
gestational age. The inclusion of such a large range of
gestational age adds possible confounding variables such
as complications due to the younger gestational age.
Another strength of this study is the requirement of
the presence of progressive cervical dilations and efface-
ment to diagnose preterm labor. Indeed, at randomiza-
tion 61% of all enrolled patients had cervical dilation
R3 cm and/or 20-25% had cervical effacement of
R80%. By including only women who are in actual
labor, we reduce potential bias in the true effects of
tocolytics in women who may not have been in active
labor.
One limitation of our study is the lack of placebo.
Although there is the potential for biased treatment by
managing physicians, all physicians provided a standard
management protocol with the same home care instruc-
tions to patients. Doing a double-blind placebo trial
would have required extensive resources. In addition, in
clinical practice it is very difficult to mask the side effects
of IV MgSO
4
that are obvious to patients, nurses and
physicians.
There is the potential for patients to be biased
regarding their subsequent behavior after randomiza-
tion; however, we found no differences between the 2
groups in the number of women returning to the
hospital for triage visits or in the number of women
who were readmitted to the hospital for subsequent
contractions. Therefore, the likelihood of bias due to the
unblinded design of the study is low.
A second weakness of our study is the small sample
size and corresponding low power (power = 37%) of
this study make it difficult to draw inferences regarding
the effects of aggressive tocolysis after 32 weeks’ gesta-
tion. A post hoc analysis of our data revealed that 306
patients per group are needed to detect a difference in
the total length of neonatal hospital stay between the
no tocolysis (5.8 G7.2 days) versus tocolysis (7.5 G
8.6; effect size = .24) groups at a= 0.05 and power
of 80%.
In addition, the low rates of RDS and IVH in this
population limit our ability to draw conclusions about
the effects of tocolysis on these conditions. There were
no cases of RDS or IVH in our study. However, since
these complications are infrequent in this gestational age
range and several thousand patients would be required,
it is unlikely that a trial will be performed to evaluate
these issues.
Future areas of investigation
Future studies with larger sample sizes are needed to
evaluate the benefits of tocolytic agents in women with
preterm labor prior to 32 weeks’gestation. A large multi-
center randomized trial will be required to further
investigate the efficacy and clinical usefulness of aggres-
sive tocolysis after 32 completed weeks of gestation
regarding neonatal length of hospital stay.
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How et al 981
