Maintenance Tocolytics for Preterm

Symptomatic Placenta Previa: A Review

Diwata A. Bose, M.D.,1 Barbara G. Assel, M.D.,1 James B. Hill, M.D.,2
and Suneet P. Chauhan, M.D.3

ABSTRACT

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The purpose of the review article is to determine if prolonged (
48 hour) tocolytics
with symptomatic preterm placenta previa improves perinatal outcome. OVID MEDLINE
and Cochrane Databases were searched from January 1950 to January 2009. Odds ratio
(OR) and 95% confidence intervals (CI) were calculated. We identified two retrospective
studies (n ¼ 217) and one randomized clinical trial (RCT; n ¼ 60), and they were analyzed
separately. Results of the RCT indicated that pregnancy is prolonged for more than 7 days
with continued tocolytics (OR 3.10, 95% CI 1.38 to 6.96) but combined results of two
retrospective studies did not confirm the prolongation (OR 1.19, 95% CI 0.63 to 2.28). The
RCT was inadequately compliant with Consolidated Standards of Reporting Trials state-
ment. While awaiting an appropriately designed RCT to determine the duration of
tocolytics with placenta previa and preterm labor, it should be limited to 48 hours.

KEYWORDS: Placenta previa, tocolytics, preterm labor

P lacenta previa, defined as a placenta located
over or near the cervix’s internal os, occurs in 2.8/1000
singletons and is associated with significant maternal as
well as neonatal morbidity and mortality. Maternal risks
include hemorrhage, transfusion, and cesarean hysterec-
tomy.1 Using data from 23 million pregnancies, Ananth
et al1 noted that 44% of pregnancies with placenta previa
were delivered before 37 weeks, compared with 10% for
other pregnancies. The neonatal mortality due to prema-
turity in patients with placenta previa has been reported
to be 10 to 12/1000 births.1,2 Considering the increasing
rate of placenta previa3 and the high likelihood of pre-
maturity, determining optimum management of preterm
labor with placenta previa is important.
The American College of Obstetricians and
Gynecologists (ACOG) practice bulletin4 on preterm
labor recommends that tocolytics should be used for a
limited time and not repeated because maintenance
tocolytics do not improve perinatal outcome. However,
some publications5,6 on symptomatic placenta previa
recommend that prolonged tocolysis (greater than 48
hours) may be effectively utilized for this condition
despite theoretical concerns about the safety of tocolytics
with obstetric hemorrhage. Within our own department,
there continues to be disagreement on how long toco-
lytics should be used for patients with placenta previa and
bleeding. To resolve this disparity in clinical practice, we
undertook this review.
The purpose of this review was to determine
whether the use of tocolytics improves perinatal out-
comes in patients with placenta previa and preterm labor.
MATERIALS AND METHODS
An Ovid MEDLINE and Cochrane Database of Sys-
tematic Reviews were searched from January 1950 to

1
Aurora Health Care, Milwaukee, Wisconsin; 2Naval Hospital Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
Portsmouth, Portsmouth, Virginia; 3Eastern Virginia Medical School, USA. Tel: +1(212) 584-4662.
Norfolk, Virginia. Received: February 25, 2010. Accepted after revision: May 17, 2010.
Address for correspondence and reprint requests: Suneet P. Published online: July 6, 2010.
Chauhan, M.D., Eastern Virginia Medical School, 825 Fairfax Avenue, DOI: http://dx.doi.org/10.1055/s-0030-1262510.
Suite 544, Norfolk, VA 23507 (e-mail: mfmchauhan@gmail.com). ISSN 0735-1631.
Am J Perinatol 2011;28:45–50. Copyright # 2011 by Thieme
45
46 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 28, NUMBER 1 2011

January 2009. We included publications in English
language that were retrospective and randomized studies
with and without tocolytic groups and that provided
information on at least one of the following outcomes:
delivery within 48 hours or
7 days of admission,
delivery <versus
34 weeks, maternal morbidity (blood
transfusion, hysterectomy, or pulmonary edema), neo-
natal morbidity (admission neonatal intensive care unit,
respiratory distress syndrome, grade III or IV intra-
ventricular hemorrhage, necrotizing enterocolitis) or
perinatal mortality.
Since the CONSORT (Consolidated Standards
of Reporting Trials) statement was published in 1996,
randomized clinical trials (RCTs) published after this
year were evaluated whether they were in compliance
with the guideline.7 The CONSORT score8 is derived
Data are presented as % (n). We calculated the
odds ratio, number needed to treat, and 95% confidence
intervals (CI). If the 95% CI did not cross the integer 1,
then the comparison was considered significant. Graph-
Pad InStat (version 3.00 for Windows 95, GraphPad
Software, San Diego, CA; www.graphpad.com) and
http://www.ebem.org/nntcalculator.html were used to
calculate the statistics.
RESULTS
The search indicated that there were 2700 publications
with the term ‘‘placenta previa,’’ but only 21 articles
were found when using the following MeSH keywords:
Placenta previa/ OR ‘‘placenta previa’’ OR ‘‘placenta
praevia’’ combined with Tocolysis/ OR tocolytic

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from identifying 50 separate items the RCT should agents/ OR tocolysis OR Albuterol/ OR albuterol
describe in the article and assigning 1 point if present; OR Fenoterol/ OR fenoterol OR Hexoprenaline/ OR
0, if absent. The CONSORT score was the total points, hexoprenaline OR Indomethacin/ OR indomethacin
expressed as a percentage. OR Isoxsuprine/ OR isoxsuprine OR Magnesium

Placenta Previa
2,700 Abstracts

Placenta Previa
& No tocolytics
N = 2,679

Placenta previa
& Tocolytics*
N = 21

Excluded
N = 18

No Control No Previa Others~

N=5 N=5 N=8

Included
N=3

Retro Report RCT

N=2 N=1

Figure 1 Literature search for placenta previa and tocolytics (January 1950 to January 2009).*MeSH keywords: Placenta
previa/ OR ‘‘placenta previa’’ OR ‘‘placenta praevia’’ combined with Tocolysis/ OR tocolytic agents/ OR tocoly$ OR Albuterol/
OR albuterol OR Fenoterol/ OR fenoterol OR Hexoprenaline/ OR hexoprenaline OR Indomethacin/ OR indomethacin OR
Isoxsuprine/ OR isoxsuprine OR Magnesium Sulfate/ OR ‘‘magnesium sulfate’’ OR Nifedipine/ OR nifedipine OR Nylidrin/ OR
nylidrin OR Orciprenaline/ OR orciprenaline OR Ritodrine/ OR ritodrine OR Terbutaline/ OR terbutaline. Read the 21 articles.
y
Excluded additional two articles for no tocolytics; two for no information on maternal-fetal outcome; one each for combining
abruption-previa, no prolonged tocolytics, review, and comment article. RCT, randomized control trial; Retro, retrospective.
 MAINTENANCE TOCOLYTICS FOR PRETERM SYMPTOMATIC PLACENTA PREVIA/BOSE ET AL 47

Table 1 Characteristics of the Studies

Study Type of
Period Study Inclusion Criteria Exclusion Criteria Tocolytics

Towers 6 y* Retro Bleeding at 23–36 wk Neonatal anomalies MgSO4

et al5 Abruption or placenta previa, incompatible with life Terbutaline—subcutaneously
confirmed TA USy or oral
Ritodrine
Indomethacin
Besinger 1987–1993 Retro Placenta previa confirmed by Gestational age >35 wk MgSO4
et al6 TA US or at delivery Delivery within 24 h of MgSO4 (þ) terbutaline—oral
Twins—1, tocolytics admission maintenance
Triplets—1, no tocolytics Previous treatment for MgSO4 (þ) terbutaline pump
preterm labor or Oral terbutaline
bleeding with index Others
pregnancy
Contraindications to

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tocolytics
Sharma NM RCT 28 to 34 wk Moderate to severe Ritodrine 10 mg every 6 h,
et al27 Symptomatic placenta previa, bleeding intramuscular injections
confirmed with TA UA Labor for 7 d
Hemoglobin
9 g% Diabetes—pre- or gestational
No change in vital signs Severe preeclampsia
No hypotension Chronic hypertension
Normal urine output Heart, liver, or renal disease
Fetal distress
*Did not provide the actual years.
y
Provided the data for abruption and placenta previa separately; our review only includes the outcome with placenta previa.
NM, no mention; RCT, randomized clinical trial; Retro, retrospective; TA US, transabdominal ultrasound.

Sulfate/ OR ‘‘magnesium sulfate’’ OR Nifedipine/ OR
nifedipine OR Nylidrin/ OR nylidrin OR Orciprena-
line/ OR orciprenaline OR Ritodrine/ OR ritodrine
OR Terbutaline/ OR terbutaline.
Of these 21 publications, 18 were excluded for
the following reasons: no control group (n ¼ 5), no
placenta previa patients (n ¼ 5), did not use any toco-
lytics (n ¼ 2), no information on maternal-neonatal
outcomes (n ¼ 2), and one each for combining abrupt-
ion-previa, no prolonged tocolytics, review and com-
ment article (Fig. 1).9–26
Thus, there are only three publications (one RCT
and two retrospective studies) on maintenance tocolytics
for preterm symptomatic placenta previa.5,6,27 We com-
bined the results of the retrospective studies and com-
pared it with the RCT.
The retrospective studies are from tertiary cen-
ters, and their characteristics are described in Table 1.
In the two retrospective reports,5,6 148 received toco-
lytics and 69 did not (Table 2). The likelihood of
delivery <versus
48 hours of admission or <versus

7 days was not significantly different for the two
groups. In contrast, the RCT (Table 3) demonstrated
that patients who received a tocolytic were significantly
less likely to deliver within 48 hours and prolonged
the pregnancy for at least 1 week. With tocolytics,

Table 2 Retrospective Studies* on Placenta Previa and Tocolytics

Tocolytics No Tocolytics Odds ratio
(N ¼ 148) (N ¼ 69) (95% CI)

Delivery <48 h from admission 14%21 12%8 1.26 (0.52–3.00)

Delivery >7 d from admission 30% (44) 26%18 1.19 (0.63–2.28)
Transfusion before delivery 19%28 12%8 1.77(0.76–4.13)
Transfusion before and after delivery 47% (69) 38%26 1.44 (0.80–2.59)
CD for distress 5%7 4%3 1.09 (0.27–4.35)
Neonatal death 2%3 4%3 0.45 (0.08–2.31)
5,6
*Towers et al and Besinger et al.
Data presented as % (n). CD, cesarean delivery; CI, confidence interval.
48 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 28, NUMBER 1
Table 3 Randomized Clinical Trial* on Tocolytic Use with Symptomatic Placenta Previa
Tocolytics
(n ¼ 30)
Delivery within 48 h of admission 7%2
25
Delivery >7 d from admission 83%
*Sharma et al.27
CI, confidence interval.
the number needed to treat to prolong pregnancy for at
least 48 hours is three parturients (95% CI 1.6 to 4.3)
and for 7 days or more, is also three (95% CI 1.5 to 4.7).
Additionally, the gestational age at delivery (34.9  2.4
versus 33.6  2.4 weeks; p < 0.05), prolongation of preg-
nancy (25.3  17.2 versus 14.4  20.3 days; p < 0.05),
and the mean birth weight (2.27  0.59 versus
1.95  0.55 kg; p < 0.05) were significantly higher in
the treatment group.
The likelihood of transfusion before or after
delivery, cesarean delivery for fetal distress, and neonatal
death did not differ between the groups when combining
the retrospective studies. The RCT did not provide
similar data. The RCT did have one unexplained still-
birth in the control group but none in the tocolytic
group.27
Neither the retrospective studies nor the RCT
provided data on the need for hysterectomy, pulmonary
edema, neonatal morbidity, or any improvement in neo-
natal outcomes. The RCT27 was published 90 months
after the publication of the CONSORT statement
(February 2004 and August 1996, respectively) and the
score was 59%. Among other things, the investigators
did not mention if the sample size was calculated if they
utilized intent-to-treat analysis. Additionally, they did
not provide a flow diagram of the progress through the
phases of trial, did not provide information on how
allocation sequence and concealment were accom-
plished, and did not report if there was evidence of
successful blinding among participants.27
DISCUSSION
Due to multiple reasons, the rate of cesarean delivery is
increasing with a concomitant increase in the rate of
placenta previa.28,29 Because 4 of 10 patients with
placenta previa deliver before 37 weeks, the management
of symptomatic placenta previa has clinical importance.
Although ACOG has no practice bulletin on the man-
agement of placenta previa, the Royal College of Ob-
stetricians Gynecologists (RCOG) has a guideline.30
The RCOG recommends that tocolytics can be used
with caution in selected cases. Within our department,
there is controversy on whether to use tocolytics with
placenta previa and if so, for how long.
There are three findings of the review. First,
there are limited numbers of publications on the man-
2011
No Tocolytic
(n ¼ 30) Relative Risk (95% CI)
50%15 0.18 (0.04–0.67)
40%12 3.10 (1.38–6.96)
agement of symptomatic placenta previa. Though there
are 2700 articles on the topic of placenta previa, only 3
(0.1%) of them focus on the treatment of third-trimes-
ter bleeding with abnormal placentation. These three
studies5,6,27 are dissimilar with regards to study design:
inclusion, exclusion criteria, and use of different regi-
mens of tocolytics. Thus, a summation of the results
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should be viewed with caution. The only RCT27 has
methodological problems because the investigators did
not comply with the CONSORT statement.7 Despite
these shortcomings, the review does provide some
insight.
Our second finding is that use of tocolytics does
prolong the pregnancy for more than 7 days. Surpris-
ingly, the summation of retrospective studies does not
demonstrate a significant prolongation of pregnancy
(Table 2) but the RCT does (Table 3). The contra-
dictory findings can be explained by the variation in the
inclusion and exclusion criteria, ensuring that all patients
were stable when tocolytics were administered, and use
of single versus multiple tocolytics. Because the only
RCT is poorly compliant with the CONSORT state-
ment, use of prolonged tocolytics is not justified at
present. Thus, we agree with RCOG30 that caution
should be exercised with use of betamimetics, and the
optimum regimen has still to be identified. The contra-
diction between the observational studies5,6 and RCT27
is not unique to this topic. Vintzileos31 commented that
nonrandomized trials have shown benefits of electronic
fetal monitoring and of ultrasonography but RCTs have
not. Elliot et al32 noted that regarding the use of
magnesium sulfate as tocolytic, there is a conflict be-
tween the findings of observational studies and the
RCT.
The third finding is that there is limited infor-
mation on the maternal and neonatal morbidity with
placenta previa and use of tocolytics. Though the retro-
spective studies did not find a higher likelihood of
transfusion with tocolytics, the RCT did not report on
this outcome. Complications like pulmonary edema,
need for cesarean hysterectomy and maternal mortality
were not mentioned, and the sample size of all three
studies was inadequate to resolve if the use of tocolytics
increases their likelihood. Regarding neonatal morbidity
with prematurity, it is reasonable to assume that
prolonging pregnancy for 7 days should decrease com-
plications like respiratory distress syndrome, intraven-
 MAINTENANCE TOCOLYTICS FOR PRETERM SYMPTOMATIC PLACENTA PREVIA/BOSE ET AL
tricular hemorrhage, and necrotizing enterocolitis, but
an RCT with sufficient sample size needs to confirm
this.
The limitations of the review article need to be
acknowledged. We limited our search to publication in
English language and it is possible that reports in other
languages offer different findings. But if there are
articles in a foreign language, it is possible that they
may manage pregnancy sufficiently differently and that
their findings are not applicable to our current practice.
Recent meta- and decision analysis indicated33 that
prostaglandin inhibitors are superior to others in pro-
longing pregnancy and should be considered as optimal
first-line agents. Thus, future RCTs with symptomatic
placenta previa may want to utilize indomethacin be-
fore 32 weeks.
In conclusion, while awaiting a sufficiently pow-
ered RCT that is compliant with the CONSORT
statement, tocolytics should be used for limited time or
with caution for a prolonged period with symptomatic
placenta previa.
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