Calcium Channel Blockers For Inhibiting Preterm Labour (Review)

Calcium channel blockers for inhibiting preterm labour
(Review)
King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2003, Issue 1
http://www.thecochranelibrary.com
Calcium channel blockers for inhibiting preterm labour (Review)

Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Calcium channel blockers for inhibiting preterm labour (Review) i

[Intervention Review]
James F King2 , Vicki Flenady1 , Dimitri Papatsonis3 , Gustaaf Dekker4 , Bruno Carbonne5
1
Mater Medical Research Institute, Mater Health Services, Woolloongabba, Australia. 2 Department of Perinatal Medicine, Royal
Womens Hospital, Carlton, Australia. 3 Department of Obstetrics and Gynaecology, Amphia Hospital Breda, Breda, Netherlands.
4 Discipline of Obstetrics and Gynaecology, University of Adelaide, Elizabethvale, Australia. 5 Department of Obstetrics and Gynecology,
Hopital Saint Antoine, Saint Antoine, France
Contact address: Vicki Flenady, Mater Medical Research Institute, Mater Health Services, Level 2 Quarters Building, Annerley Road,
Woolloongabba, Queensland, 4102, Australia. vicki.flenady@mmri.org.au.
Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: Edited (no change to conclusions), published in Issue 2, 2011.
Review content assessed as up-to-date: 19 September 2002.
Citation: King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane
Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002255. DOI: 10.1002/14651858.CD002255.
ABSTRACT
Background
Preterm birth is a major contributor to perinatal mortality and morbidity and affects approximately six to seven per cent of births in
developed countries. Tocolytics are drugs used to suppress uterine contractions. The most widely tested tocolytics are betamimetics.
Although they have been shown to delay delivery, betamimetics have not been shown to improve perinatal outcome, and they have a
high frequency of unpleasant and even fatal maternal side effects. There is growing interest in calcium channel blockers as a potentially
effective and well tolerated form of tocolysis.
Objectives
To assess the effects on maternal, fetal and neonatal outcomes of calcium channel blockers, administered as a tocolytic agent, to women
in preterm labour.
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (October 2002), the Cochrane Controlled Trials Register
(The Cochrane Library 2002, Issue 2), MEDLINE (1965 to June 2002), EMBASE (1988 to June 2002), and Current Contents (1997
to June 2002). We also contacted recognised experts and cross referenced relevant material. We updated the search of the Cochrane
Pregnancy and Childbirth Groups Trials Register on 4 January 2010 and added the results to the awaiting classification section.
Selection criteria
All published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in labour
between 20 and 36 weeks gestation.
Data collection and analysis
Standard methods of the Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of
methodological quality and trial data extraction were undertaken independently by three authors. Additional information was sought
to enable assessment of methodology and conduct of intention-to-treat analyses. Meta-analysis was conducted assessing the effects of
calcium channel blockers compared with any other tocolytic agent. Results are presented using relative risk for categorical data and
weighted mean difference for continuous data.
Calcium channel blockers for inhibiting preterm labour (Review) 1
Main results
Twelve randomised controlled trials involving 1029 women were included. When compared with any other tocolytic agent (mainly
betamimetics), calcium channel blockers reduced the number of women giving birth within seven days of receiving treatment (relative
risk (RR) 0.76; 95% confidence interval (CI) 0.60 to 0.97) and prior to 34 weeks gestation (RR 0.83; 95% CI 0.69 to 0.99). Calcium
channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction (RR 0.14; 95% CI 0.05
to 0.36), the frequency of neonatal respiratory distress syndrome (RR 0.63; 95% CI 0.46 to 0.88), necrotising enterocolitis (RR 0.21;
95% CI 0.05 to 0.96), intraventricular haemorrhage (RR 0.59 95% CI 0.36 to 0.98) and neonatal jaundice (RR 0.73; 95% CI 0.57
to 0.93).
Authors conclusions
When tocolysis is indicated for women in preterm labour, calcium channel blockers are preferable to other tocolytic agents compared,
mainly betamimetics. Further research should address the effects of different dosage regimens and formulations of calcium channel
blockers on maternal and neonatal outcomes.
[Note: The 39 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
PLAIN LANGUAGE SUMMARY
Calcium channel blockers have fewer adverse effects for women in preterm labour than betamimetic drugs, and appear at least as good
at postponing preterm birth.
Even short-term postponement of preterm birth (before 37 weeks) can help improve outcomes for babies, as the mother can take steroid
drugs which help develop the babys lungs in a short time. The most common drugs to try and stop preterm labour are betamimetics.
Calcium channel blocker drugs are another option (usually nifedipine). They are commonly used for high blood pressure, but might
also relax uterine contractions. The review found that calcium channel blockers seem to be at least as good as betamimetics, and maybe
better, for postponing preterm labour. Calcium channel blockers have far fewer adverse effects on the mother.
BACKGROUND tal lung maturation (Crowley 1998) and to effect transfer to a cen-
tre with neonatal intensive care facilities (Powell 1995). A range of
Preterm birth, defined as birth occurring between 20 and 36 weeks drugs (tocolytics) has been used to inhibit preterm labour in order
of gestation is a major contributor to perinatal mortality and mor- to allow time for such co-interventions to occur. The tocolytics
bidity, and affects approximately six to seven per cent of births in which have been most widely tested are the betamimetics (rito-
developed countries (Lumley 1993). The birth of a preterm infant drine, salbutamol and terbutaline), and they have been shown to
who requires intensive care for its survival is a crisis, not only for be effective in delaying delivery by up to seven days and longer,
the infant, but also for the parents (McCain 1993). although no impact has yet been shown on perinatal mortality
(King 1988; Gyetvai 1999). Betamimetics have a high frequency
of unpleasant, sometimes severe maternal side effects including
Of all perinatal deaths, approximately 75 per cent occur in infants tachycardia, hypotension, tremulousness and a range of biochem-
born preterm, although many of these infants are already either ical disturbances. Furthermore, betamimetic treatment has been
dead or lethally malformed at the onset of preterm labour (Keirse reported to have been associated with at least 25 maternal deaths
1989). No progress has been made over the last two decades in mainly from pulmonary oedema (Papatsonis 2001). There is a
reducing the incidence of preterm birth in high income countries need, therefore, for an effective tocolytic agent with less side effects
but some benefits have been identified from prolongation of preg- than the betamimetics.
nancy by enabling corticosteroids to be administered to hasten fe-
Calcium channel blockers or calcium antagonists are non-specific Types of outcome measures
smooth muscle relaxants, predominantly used for the treatment Maternal outcomes:
of hypertension in adults. They exert their tocolytic effect by pre- pregnancy prolongation (interval between randomisation and de-
venting the influx of extracellular calcium ions into the myome- livery);
trial cell. They are entirely non-specific for uterine as distinct from delivery prior to 37 completed weeks;
other smooth muscle cells, but have been demonstrated in vitro to delivery prior to 34 completed weeks;
have potent relaxant effect on human myometrium (Saade 1994). delivery within seven days of treatment;
The most widely used and studied calcium channel blocker is delivery within 48 hours of treatment;
nifedipine which (like nicardipine) belongs to the dihydropiridine maternal adverse drug reaction;
group. Nifedipine was first reported in 1980 in an observational cessation of treatment for maternal adverse drug reaction;
study to be an effective tocolytic agent with minimal side effects maternal sepsis;
(Ulmsten 1980) but it has not replaced the betamimetics as the antepartum haemorrhage;
most commonly used tocolytic agent in clinical practice. Concerns postpartum haemorrhage;
arose from animal studies (Harake 1987) that nifedipine may have maternal admission to intensive care unit;
adverse effects on the fetal and placental circulation, and although maternal death;
there have been subsequent studies which failed to confirm this maternal length of hospital stay;
(Meyer 1990), it is necessary to review the evidence for the safety maternal satisfaction with treatment.
and efficacy of this treatment. Fetal outcomes:
fetal death;
fetal death excluding congenital abnormality;
OBJECTIVES oligohydramnios.
Neonatal outcomes:
1. To assess the effects on maternal, fetal and neonatal outcomes gestation at birth;
of calcium channel blockers administered as a tocolytic agent to neonatal death;
women in preterm labour when compared with either placebo or neonatal death excluding congenital abnormality;
no intervention. perinatal mortality;
2. To assess the effects on maternal, fetal and neonatal outcomes perinatal mortality excluding congenital abnormality;
of calcium channel blockers administered as a tocolytic agent to birthweight;
women in preterm labour when compared with any other tocolytic birthweight < 10th centile for gestational age;
agent. Apgar score of < 7 at five minutes;
neonatal sepsis;
neonatal jaundice;
respiratory distress syndrome;
METHODS
duration of mechanical ventilation;
intraventricular haemorrhage;
intraventricular haemorrhage (grade three or four);
Criteria for considering studies for this review bronchopulmonary dysplasia;
necrotising enterocolitis;
admission to neonatal intensive care unit;
Types of studies neonatal length of hospital stay;
All published and unpublished randomised trials in which calcium retinopathy of prematurity;
channel blockers were used for tocolysis in the management of long term disability.
preterm labour. A priori sub-group analyses:
any dihydropiridine calcium channel blocker compared with any
betamimetic agent;
Types of participants tocolysis commenced prior to 28 weeks gestation;
Women assessed as being in preterm labour (between 20 and 36 tocolysis commenced prior to 32 weeks gestation;
weeks) and considered suitable candidates for tocolysis. tocolysis commenced after membrane rupture;
tocolysis for women with multiple gestation.
Types of interventions
Calcium channel blockers administered as a tocolytic by any route.
Search methods for identification of studies

Electronic searches assessment was based on the systematic assessment for the oppor-
We searched the Cochrane Pregnancy and Childbirth Groups Tri- tunity for each of these biases to arise. Thus, the reviewers judged
als Register by contacting the Trials Search Co-ordinator (October for each trial whether each criterion was met. A rating of A-Yes, B-
2002). We updated this on 4 January 2010 and added the results Unclear, or C-No was allocated to each criterion. The quality as-
to Studies awaiting classification sessment rating included in the Table of Included Studies refers to
The Cochrane Pregnancy and Childbirth Groups Trials Register the blinding of randomisation only where a rating of A-Adequate,
is maintained by the Trials Search Co-ordinator and contains trials B-Unclear, C-Inadequate or D-Not used was given for each trial.
identified from: An a priori decision was made to exclude trials when outcome data
1. quarterly searches of the Cochrane Central Register of were unavailable for more than 20 per cent of participants.
Controlled Trials (CENTRAL); Data collection and analysis
2. weekly searches of MEDLINE; Additional information was sought from investigators of ten in-
3. handsearches of 30 journals and the proceedings of major cluded studies (Read 1986; Ferguson 1990; Janky 1990; Bracero
conferences; 1991; Kupferminc 1993; Papatsonis 1997; Garcia-Velasco 1998;
4. weekly current awareness alerts for a further 44 journals Koks 1998; Larmon 1999; Weerakul 2002) and data were pro-
plus monthly BioMed Central email alerts. vided and included for seven of these studies (Ferguson 1990;
Details of the search strategies for CENTRAL and MEDLINE, Janky 1990; Kupferminc 1993; Papatsonis 1997; Garcia-Velasco
the list of handsearched journals and conference proceedings, and 1998; Koks 1998; Larmon 1999; Weerakul 2002). Three tri-
the list of journals reviewed via the current awareness service can als included women with a multiple pregnancy (Janky 1990;
be found in the Specialized Register section within the edito- Kupferminc 1993; Koks 1998). In the analysis of these trials, out-
rial information about the Cochrane Pregnancy and Childbirth comes for all babies are presented.
Group. Analysis was conducted to assess the effects of calcium channel
Trials identified through the searching activities described above blockers when compared with any other tocolytic. The prespec-
are each assigned to a review topic (or topics). The Trials Search ified comparison of calcium channel blockers and no treatment
Co-ordinator searches the register for each review using the topic or placebo was not able to be conducted as no trials which ad-
list rather than keywords. dressed this question were identified. One subgroup analysis was
In addition, authors conducted a systematic literature search of the performed comparing tocolysis with the dihydropiridine class of
Cochrane Controlled Trials Register (The Cochrane Library 2002, calcium channel blockers (nifedipine and nicardipine) with be-
Issue 2), MEDLINE (1965 to June 2002), EMBASE (1988 to tamimetics, as this was thought to be an important clinically rel-
June 2002), Current Contents (1997 to June 2002), using search evant comparison. The other prespecified subgroup analyses were
terms listed in Appendix 1. not able to be undertaken due to insufficient data. Also due to in-
sufficient data, a planned sensitivity analysis by trial quality was not
conducted. Analyses were conducted using a fixed effects model or
Searching other resources a random effects model in the presence of statistically significant
heterogeneity. Statistical heterogeneity between trials was assessed
We conducted a manual search of the references of all retrieved using the chi squared test for heterogeneity. Results are presented
articles, sought unpublished trials and abstracts submitted to major using relative risk for categorical data and weighted mean differ-
international congresses and contacted expert informants. ence for variables measured on a continuous scale and include
95% confidence intervals. Results are also expressed using num-
bers needed to treat (NNT) where appropriate.
Data collection and analysis
The standard methods of the Cochrane Collaboration were used
for the consideration of trials for inclusion. Evaluation of method-
RESULTS
ological quality, and trial data extraction were undertaken inde-
pendently by the authors (J King, V Flenady, D Papatsonis) as
described in Clarke 2001. Differences in interpretation were re-
solved by discussion.
Description of studies
Methods used for assessing data quality See: Characteristics of included studies; Characteristics of excluded
Four major sources of potential bias and methods of avoidance studies.
of these biases were considered when assessing trial quality: (1) Thirty-two studies were identified as potentially eligible for inclu-
selection bias - blinding of randomisation; (2) performance bias - sion in this review. Eight trials were excluded and a further twelve
blinding of intervention; (3) attrition bias - complete follow-up; studies are unable to be included until additional information is
(4) detection bias - blinding of outcome assessment. The quality provided by the authors. Therefore, this review includes twelve

randomised trials testing the effects of calcium channel blockers 1993; Kupferminc 1993; Papatsonis 1997; Garcia-Velasco 1998;
for tocolysis in preterm labour. Koks 1998; Weerakul 2002). Eight of these trials used ritodrine
(Twenty-six reports from an updated search in January 2010 have as the other tocolytic. Initial tocolytic therapy with nifedipine was
been added to Studies awaiting classification.) administered orally or sublingually, as either capsules or tablets
Excluded studies (whole, or crushed and dissolved in water). Dosage varied from
As this review evaluated tocolytic therapy for women in preterm 30 mg/day to 160 mg/day until uterine contractions stopped. The
labour, two trials evaluating maintenance therapy of women fol- largest trial (Papatsonis 1997) used a higher dose of nifedipine
lowing successful tocolysis were excluded (Carr 1993; El-Sayed than most of the included trials (up to 40mg in the first hour). All
1998). Another trial (Meyer 1990) was excluded because it en- ten trials continued oral nifedipine after the initial treatment but
rolled women only after subcutaneous terbutaline failed to stop three trials (Ferguson 1990; Bracero 1991; Garcia-Velasco 1998)
regular uterine contractions. This may have introduced a system- did not report the total duration of treatment. Ritodrine was usu-
atic bias favouring nifedipine since only women who did not re- ally started at 50 g/minute except for Janky 1990; Papatsonis
spond to the beta-adrenergic agonist were admitted to the trial. 1997; Koks 1998. Janky 1990 and Koks 1998 started at a loading
Furthermore, the treatment groups were unbalanced (24 versus dose of 150 to 200 g/minute and the rate was increased up to 300
34). Another trial (Kose 1995), which was translated from Turk- or 350 g/minute until uterine contractions stopped. Papatsonis
ish, was excluded because the treatment groups were unbalanced: 1997 started ritodrine at a loading dose of 383 g/minute and
52 women received nifedipine and only 21 ritodrine. The reason gradually decreased to a minimum of 100 g/minute. Two trials
for this imbalance and also the method of randomisation was not used nicardipine as the calcium channel blocker, one trial com-
able to be determined. Two trials were excluded as the intervention pared intravenous nicardipine with salbutamol (Jannet 1997) and
tested was the addition of a calcium channel blocker for women the other oral nicardipine with magnesium sulphate (MgSO4)
receiving tocolysis with a betamimetic agent (Rodriguez-Esc 1981; (Larmon 1999).
Piovano 1985).Two trials were excluded on the basis of quasi-ran-
dom allocation to treatment (Dunstan-Boone 1990; Smith 1993). Most trials used oral maintenance in both treatment groups until
Included studies 34 to 37 weeks gestation.
A total of 1029 women participated in the 12 included trials com- Outcomes
paring calcium channel blockers with other tocolytic agents for There was some inconsistency across the trials with respect to the
preterm labour (Read 1986; Ferguson 1990; Janky 1990; Bracero way in which maternal outcomes were reported. Although the
1991; Glock 1993; Kupferminc 1993; Jannet 1997; Papatsonis clinically important outcome of delay in delivery for greater than
1997; Garcia-Velasco 1998; Koks 1998; Larmon 1999; Weerakul or equal to 48 hours was reported in nine trials, only four trials
2002). In one trial (Koks 1998) only the subset of trial partici- reported delay for greater than or equal to seven days. Discontin-
pants who did not receive prior betamimetic therapy (57 of 102 uation of treatment because of adverse side effects was reported in
subjects) was included. eleven of the 13 trials. With the exception of neonatal mortality,
Participants neonatal outcomes were less consistently reported, and definitions
The participants included in these trials were reasonably homo- were often lacking (eg criteria for diagnosing respiratory distress
geneous. The minimum gestational age at inclusion ranged from syndrome, sepsis or for admission to neonatal intensive care unit
20 to 26 weeks, and the maximum from 33.5 to 36 weeks. The (NICU)).
mean gestational age at entry, when described, was between 28
and 32 weeks gestation. Preterm labour was reasonably consis- The neonatal outcomes of the trial of Papatsonis 1997 were re-
tently defined across the trials, most excluding those women with ported more comprehensively in a subsequent publication, with
a cervical dilatation of greater than 4cm. Four trials included precise definitions. This second report used a more stringent def-
women admitted for preterm labour with preterm premature rup- inition for admission to the NICU than the one used in the ini-
ture of membranes (Ferguson 1990; Janky 1990; Papatsonis 1997; tial report. Because the other trials used a more general definition
Koks 1998) and three trials included twin pregnancies (Janky (usually not defined, but presumably any admission to NICU)
1990; Kupferminc 1993; Koks 1998). All the trials excluded in order to maintain consistency, we have chosen to use the data
those women who had contra-indications to either calcium chan- from the primary publication for Papatsonis 1997. Some degree
nel blockers or to betamimetics. The standard contra-indications of assessment bias is possible for the neonatal morbidity indices
for tocolysis were reported as exclusion criteria in the major- in all of the trials because neonatal assessment was undertaken by
ity of included trials, i.e., fetal distress, chorioamnionitis, severe clinicians not blinded to maternal treatment allocation. None of
preeclampsia/eclampsia, and abruptio placentae. the trials described any intention to undertake longer term neona-
Tocolysis tal assessment, which is an important deficiency in this evidence.
Ten trials compared oral nifedipine with other tocolytic agents Please see Table of Characteristics of Included Studies for further
(Read 1986; Ferguson 1990; Janky 1990; Bracero 1991; Glock details.

Risk of bias in included studies When compared with any other tocolytic agent, the use of calcium
channel blockers resulted in a statistically significant increase in
The included trials were considered to be of reasonable quality.
gestation at birth (WMD 0.70 weeks; 95% CI 0.19 to 1.20), and
Ten of the included trials reported concealed random allocation
a reduction in neonatal respiratory distress syndrome (RDS) (RR
to treatment and therefore received an A quality rating. In two
0.63; 95% CI 0.46 to 0.88), necrotising enterocolitis (RR 0.21;
trials the precise method of random allocation to treatment was
95% CI 0.05 to 0.96) and intraventricular haemorrhage (RR 0.59;
not described (Kupferminc 1993; Jannet 1997). For all of the
95% CI 0.36 to 0.98). The risk reduction for the outcome of
included trials, blinding of the intervention was not performed.
respiratory distress syndrome (RDS) gives a NNT of 14 (95% CI
Blinded assessment of outcomes was not reported in any of the
8 to 50) and for intraventricular haemorrhage 13 (95% CI 7 to
included studies. In this review, an attempt was made to conduct
100). Less neonatal jaundice was also shown for infants of women
an intention-to-treat analysis for all outcomes. Although some
receiving calcium channel blockers (RR 0.73; 95% CI 0.57 to
trials had post-randomisation exclusions, the rate of exclusions
0.93). No statistically significant differences were shown for the
was generally low and not considered by the authors of this review
outcomes of birthweight, admissions to neonatal intensive care
to be a threat to its validity. In one trial (Glock 1993) 20% of
unit, Apgar score less than seven at five minutes, neonatal sepsis,
randomised women were excluded from the analysis because they
or perinatal mortality.
failed to meet the inclusion criteria.
Subgroup analysis: Any dihydropiridine calcium channel blocker
Further information on methods and outcomes has been sought
compared with any betamimetic agent.
from trial investigators and will be included in future updates when
Nine of the 12 trials were included in the subgroup analysis of
available. Please see Table of Characteristics of Included Studies
any dihydropiridine compared with any betamimetic agent. This
for further details.
analysis demonstrated similar effects as shown in the overall anal-
ysis on the prolongation of pregnancy indices. In addition to the
statistically significant reduction in the number of women giving
Effects of interventions birth within seven days of initiation of treatment and prior to 34
weeks gestation, this subgroup analysis demonstrated a statistically
This review includes data from 12 trials with a total of 1029
significant reduction in birth within 48 hours (RR 0.72; 95% CI
women.
0.53 to 0.97). This subgroup analysis also showed similar neonatal
Maternal outcomes
effects to that of the overall analysis (statistically significant reduc-
When compared with any other tocolytic agent, the use of calcium
tion in RDS and jaundice). In addition, a statistically significant
channel blockers resulted in a statistically significant decrease in
increase in mean birthweight was demonstrated (WMD 122.68g;
the number of women giving birth within seven days of initiation
95% CI 3.50 to 241.86).
of treatment (relative risk (RR) 0.76; 95% confidence interval
A sensitivity analysis was undertaken to test the effect of the deci-
(CI) 0.60 to 0.97) and prior to 34 weeks gestation (RR 0.83;
sion made by the reviewers to include data for the outcome of ad-
95%CI 0.69 to 0.99). The number needed to treat (NNT) for the
mission to neonatal intensive care unit (NICU) from the primary
outcome of birth within seven days is 11 (95% CI 6 to 100). This
publication for the Papatsonis 1997 trial. When data were used
means that, on average, for every 11 women treated with calcium
from the subsequent publication (which applied a more stringent
channel blockers instead of any other tocolytic drug, one less birth
admission definition), the trend toward a reduction in NICU ad-
occurs within this time period. However, the confidence intervals
missions for infants of women treated with calcium channel block-
indicate that as few as six or as many 100 women would need to
ers is strengthened, and becomes statistically significant (RR 0.78
be treated with a calcium channel blocker to achieve this result.
95% CI 0.64 to 0.94) in the overall comparison; however, it does
Maternal adverse drug reaction was reduced (RR 0.32; 95% CI
not reach statistical significance for the subgroup analysis of any
0.24 to 0.41) and cessation of treatment for maternal drug reaction
dihydropiridine compared with any betamimetic agent.(RR 0.84;
was markedly reduced (RR 0.14; 95% CI 0.05 to 0.44). The NNT
95% CI 0.71 to 1.00) (data not shown).
for maternal adverse drug reaction was three (95% CI 3 to 4) and
A number of clinically important outcomes were unable to be ad-
for drug reaction requiring cessation of treatment was 14 (95% CI
equately assessed due to insufficient data, including fetal growth
10 to 25). A trend toward superior tocolytic benefit was apparent
restriction which might be increased in the circumstance of arti-
in the outcomes of birth prior to 37 weeks gestation (RR 0.95;
ficially prolonged pregnancy. The planned subgroup analyses to
95% CI 0.83 to 1.09), within 48 hours of initiation of treatment
explore the effects at different gestational age thresholds and ac-
(RR 0.80; 95%CI 0.61 to 1.05) and for pregnancy prolongation
cording to membrane status and multiple gestation were unable
(interval from treatment to delivery), (weighted mean difference
to be conducted due to unavailability of data.
(WMD) 3.83 days; 95% CI -3.04 to 10.70). For the outcome of
pregnancy prolongation, a random effects model was used in the
meta-analysis due to statistical heterogeneity.
Neonatal outcomes

DISCUSSION tamimetics for those women who are considered likely to benefit
from tocolytic treatment.
Based on the data included in this review comparing the effects
of calcium channel blockers (mainly nifedipine) with other to-
colytic agents (mainly betamimetics), calcium channel blockers
are shown to be a more effective tocolytic agent (less births within AUTHORS CONCLUSIONS
seven days of imitation of treatment and before 34 weeks gesta-
tion) with improvement in some clinically important neonatal out- Implications for practice
comes (less respiratory distress syndrome, intraventricular haem- Based on the results of this review, it would seem justified to con-
orrhage, necrotising enterocolitis and jaundice) and a marked re- clude that when tocolysis is indicated for women in preterm labour,
duction in adverse maternal side effects. calcium channel blockers should be preferred to betamimetics.
The formulation (capsules versus tablets) and dosage regimens dif-
An important clinical aspect to tocolysis, particularly if maternal
fered somewhat amongst the included trials, and it was not possi-
transport to a tertiary centre is being planned, is speed of onset of
ble to determine from the data in this review that one regimen is
action. Because in most of the trials of calcium channel blockers
preferable to another.
the medication was administered as an oral preparation, and in the
trials of betamimetics the agents were administered intravenously,
Implications for research
there is the possibility that betamimetics might have a more rapid
onset of action enabling a more expeditious transfer with less risk The findings of this review suggest that it does not seem justi-
of delivery prior to arrival at the referral centre. Two trials (Read fiable to ask women in preterm labour to participate in further
1986 and Janky 1990) assessed uterine quiescence at two hours trials comparing betamimetics with nifedipine or other calcium
as an index of successful tocolysis, and no statistically significant channel blockers. Although it would be informative to see the re-
difference was seen between the two agents. sults of placebo controlled trials of calcium channel blockers, it
is considered unlikely that these will be conducted given the un-
The largest trial (Papatsonis 1997), which had the most favourable equivocal impact that this method of tocolysis has on short term
outcomes, used a higher dosage regimen for nifedipine than that postponement of delivery and the opportunity that this provides
used in most of the other trials (up to 40mg in the first hour) and for effecting in-utero transfer and steroid administration. Further
this might be the most appropriate one to use. The manufactur- trials testing different dosage regimens (high versus low, particu-
ers withdrawal of the capsule formulation for sublingual use of larly addressing speed of onset of uterine quiescence) and formula-
nifedipine has limited clinicians options for a fast acting means tion (capsules versus tablets) utilising blinding of the intervention
of administering the drug, and alternative methods are being used would add to our understanding about optimal usage of nifedip-
such as dissolving tablets in water. The impact of this on tocolytic ine as a tocolytic. Long term follow-up of the neurodevelopmen-
effectiveness is unable to be addressed in this review. tal status of infants should be included as an important outcome
There is a substantial amount of evidence from controlled trials variable in any further trials of tocolytic agents.
(a further 12 trials) comparing calcium channel blockers with be- [Note: The 39 citations in the awaiting classification section of
tamimetic agents for which the data were not available in a format the review may alter the conclusions of the review once assessed.]
which allowed inclusion in this review. The reviewers regard this
as an important deficiency, and are making determined efforts to
obtain further information for inclusion in subsequent versions
of this review. However, in reviewing the information currently
ACKNOWLEDGEMENTS
available from these trials awaiting assessment, it does not appear
that as a group, their results differ substantially or systematically We wish to thank Drs JA Garcia-Velasco, JE Ferguson, E Janky,
from the trials included in this review. This supports the conclu- CAM Koks, M Kupferminc, J Morrison, V Cararach, and A Chit-
sion that calcium channel blockers should be preferred over be- tacharoen who provided additional information for this review.

REFERENCES
References to studies included in this review suppression of preterm labor. European Journal of Obstetrics,
Gynecology and Reproductive Biology 1998;77(2):1716.
Bracero 1991 {published data only}
Kupferminc 1993 {published and unpublished data}
Bracero LA, Leiken E, Kirshenbaum N, Tejani N.
Comparison of nifedipine and ritodrine for the treatment Kupferminc M, Lessing JB, Peyser MR. A comparative,
prospective, randomized study of nifedipine vs ritodrine for
of preterm labor. Proceedings of 10th Annual Meeting
of Society of Perinatal Obstetricians; 1990 Jan 23-27; suppressing preterm labor. Proceedings of 39th Annual
Meeting of the Society for Gynecologic Investigation; 1992
Houston, Texas, USA. 1990:77.

Bracero LA, Leikin E, Kirshenbaum N, Tejani N. March 18-21; San Antonio, Texas, USA. 1992:335.

Kupferminc M, Lessing JB, Yaron Y, Peyser MR.
Comparison of nifedipine and ritodrine for the treatment of
preterm labor. American Journal of Perinatology 1991;8(6): Nifedipine versus ritodrine for suppression of preterm
labour. British Journal of Obstetrics and Gynaecology 1993;
3659.
100(12):10904.
Ferguson 1990 {published and unpublished data}
Ferguson JE, Dyson DC, Holbrook RH Jr, Schultz T, Larmon 1999 {published and unpublished data}
Stevenson DK. Cardiovascular and metabolic effects

Larmon J, Ross B, May W, Dickerson G, Fischer
associated with nifedipine and ritodrine tocolysis. American R, Morrison JC. Oral nicardipine versus intravenous
Journal of Obstetrics and Gynecology 1989;161(3):78895. magnesium sulfate for the treatment of pretem labor.

Ferguson JE, Dyson DC, Schutz T, Stevenson DK. American Journal of Obstetrics and Gynecology 1999;181:
A comparison of tocolysis with nifedipine or ritodrine: 14327.
analysis of efficacy and maternal, fetal, and neonatal Ross E, Ross B, Dickerson G, Fischer R, Morrison J. Oral
outcome. American Journal of Obstetrics and Gynecology nicardipine versus intravenous magnesium sulfate for the
1990;163(1 Pt 1):10511. treatment of preterm labor. American Journal of Obstetrics
Ferguson JE, Schultz TE, Stevenson DK. Neonatal bilirubin and Gynecology 1998;178(1):181. [: 641]
production after preterm labor tocolysis with nifedipine. Papatsonis 1997 {published and unpublished data}
Developmental Pharmacology Therapeutics 1989;12(3): Papatsonis DN, Kok JH, van Geijn HP, Bleker OP, Ader
1137. HJ, Dekker GA. Neonatal effects of nifedipine and ritodrine
Garcia-Velasco 1998 {published and unpublished data} for preterm labor. Obstetrics and Gynecology 2000;95(4):
Garcia-Velasco JA, Gonzalez Gonzalez A. A prospective, 47781.
randomized trial of nifedipine vs. ritodrine in threatened

Papatsonis DN, van Geijn HP, Ader HJ, Lange FM,
preterm labor. International Journal of Gynaecology and Bleker OP, Dekker GA. Nifedipine and ritodrine in the
Obstetrics 1998;61:23944. management of preterm labor: a randomized multicenter
trial. Obstetrics and Gynecology 1997;90(2):2304.
Glock 1993 {published data only}
Papatsonis DN, van Geijn HP, Ader HJ, Lange FM, Bleker

Glock JL, Morales WJ. Efficacy and safety of nifedipine
OP, Dekker GA. Tocolytic efficacy of nifedipine versus
vs magnesium sulfate in the management of preterm labor:
ritodrine; results of a randomized trial. American Journal of
a randomized study. American Journal of Obstetrics and
Obstetrics and Gynecology 1996;174:306.
Gynecology 1993;169(4):9604.
Papatsonis DNM, Kok JH, Samson JF, Lange FM, Ader
Morales WJ, Glock D. Efficacy and safety of nifedipine vs
HJ, Dekker GA. Neonatal morbidity after randomised trial
magnesium sulfate in the management of preterm labor:
comparing nifedipine with ritodrine in the managment of
a randomized study. American Journal of Obstetrics and
preterm labor. American Journal of Obstetrics and Gynecology
Gynecology 1993;168:375.
1997;176(1):S117.
Janky 1990 {published and unpublished data} Papatsonis DNM, Kok JH, van Geijn HP, Bleker OP, Ader
Janky E, Leng JJ, Cormier PH, Salamon R, Meynard J. A HJ, Dekker GA. Neonatal effects of nifedipine and ritodrine
randomized study of the treatment of threatened premature in the management of preterm labor. Proceedings of the 5th
labor. Nifedipine versus ritodrine. Journal de Gynecologie, Annual Congress of the Perinatal Society of Australia and
Obstetrique et Biologie de la Reproduction (Paris) 1990;19: New Zealand; 2001 March 13-16; Canberra, Australia.
47882. 2001:100.
Jannet 1997 {published data only} Papatsonis DNM, van Geijn HP, Dekker GA. Nifedipine
Jannet D, Abankwa A, Guyard B, Carbonne B, Marpeau L, as a safe and effective tocolytic agent in the treatment of
Milliez J. Nicardipine versus salbutamol in the treatment of preterm labor (letter). American Journal of Obstetrics and
premature labor. A prospective randomized study. European Gynecology 2000;183:513.
Journal of Obstetrics, Gynecology and Reproductive Biology Papatsonis DNM, van Geijn HP, Kok JH, Ader HJ, Dekker
1997;73(1):116. GA. Adjuvant use of indomethacin for preterm labor: is it
Koks 1998 {published and unpublished data} safe to use?. Proceedings of the 5th Annual Congress of
Koks CA, Brolmann HA, de Kleine MJ, Manger PA. A the Perinatal Society of Australia and New Zealand; 2001
randomized comparison of nifedipine and ritodrine for March 13-16; Canberra, Australia. 2001:296.
Read 1986 {published data only} References to studies awaiting assessment
Read MD, Wellby DE. The use of a calcium antagonist
(nifedipine) to suppress preterm labour. British Journal of
Al-Omari 2004 {published data only}
Obstetrics and Gynaecology 1986;93(9):9337.
Al-Omari WR, Al-Tikriti E, Al-Shamma H. Atosiban and
Weerakul 2002 {published and unpublished data} nifedipine in acute tocolysis, comparative study [abstract].
Weerakul W, Chittacharoen A, Suthutvoravut S. Nifedipine XVIIIth European Congress of Obstetrics and Gynaecology;
versus terbutaline in management of preterm labor. 2004 May 12-15; Athens, Greece. 2004:103.
International Journal of Gynecology and Obstetrics 2002;76:
3113. Al-Omari 2006 {published data only}
Al-Omari WR, Al-Shammaa HB, Al-Tikriti EM, Ahmed
References to studies excluded from this review KW. Atosiban and nifedipine in acute tocolysis: a
comparative study. European Journal of Obstetrics &
Carr 1993 {published data only} Gynecology and Reproductive Biology 2006;128(1-2):12934.
Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance
oral nifedipine for preterm labor: a randomised clinical Al-Qattan 2000 {published data only}
trial. American Journal of Obstetrics and Gynecology 1999; Al-Qattan F, Omu AE, Labeeb N. A prospective randomized
181(4):8227. study comparing nifedipine versus ritodrine for the
Dunstan-Boone 1990 {published data only} suppression of preterm labour. Medical Principles & Practice
Dunstan-Boone G, Bond A, Thornton YS. A comparison 2000;9:16473.
of verapamil vs ritodrine for the treatment of preterm labor. Breart 1979 {published data only}
Proceedings of 10th Annual Meeting of Society of Perinatal Breart G, Sureau C, Rumeau-Rouquette C. A study of the
Obstetricians; 1990 Jan 23-27; Houston, Texas, USA. comparative efficiency of ifenprodil and ritodrine in the
1990:83. [: 73] treatment of threatening premature labour [translation].
El-Sayed 1998 {published data only} Journal de Gynecologie, Obstetrique et Biologie de la
El-Sayed YY, Holbrook RH Jr, Gibson R, Chitkara U, Reproduction (Paris) 1979;8(3):2613.
Druzin ML, Baba D. Diltiazem for maintenance tocolysis
Choong 1991 {published data only}
of preterm labor: comparison to nifedipine in a randomized
Yi CS, Kim DK. A comparison of tocolytic effects of
trial. Journal of Maternal-Fetal Medicine 1998;7(5):21721.
ritodrine hydrochloride and nifedipine in the treatment
Kose 1995 {published data only} of preterm labour. The Journal of Catholic Medical College
Kose D, Karaosmanoglu S, Yeniguc CT, Yucesoy I, Ozben 1991;44:231.
C, Baysal C. Efficacy and safety of nifedipin in the
Dasari 2007 {published data only}
management of preterm labor. Jinekoloji Ve Obstetrik Dergisi
Dasari P, Kodenchery MM. Psychological factors in preterm
1995;9(3):16570.
labor and psychotherapeutic intervention. International
Meyer 1990 {published data only} Journal of Gynecology & Obstetrics 2007;97(3):1967.
Meyer WR, Randall HW, Graves WL. Nifedipine versus
ritodrine for suppressing preterm labor. Journal of Dubay 1992 {published data only}
Reproductive Medicine 1990;35:64953. Dubay P, Singhal D, Bhagoliwal A, Mishra RS. Assessment
of new borns of mothers treated with nifedipine and
Piovano 1985 {published data only}
isoxsuprine. Journal of Obstetrics and Gynecology of India
Piovano A, Carboni F, Casale O, DAngelo A, Oses A.
1992;42(6):77880.
Calcium antagonism in the control of adverse reactions
during utero-inhibition. Archives of Gynecology 1985; Vol. Fan 2003 {published data only}
237 Suppl 1:98. [: 04.41.03] Fan L, Wu GF, Huang XH. The effect of calcium entry
Rodriguez-Esc 1981 {published data only} blocker on the management of preterm labor: a randomized
Rodriguez-Escudero FJ, Aranguren G, Benito JA. Verapamil controlled study. Chinese Journal of Practical Gynecology and
to inhibit the cardiovascular side effects of ritodrine. Obstetrics 2003;19(2):879.
International Journal of Gynecology and Obstetrics 1981;19: Floyd 1992 {published data only}
3336.
Floyd RC, McLaughlin BN, Martin RW, Roberts WE,
Smith 1993 {published data only} Wiser WL, Morrison JC. Comparison of magnesium and

Smith CS, Woodland MB. Clinical comparison of oral nifedipine for primary tocolysis and idiopathic preterm
nifedipine and subcutaneous terbutaline for initial tocolysis. labor. American Journal of Obstetrics and Gynecology 1992;
American Journal of Perinatology 1993;10:2804. 166:446. [: 662]
Woodland MB, Smith C, Byers J, Bolognese R, Weiner S. Floyd RC, McLaughlin BN, Perry KG Jr, Martin RW,
Clinical comparison of oral nifedipine and subcutaneous Sullivan CA, Morrison JC. Magnesium sulfate or nifedipine
terbutaline use for initial tocolysis. Proceedings of 10th hydrochloride for acute tocolysis of preterm labor: efficacy
Annual Meeting of Society of Perinatal Obstetricians; 1990 and side effects. Journal of Maternal-Fetal Investigation
Jan 23-27; Houston, Texas, USA. 1990:523. 1995;5(1):259.
Ganla 1999 {published data only} Martinez 1994 {published data only (unpublished sought but not
Ganla KM, Shroff SA, DesaiI S, Bhinde AG. A prospective used)}
comparison of nifedipine and isoxsuprine for tocolysis. Martinez S, Manau MD, Vives A, Carmona F, Deulofeu P,
Bombay Hospital Journal 1999;41(2):25963. Cararach V. A prospective and randomized study about
Garmi 2008 {published data only} the use of calcium blockers vs betamimetics in preterm
Garmi G. Nifedipine compared to atosiban for treating labour. Proceedings of 14th European Congress of Perinatal
preterm labor. ClinicalTrials.gov (http://clinicaltrials.gov/) Medicine; 1994 June 5-8; Helsinki, Finland. 1994. [: 414]
(accessed 9 April 2008). Mathew 1997 {published data only}
Haghighi 1999 {published data only} Mathew S, Ashok. A comparative study of tocolytic effect of
Haghighi L. Prevention of preterm delivery: nifedipine or nifedipine and isoxsuprine hydrochloride. Acta Obstetricia
magnesium sulfate. International Journal of Gynecology and et Gynecologica Scandinavica 1997;76(167):90.
Obstetrics 1999;66(3):2978. Mawaldi 2008 {published data only}
Houtzager 2005 {published data only} Mawaldi L, Duminy P, Tamim H. Terbutaline versus
Houtzager BA, Hogendoorn S, Samson JF, Papatsonis D, nifedipine for prolongation of pregnancy in patients with
Van Wassenaer AG. Nine years follow up of children born preterm labor. International Journal of Gynecology &
from mothers who participated in a RCT of nifedipine Obstetrics 2008;100(1):658.
versus ritrodine for threatened preterm labor [abstract]. Nassar 2007 {published data only}
Pediatric Academic Societies Annual Meeting; 2005 May Nassar A, Khalil A, Awwad J, Musa AA, Tabbara J, Usta
14-17; Washington DC, USA. 2005:Abstract no: 2100. I. A randomized trial of two dose regimens of nifedipine
Houtzager 2006 {published data only} for management of preterm labor. American Journal of
Houtzager BA, Hogendoorn SM, Papatsonis DN, Samsom Obstetrics and Gynecology 2007;197(6 Suppl 1):S206,
JF, van Geijn HP, Bleker OP, et al.Long-term follow up of Abstract no: 724.
children exposed in utero to nifedipine or ritodrine for the Nassar 2009 {published data only}
management of preterm labour. BJOG: an international Nassar AH, Abu-Musa AA, Awwad J, Khalil A, Tabbara J,
journal of obstetrics and gynaecology 2006;113(3):32431. Usta IM. Two dose regimens of nifedipine for management
Juon 2008 {published data only} of preterm labor: a randomized controlled trial. American
Juon AM, Kuhn-Velten WN, Burkhardt T, Krahenmann Journal of Perinatology 2009;26(8):57581.
F, Zimmermann R, von Mandach U. Nifedipine Papadopoulos 1997 {published data only}
gastrointestinal therapeutic system (GITS) as an alternative Papadopoulos V, Decavalas G, Tzingounis V. Nifedipine
to slow-release for tocolysis--tolerance and pharmacokinetic versus ritodrine in the treatment of preterm labor. Acta
profile. European Journal of Obstetrics & Gynecology and Obstetricia et Gynecologica Scandinavica 1997;76(167):1. [:
Reproductive Biology 2008;140(1):2732. P45.17]
Kashanian 2005 {published data only} Papatsonis 2003 {published data only}
Kashanian M, Akbarian AR, Soltanzadeh M. Atosiban and Papatsonis DN, van Geijn HP, Bleker OP, Ader HJ, Dekker
nifedipin for the treatment of preterm labor. International GA. Hemodynamic and metabolic effects after nifedipine
Journal of Gynecology & Obstetrics 2005;91(1):104. and ritodrine tocolysis. International Journal of Gynecology
Laohapojanart 2007 {published data only} & Obstetrics 2003;82(1):510.
Laohapojanart N, Soorapan S, Wacharaprechanont T, Papatsonis 2004 {published data only}
Ratanajamit C. Safety and efficacy of oral nifedipine versus Papatsonis DNM, Hogendoorn SM, Houtzager BA, van
terbutaline injection in preterm labor. Journal of the Medical Wassenaer AG, Samsom JF. Long-term follow-up of
Association of Thailand 2007;90(11):24619. children exposed in utero to nifedipine or ritodrine in the
Lyell 2007 {published data only} management of preterm labor [abstract]. American Journal
Lyell DJ, Pullen K, Campbell L, Ching S, Druzin ML, of Obstetrics and Gynecology 2004;191(6 Suppl 1):S106.
Chitkara U, et al.Magnesium sulfate compared with Raymajhi 2003 {published data only}
nifedipine for acute tocolysis of preterm labor: a randomized Raymajhi R, Pratap K. A comparative study between
controlled trial. Obstetrics & Gynecology 2007;110(1):617. nifedipine and isoxsuprine in the suppression of preterm
Maitra 2007 {published data only} labour. Kathmandu University Medical Journal 2003;1(2):
Maitra N, Christian V, Kavishvar A. Tocolytic efficacy of 8590.
nifedipine versus ritodrine in preterm labor. International Roy 1993 {published data only}
Journal of Gynecology & Obstetrics 2007;97(2):1478. Roy UK, Pan S. Use of calcium antagonist (nifedipine) in
Maitra 2007a {published data only} premature labour. Journal of the Indian Medical Association
Maitra N, Christian V, Verma RN, Desai VA. Maternal and 1993;91(1):810.
fetal cardiovascular side effects of nifedipine and ritodrine Sharma 2000 {published data only}
used as tocolytics. Journal of Obstetrics and Gynaecology of Sharma A. A randomized comparison of nifedipine and
India 2007;57(3):1314. ritodrine for suppression of preterm labour [abstract]. XVI

FIGO World Congress of Obstetrics & Gynecology (Book Gyetvai 1999
2); 2000 Sept 3-8; Washington DC, USA. 2000:156. Gyetvai K, Hannah M, Hodnett E, Ohlsson A. Tocolysis
for preterm labor: a systematic review. Obstetrics and
Shim 2006 {published data only} Gynecology 1999;94(5):86977.
Shim JY, Park YW, Yoon BH, Cho YK, Yang JH, Lee Y,
et al.Multicentre, parallel group, randomised, single-blind Harake 1987
study of the safety and efficacy of atosiban versus ritodrine Harake B, Gilbert RD, Ashwal S, Power GG. Nifedipine:
in the treatment of acute preterm labour in Korean women. effects on fetal and maternal haemodynamics in pregnant
BJOG: an International Journal of Obstetrics and Gynaecology sheep. American Journal of Obstetrics and Gynecology 1987;
2006;113(11):122834. 157:10038.
Keirse 1989
Snyder 1989 {published data only} Keirse MJNC, Grant A, King JF. Preterm labour. In:
Snyder S. Trial to compare the efficacy of nifedipine and Chalmers I, Enkin M, Keirse MJNC editor(s). Effective Care
magnesium sulfate as tocolytics. Personal Communication in Pregnancy and Childbirth. Oxford: Oxford University
1989. Press, 1989:694745.
Sofat 1994 {published data only} King 1988
Sofat R, Gill BK, Goyal A. Comparison of nifedipine and King JF, Grant A, Keirse MJNC, Chalmers I. Beta-
isoxsuprine in the arrest of preterm labour. International mimetics in preterm labour: an overview of the randomized
Journal of Gynecology and Obstetrics 1994;46:59. controlled trials. British Journal of Obstetrics and Gynaecology
1988;95:21122.
Taherian 2007 {published data only}
Lumley 1993
Taherian AA, Dehdar P. Comparison of efficacy and safety
Lumley J. Epidemiology of preterm birth. Baillieres Clinical
of nifedipine versus magnesium sulfate in treatment of
Obstetrics and Gynaecology 1993;7:47798.
preterm labor. Journal of Research in Medical Sciences 2007;
12(3):13642. McCain 1993
McCain GC, Deatrick JA. The experience of high-risk
Trabelsi 2008 {published data only} pregnancy. Journal of Obstetric, Gynecologic and Neonatal
Trabelsi K, Hadj Taib H, Amouri H, Abdennadheur W, Nursing 1993;23:4217.
Ben Amar H, Kallel W, et al.Nicardipine versus salbutamol
Papatsonis 2001
in the treatment of premature labor: comparison of their
Papatsonis DNM, Lok CAR, Bos J, Van Geijn HP, Dekker
efficacy and side effects. Tunisie Medicale 2008;86(1):438.
GA. Calcium channel blockers in the management of
Van De Water 2008 {published data only} preterm labor and hypertension in pregnancy. European
Van De Water M, Kessel ET, De Kleine MJ, Oei SG. Journal of Obstetrics, Gynecology and Reproductive Biology
Tocolytic effectiveness of nifedipine versus ritodrine and 2001;97:12240.
follow-up of newborns: a randomised controlled trial. Acta Powell 1995
Obstetricia et Gynecologica Scandinavica 2008;87(3):3405. Powell SL, Holt V L, Hickok DE, Easterling T, Connell FA.
Recent changes in delivery site of low-birth-weight infants
Zhang 2002 {published data only} in Washington: impact on birth weight-specific mortality.
Zhang X, Liu M. Clinical observations on the prevention American Journal of Obstetrics and Gynecology 1995;173(5):
and treatment of premature labor with nifedipine. 158592.
[Chinese]. Hua-Hsi i Ko Ta Hsueh Hsueh Pao [Journal of
Saade 1994
West China University of Medical Sciences] 2002;33(2):
Saade GR, Taskin O, Belfort MA, Erturan B, Moise KJ Jr.
28890.
In vitro comparison of four tocolytic agents, alone and in
combination. Obstetrics and Gynecology 1994;84:3748.
Additional references
Tsatsaris 2001
Tsatsaris V, Papatsonis D, Goffinet F, Dekker G, Carbonne
Clarke 2001
B. Tocolysis with nifedipine or beta-adrenergic agonists:
Clarke M, Oxman AD, editors. Cochrane Reviewers
a meta-analysis. Obstetrics and Gynecology 2001;97(5):
Handbook 4.1.1 [updated October 2001]. In: Review
84047.
Manager (RevMan) [Computer program]. Version 4.1.
Oxford, England: The Cochrane Collaboration, 2001. Ulmsten 1980
Ulmsten U, Andersson KE, Wingerup L. Treatment of
Crowley 1998 premature labor with the calcium antagonist nifedipine.
Crowley P. Corticosteroids prior to preterm delivery Archives of Gynecology 1980;229:15.
(Cochrane Review). The Cochrane Library 1998, Issue 3.
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bracero 1991
Methods Blinding of randomisation: Yes, sealed envelopes.

Blinding of intervention: No.
Blinded outcome assessment: No.
Completeness of follow-up: 7 post randomisation exclusions.
Participants 49 women in preterm labour at 20-36 weeks.

Exclusion criteria: ruptured membranes, multiple pregnancy.
Interventions CCB Group: Nifedipine

30mgs po initially then 20mgs q6h for 24hrs then 20mgs q8h for 24hrs followed by maintenance 20mgs
q8-12h prn.
Other tocolytic group: Ritodrine, 100 g/min increasing by 50g/min q10min prn to a maximum of
350g/min. Oral maintenance 10-20mg q4-6 h
Outcomes Delivery < 48 hrs;

pregnancy prolongation;
maternal adverse drug reaction and maternal adverse drug reaction requiring cessation of treatment;
GA at birth;
admission to NICU;
RDS;
neonatal jaundice, sepsis, NEC;
fetal and neonatal death.
Notes No additional data received.

Sample size calculation: Not reported.
Antenatal corticosteroids: Not reported.
GBS protocol: Not reported.
Risk of bias
Bias Authors judgement Support for judgement
Allocation concealment? Low risk A - Adequate

Ferguson 1990

Completeness of follow-up: No.
3 post randomisation
exclusions.
Participants 66 women in preterm labour at 20-36 weeks gestation.

Exclusion criteria: multiple pregnancy.

10mg capsule s/l repeated in 20 mins oral maintenance 20 mg q4-6h.
Other tocolytic group: Ritodrine, 50 g/min increasing by 50 g 15-30 mins up to a maximum of 350g/
min. Oral maintenance 10-20 q4-6 h
Outcomes Delivery < 37 wks;

delivery < 48 hrs;
maternal adverse drug reaction and maternal adverse drug reaction requiring cessation of treatment;
RDS;
IVH all Grades;
fetal deaths;
neonatal deaths.
Notes Additional data received.

Antenatal corticosteroids: Yes.
GBS protocol: Vaginal cultures and intrapartum antibiotics for GBS positive
Risk of bias
Garcia-Velasco 1998

Completeness of follow-up: Yes.

Exclusion criteria: women with ruptured membranes, multiple pregnancy

10mgs s/l and 20mgs po then 10-20 q4-6 h prn.
Other tocolytic group: IV Ritodrine, 50 g/min increasing by 50 ug q20mins to max of 350g/min
maintained for 12 hrs. The oral maintenance 5mgs q3h.

Garcia-Velasco 1998 (Continued)
Indomethacin given in both groups for continued uterine activity after 12 h or treatment was not well
tolerated

delivery < 37 wks;
maternal adverse drug reaction requiring cessation of treatment;
birthweight;
admission to NICU;
RDS;
maternal length of hospital stay.

Sample size calculation: Yes - based on change in maternal BP and pulse.
Risk of bias
Glock 1993

20 post randomisation
exclusions.
Participants 100 women in preterm labour less than 34 wks gestation.

Exclusion crtiteria: Multiple pregnancy, ROM, tocolysis this pregnancy, maternal medical complications,
congenital malformations, IUGR
Interventions CCB: Nifedipine 10mg s/l repeated prn every 20 mins to max of 40mg in first hr. Once contractions
ceased 20mg q4h for 48 h, then maintenance 10mg q8h until 34 wks.
Other tocolytic group:
MgSO4 load 6gIV over 30 mins then 2g per hr IV up to 4g per hr as required for 24 h, then weaned at
0.5g every 4-6 hrs, then maintenance therapy of oral terbutaline 5mg q6h until 34 wks

delivery < 37 wks;
delivery < 34 wks;
pregnancy prolongation index;
birthweight;

Glock 1993 (Continued)
perinatal mortality.
Notes Sample size calculation: No.

GBS protocol: Vaginal culture and intrapartum antibiotics
for GBS positive.
Risk of bias
Janky 1990

Blinded intervention: No.
Participants 62 women in preterm labour at 28-36 weeks gestation.

Exclusion criteria: Chorioamnionitis and maternal medical conditions, cervix > 4cms, ROM after 34
weeks

10mgs s/l then 20mgs q8h. Ceased after 7 days
Other tocolytic group: IV Ritodrine, 200 to 300 g/min until contractions ceased then 100g/min for
24 hr then oral maintenance 20mgs 4-6 h for 6 days
Outcomes Pregnancy prolongation;

birthweight;
fetal death neonatal death.

Risk of bias

Jannet 1997
Methods Blinding of randomisation: Unclear.

Blinded intervention: No.
Participants 90 women in preterm labour 25 to 35.5 wks.

Exclusion criteria: multiple pregnancy
ROM, maternal medical conditions, standard contraindications to tocolytics
Interventions CCB Group: IV Nicardipine 3mg/h for 2 hrs increasing prn up to a maximum of 6mg/hr until contractions
cease then oral 20mgs q8h until 37 wks.
Other tocolytic group: IV Salbutamol 150g/hr, increasing after 2 h to 300g/hr maintained for 48 hrs
then oral maintenance 8mg q6h po and 2 rectal suppositories of salbutamol 2mgs daily until 37 weeks

delivery < 34 wks;
maternal adverse drug reaction;
birthweight;
GA at birth;
admission to NICU.
Notes 4 post randomisation exclusions (2 in each group).

Sample size calculation: No.
Antenatal steroids: Not reported.
Risk of bias
Allocation concealment? Unclear risk B - Unclear
Koks 1998

2 post randomisation exclusions.
Participants 102 women in preterm labour at 24-34 wks.

Exclusion criteria: maternal medical conditions, chorioamnionitis

s/l 30mgs then po 20mgs q4-12 h reducing to 20mgs q8h to 34 wks prn.
Other tocolytic group: IV Ritodrine, 200g/min up to max of 400g/min then oral maintenance 80mgs
q8h to 34 weeks

Koks 1998 (Continued)

delivery < 48 hrs;
delivery < 7 days;
GA at birth;
birthweight;
Apgar score < 7 at 5 min;
NICU admission;
RDS;
neonatal jaundice;
fetal death;
neonatal death.
Notes Outcomes for a subset of trial participants (57) included in review.

Additional data received.
Antenatal corticosteroids: Yes - wkly to 32 wks.
GBS protocol: Vaginal culture and intrapartum antibiotics for GBS positive
Risk of bias
Kupferminc 1993
Methods Blinding of randomisation: Unclear, Computerised list - Blinding of intervention: No.


Exclusion criteria: women with ruptured membranes.

30 mg po then 20mgs after 90 min if required then maintenance 20mgs q8h until 34-35 wks. Switch to
Ritodrine if contractions continue after 150 mins.
Other tocolytic group: IV Ritodrine 50g/min increasing by 15 g q15 to a maximum of 300ug/min for
12 hours, oral maintenance 10mgs q3h until 34-35 wks

delivery < 48 hrs;
delivery <7 days;
NICU admission;
RDS;
fetal death;
neonatal death.
Kupferminc 1993 (Continued)

Sample size calculation: Yes - based on maternal cardiovascular changes.
Risk of bias
Larmon 1999

Participants 122 women in preterm labour between 22-34 wks.

Exclusion criteria: multiple pregnancy,
ROM, chorioamnionitis, medical conditions, standard contraindications to tocolytics
Interventions CCB Group: Nicardipine

40 mg po then 20mgs q2h prn up to 3 doses then oral maintenance 45mgs q12h until 37 wks.
Other tocolytic group: IV MgSO4 loading dose of 6g then 2g/hr increasing up to a maximum of 4g/hr
prn. Oral maintenance Mg lactate 4 tabs q12h until 37 wks
Outcomes Maternal adverse reaction;

NICU admission;
GA at birth; birthweight; fetal death;
neonatal death.
Additional data received for:
birth prior to 37 wks and 34 wks;
birth within 48hrs and 7days of treatment;
maternal adverse drug reaction requiring cessation of treatment; Apgar score <7 at 5 mins; RDS
Notes Sample size calculation: Yes - based on successful tocolysis at 6 hrs.

Antenatal steroids: Yes, for women 24-34 weks gestation.
GBS protocol: All women received ampicillin awaiting results of vaginal culture for GBS, 7 day course
for those GBS positive
Addtional data and information were received from authors and included in the review
Risk of bias

Larmon 1999 (Continued)
Papatsonis 1997


Exclusion criteria: multiple pregnancy, chorioamnionitis, maternal medical conditions

10mgs s/l, repeated if necessary po 10mg q15mins up to 40mg in the first hour. Maintenance 60-160mgs/
day up to 34 weeks.
Other tocolytic group: Ritodrine commencing at 383g/min increasing prn until cessation of contractions
then decreasing depending on the time lag after which tocolysis is established (minimum 100 g/min)
and continued for 3 days.
Maintenance 40mg po q8h up to 34 weeks in two of the three participating hospitals
Outcomes Delivery < 37 wks; delivery < 34 wks; delivery < 7 days; delivery < 48 hrs; gestational age;
birthweight; maternal adverse drug reaction requiring cessation of treatment;
fetal death; NICU admission;
RDS; neonatal death;
Apgar score < 7 at 5 mins;
neonatal jaundice;
NEC; IVH.
Notes 12 exclusions in published report - additional data received and included.

Sample size calculation: Yes - based on delay in delivery < 7 days.
GBS protocol: vaginal culture on admission and antibiotics for positive GBS
Risk of bias

Read 1986
Methods Blinding of randomisation: Unclear.


Exclusion criteria: multiple pregnancy, chorioamnionitis, maternal medical conditions, ROM

30mgs po then 20mg q8h for 3 days. Ritodrine started after 2 hrs if contractions were undiminished.
Other tocolytic group: Ritodrine 50 g/min increasing by 50g q 10 mins to a maximum of 300g.
Maintained for 12 h then oral maintenance for 48 h

maternal adverse drug reaction;
birthweight.
Notes No additional outcomes data available.

Sample size calculation: No.
Risk of bias
Weerakul 2002

Completeness of follow-up: One post randomisation exclusion.
Participants 90 women in preterm labour with a singleton pregnancy between 28-34 wks gestation.
Exclusion criteria: multiple pregnancy, ruptured membranes, previous tocolytics, cervix >3cms dilated,
chorioamnionitis, infection, fetal distress, fetal anomalies, medical or obstetric complications

10mgs s/l capsule crushed repeated after 15 mins, then 20mg after 30 mins to a maximum in the first hr
of 40mg. Maintenance of 60-120 mg daily for 3 days
Other tocolytic group: Terbutaline IV loading of 0.25mg, then infusion commencing at 5g/min increas-
ing by 5g/min every 15 mins depending on contractions to a maximum of 15g/min. Following uterine
quiesence infusion maintained for 2 hrs then subcutaneous injection 0.25mg q4h for 24hrs

Weerakul 2002 (Continued)
Outcomes Delivery after 48 hrs;

delivery after 7 days;
delivery after 37 weeks;
pregnancy prolongation; GA at birth; birthweight; maternal adverse drug reaction
Additional data received on the following:
Delivery within 48 hrs;
Delivery within 7 days;
Delivery within 37 weeks;
Delivery within 34 weeks;
Use of antenatal steroids;
Maternal sepsis, maternal death, APH, PPH.
Apgar score<7 at 5 mins; admission to NICU; neonatal mechanical ventilation, jaundice, sepsis, NEC,
IVH, ROP; Perinatal death
Notes Additional information on methods and outcomes data were received.

Sample size calculation: Yes - no details given.
Antenatal corticosteroids: Yes - all women enrolled.
GBS protocol: No.
One post randomisation exclusion in the other tocolytic group (terbutaline) due to patient transfer to
private hospital
Risk of bias
AB: antibiotics
APH: antepartum haemorrhage
BP: blood pressure
CCB: calcium channel blocker
GA: gestational age
GBS: group B Streptococcus
hrs: hours
IUGR: intrauterine growth restriction
IV: intravenous
IVH: intraventricular haemorrhage
MgSO4: magnesium sulphate
min: minute
NEC: neonatal necrotising enterocolitis
NICU: neonatal intensive care unit
po: orally
PPH: postpartum haemorrhage
prn: as necessary
q6h: every six hours
RDS: neonatal respiratory distress syndrome
ROM: rupture of membranes

s/l: sublingual
g: micrograms
wks: weeks
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Carr 1993 Trial of maintenance tocolytic therapy.
Dunstan-Boone 1990 Quasi-random allocation to treatment.
El-Sayed 1998 Trial of maintenance tocolytic therapy.
Kose 1995 Information was not available on:

1. reasons for imbalance in numbers in study groups: 52 women in nifedipine group and 21 in ritodrine
group; and
2. method of randomisation.
Meyer 1990 Women were eligible for trial entry only after subcutaneous terbutaline failed to stop regular uterine con-
tractions and the numbers in each group (34 versus 24) raise concerns about the randomisation process
Piovano 1985 Trial tested the addition of a calcium channel blocker for women receiving tocolysis with a betamimetic
agent
Rodriguez-Esc 1981 Trial tested the addition of a calcium channel blocker for women receiving tocolysis with a betamimetic
agent
Smith 1993 Quasi-random allocation to treatment.

DATA AND ANALYSES
Comparison 1. Any calcium channel blocker compared with any other tocolytic agent
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Birth prior to 37 weeks gestation 6 558 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.83, 1.09]
3 Birth within seven days of 4 453 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.60, 0.97]
treatment
4 Birth within 48 hours of 9 761 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.61, 1.05]
treatment
5 Pregnancy prolongation (days) 7 592 Mean Difference (IV, Fixed, 95% CI) 5.71 [1.95, 9.47]
6 Maternal adverse drug reaction 8 717 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.24, 0.41]
7 Maternal drug reaction requiring 10 833 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.05, 0.36]
cessation of treatment
8 Duration of maternal hospital 1 52 Mean Difference (IV, Fixed, 95% CI) 0.18 [-1.04, 1.40]
stay (days)
9 Gestation at birth (completed 6 587 Mean Difference (IV, Fixed, 95% CI) 0.70 [0.19, 1.20]
weeks)
10 Birthweight (grams) 8 717 Mean Difference (IV, Fixed, 95% CI) 84.42 [-10.13, 178.
97]
11 Apgar score < 7 at five minutes 4 478 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.35, 1.71]
12 Admission to intensive care 9 771 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.64, 0.95]
nursery
13 Respiratory distress syndrome 9 763 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.46, 0.88]
14 Neonatal jaundice 2 227 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.57, 0.93]
15 Neonatal sepsis 4 378 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.46, 1.16]
16 Necrotising enterocolitis 3 323 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.05, 0.96]
17 Intraventricular haemorrhage 3 340 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.36, 0.98]
grades three or four
19 Retinopathy of prematurity 1 185 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.01, 1.93]
20 Perinatal mortality 10 810 Risk Ratio (M-H, Fixed, 95% CI) 1.65 [0.74, 3.64]
21 Perinatal mortality excluding 10 820 Risk Ratio (M-H, Fixed, 95% CI) 1.42 [0.61, 3.31]
congenital abnormality
22 Fetal death 10 820 Risk Ratio (M-H, Fixed, 95% CI) 3.0 [0.13, 71.07]
23 Fetal death excluding 10 820 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
24 Neonatal death 11 883 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [0.74, 3.39]
25 Neonatal death excluding 10 820 Risk Ratio (M-H, Fixed, 95% CI) 1.42 [0.61, 3.31]

Comparison 2. Any dihydropyridine calcium channel blocker compared with any betamimetic agent
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
3 Birth within seven days of 2 242 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.59, 0.99]
treatment
4 Birth within 48 hours of 6 470 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.53, 0.97]
treatment
5 Pregnancy prolongation (days) 5 381 Mean Difference (IV, Fixed, 95% CI) 8.24 [3.67, 12.81]
6 Maternal adverse drug reaction 5 426 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.30, 0.55]
7 Maternal drug reaction requiring 7 542 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.02, 0.38]
cessation of treatment
8 Duration of maternal hospital 1 52 Mean Difference (IV, Fixed, 95% CI) 0.18 [-1.04, 1.40]
stay (days)
9 Gestation at birth (completed 4 376 Mean Difference (IV, Fixed, 95% CI) 0.83 [0.21, 1.44]
weeks)
10 Birthweight (grams) 5 426 Mean Difference (IV, Fixed, 95% CI) 122.68 [3.51, 241.
86]
11 Apgar score < 7 at five minutes 2 267 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.21, 1.52]
12 Admission to intensive care 7 572 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.71, 1.00]
nursery
13 Respiratory distress syndrome 7 552 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.45, 0.91]
14 Neonatal jaundice 2 227 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.57, 0.93]
15 Neonatal sepsis 3 289 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.47, 1.19]
16 Necrotising enterocolitis 2 234 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.04, 1.25]
grades three or four
19 Retinopathy of prematurity 1 185 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.01, 1.93]
20 Perinatal mortality 7 529 Risk Ratio (M-H, Fixed, 95% CI) 1.39 [0.60, 3.24]
21 Perinatal mortality excluding 7 529 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.49, 2.94]
22 Fetal death 7 529 Risk Ratio (M-H, Fixed, 95% CI) 3.0 [0.13, 71.07]
23 Fetal death excluding 7 529 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
25 Neonatal death 8 592 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [0.63, 3.12]
26 Neonatal death excluding 7 529 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.49, 2.94]

FEEDBACK
Thornton, July 2006
Summary
I am concerned that there is unintentional bias in favour of the use of calcium channel blockers and against oxytocin antagonists in
two recent Cochrane reviews, this one and the review of oxytocin antagonists (1).
Objective judgement of trial quality
Four studies of oxytocin antagonists (European 2001, French/Austr. 2001, Moutquin 2000, and Romero 2000) in the review of
oxytocin antagonists (1) are recorded as Blinding outcome assessment: unknown despite their using a double dummy technique with
no mention that the blinding was broken. Another, Goodwin 1994, is classified as Blinding outcome assessment: no despite the review
authors correctly noting that a double dummy technique was used. The relevant section of the published paper reads as follows: the
pharmacist would open the envelope to reveal the patients treatment assignment for the purpose of preparing the study drug infusion
solution. The treatment assignment was not revealed to other persons, and the individual preparing the drug was not involved in patient
care. Surely all five trials should be classified as Blinding outcome assessment: yes.
Subjective judgement of trial quality
In the text of the calcium channel review review, the trials are classified as of reasonable quality and no statement is made about quality
in the abstract.
In fact none were blinded; they were all relatively small (mean group size 43) and only four had performed a sample size calculation.
The lack of blinding is particularly important since all the reported outcomes favouring calcium channel blockers are susceptible to
biased ascertainment, and the only hard outcome, perinatal death, showed a trend against calcium channel blockers (see below).
In contrast the oxytocin antagonist reviewers classify Goodwin 1996a as not high quality because it was unblinded.
Choice of outcomes to report in the abstract
The calcium channel review abstract finds space to report seven beneficial effects of calcium channel blockers on surrogate outcomes,
either prolongation of labour or surrogate fetal outcomes, but fails to mention perinatal deaths which had a relative risk 1.65 (95%
CI 0.74-3.64) favouring other tocolytics. Nor are total pregnancy losses mentioned. These would include the four neonatal deaths
reported by Koks 1993 in a ratio of 3:1 against calcium channel blockers.
In the oxytocin antagonist review (1) abstract, five unfavourable conclusions against placebo are reported. Although all of them might
be explained by the gestational age imbalance at trial entry in the relevant trial (Romero 2000), this qualification is only mentioned
in relation to one, infant death, and is removed from the synopsis where the association is repeated. In the comparison with beta-
mimetics, the first outcome reported is birth weight under 1,500g, an outcome which was not pre-specified in the review methods and
which is the only statistically significant outcome out of 21 reported for this comparison. Only later is the reduction in adverse drug
reactions compared to beta-mimetics reported.
Choice of language
In the review of calcium channel blockers, all of the seven sentences in the abstract conclusions and the plain language summary contain
a favourable opinion of calcium channel blockers. The single exception is a call for research into the effect of different dosing regimes,
with the implication that the primary effectiveness question has been answered.
The authors conclude: it is considered unlikely that [placebo controlled trials of calcium channel blockers] will be conducted given
the unequivocal impact that this method of tocolysis has on short term postponement of delivery. This statement is much too strong.
It is based entirely on unblended trials against other tocolytics. Two of the five relevant outcomes (birth prior to 37 weeks, and birth
within 48 hours) showed only a non-significant effect, two (birth prior to 34 weeks and within seven days) just reached the 0.05 level,
and the final outcome (pregnancy prolongation in days), while statistically significant, shows significant heterogeneity between trials.
In neither the abstract nor the conclusion section of the calcium channel blocker review is it mentioned that there have been no placebo-
controlled trials of calcium channel blockers in preterm labour.
In contrast, instead of saying that oxytocin antagonists had shown equivalent efficacy to other tocolytics in four high quality trials, the
authors phrase their summaries as either has failed to demonstrate superiority or is no better than other drugs. This seems gratuitous
negativity.
Choice of outcomes to report
The outcomes selected for the oxytocin review differ significantly from those chosen for the calcium channel blocker review. The reason
is not clear.
Finally, the oxytocin antagonist review claims to be going to look at predefined outcomes measured related to the prolongation of
pregnancy. However the predefined outcomes for the two placebo-controlled trials, namely time to delivery or therapeutic failure
were not reported.
Authorship of the reviews
I note that both these reviews share an author, Dimitri Papatsonis, who is the first author of the largest trial of calcium channel blockers,
upon which many of the favourable calcium channel blocker meta analyses depend.
I recognise that it is probably impossible to always avoid using trial authors to write systematic reviews, and that Dr Papatsonis
acknowledges his possible conflict of interest. Nor do I accuse him, or any of the review authors, of any intentional bias. Nevertheless, I
am concerned about possible unintentional bias against commercially developed pharmacological agents. This risks harming the future
development of drugs for use in pregnancy, something which I am sure everyone would support.
Conflict of Interest
I have acted as advisor to Ferring and when I was editor of BJOG the journal received sponsorship from Ferring to publish supplements.
Jim Thornton, July 2006
References
Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database of Systematic
Reviews 2005, Issue 3. Art. No.: CD004452. DOI: 10.1002/14651858.CD004452.pub2.
Reply
On behalf of the review authors, we respond to Professor Thorntons comments about the review of calcium channel blockers (CCB)
[1] and the review of oxytocin receptor antagonists (ORA) [2] for preventing preterm birth.
Judgement of trial quality
For the ORA review, blinding of the intervention is not synonymous with blinding of outcome assessment. Unless authors stated
so in their original reports, or in response to further queries, we cannot presume that those assessing the outcome of interest were
blinded to the allocated intervention. For example, in trials comparing betamimetics with atosiban, blinding of the intervention is
difficult due to the maternal and fetal side effects of betamimetics, particularly tachycardia and maternal palpitations. Therefore, until
further information is received from the trial authors, blinding of assessment of outcome is classified as unknown for these four
trials (European 2001, French/Austr. 2001, Moutquin 2000, and Romero 2000). We agree Goodwin 1994 should also be classified as
unknown, and this is now corrected.
We disagree that assessment of trial quality was subjective. The statements reasonable quality used in the calcium channel blocker
(CCB) review and not high quality in the ORA review are intended to imply that the trials were neither poor quality nor high quality.
Studies were judged to be of poor quality if no adequate method of allocation concealment was described, as this is one of the most
important quality indicators regardless of whether the intervention was blinded. In accordance with Cochrane methodology, small
numbers and lack of sample size calculations were not considered indicators of trial quality.
Choice of outcomes to report in the abstract
For the CCB review, we believe we have adequately acknowledged the potential for bias in the ascertainment of neonatal outcomes.
We also note that the results were consistent across the included trials, but acknowledge that this does not rule out bias. A statement
regarding trial quality will be included in the abstract for the next update of the CCB review
The outcome measures in the abstract of the CCB review were considered to be clinically important outcomes for this review. We will
include the outcome of perinatal mortality in the abstract for the next update of the review.
In the ORA review abstract, the potential for bias due to the gestational age imbalance at trial entry in the Romero trial is acknowledged.
We have made it clearer how this relates to the other data presented by stating at the start of this paragraph the number of trials and
women in this comparison. We prespecified birthweight as a clinically important outcome measure for the review, and considered it
reasonable to include the finding of birthweight <1500gms in the abstract. In the abstract results, the ordering of text on maternal drug
reaction for the comparison of ORA with betamimetics provides consistency with the reporting of the outcomes for the comparison of
atosiban versus placebo.
Choice of language
We appreciate that the upper confidence interval for a number of the statistically significant outcomes reported approached 1, no
difference. However, based on the point estimates of the effects and the consistency in the findings across these outcomes, we believe
that the conclusions of the CCB review and wording of the abstract accurately reflects the findings. The statistical heterogeneity found
for the outcome of pregnancy prolongation we believe was appropriately managed in this review with the use of a random-effects model
for the meta-analysis of this outcome.
While we feel the language used in the ORA review abstract accurately reflects the results, we will rephrase to take account of the
perception we may have been too negative about atosiban.
Choice of outcomes to report
We accept the outcomes for the ORA and CCB reviews differ, as they do in other tocolysis reviews, and that this is not helpful for
readers of the review. As there is overlap between the review teams for these two reviews, we will rectify this during the next update of
these reviews.
Regarding the use of predefined outcomes, this term relates to outcomes chosen by the reviewers as clinically meaningful and defined
in the review protocol before the review begins. These outcomes may or may not match those reported for individual trials. If reported
outcomes did not match those pre-specified for the review, wherever possible, additional information was sought from authors. For
the placebo controlled trials in the ORA review, data on pregnancy prolongation was not provided in a format to enable inclusion in
the review; while additional data were sought from the authors, these were not forthcoming. The outcome of therapeutic failure was
reported in the individual trials, but was not chosen as an outcome for either the ORA or CCB reviews as it was considered susceptible
to bias.
Authorship of the reviews
Whilst it is appropriate and common practice for experts to undertake systematic reviews within their area of expertise, we agree that
this carries with it the potential for bias. For Cochrane reviews, however (including the ORA and CCB reviews), a number of steps
are in place to ensure that this risk is minimised. These steps include: transparency of the review process through publication of the
protocol for the review prior to commencement, rigorous peer review (including an external referee) of the protocol and the review,
multiple review authors aiming for a mix of expertise and experience, and a feedback system which allows anyone to comment on
reviews and protocols. In addition, the regular updating of reviews means that any errors or misperceptions can be corrected. We think
it unlikely therefore that any harm will come to future development of drugs for use in pregnancy due to bias, whether intentional or
not, in our review.
(Summary of response, October 2007: Vicki Flenady, Dimitri Papatsonis, James King and Helen Liley on behalf of the authors for the
ORA and CCB reviews.)
References
[1] King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane
Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002255. DOI: 10.1002/14651858.CD002255.
[2] Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database of
Systematic Reviews 2005, Issue 3. Art. No.: CD004452. DOI: 10.1002/14651858.CD004452.pub2.
Contributors
Feedback: Jim Thornton
Response: Vicki Flenady, Dimitri Papatsonis, James King and Helen Liley on behalf of the authors for the ORA and CCB reviews
WHATS NEW
Last assessed as up-to-date: 19 September 2002.
Date Event Description
10 January 2011 Amended Contact details updated.

HISTORY
Protocol first published: Issue 3, 2000
Review first published: Issue 2, 2002
Date Event Description
4 January 2010 Amended Search updated. Twenty-six reports added to Studies awaiting classification
29 January 2009 Amended Author contact details edited.
31 October 2008 Amended Converted to new review format.
14 November 2007 Feedback has been incorporated Response to feedback added.
1 October 2002 New search has been performed This review updates the review Calcium channel blockers for inhibiting
preterm labour which was first published in The Cochrane Library Issue 2,
2002.
This update includes published and unpublished data from one additional
trial (Weerakul 2002) and unpublished information from the author of one
previously included trial (Larmon 1999). The review now contains twelve
trials which enrolled 1029 women.
The extra data included in this review result in a marginal decrease in the
previously demonstrated effect on the outcome of birth within 48 hours of
commencement of treatment (no longer statistically significant) but show
a reduction (which reached statistical significance) in the outcome of birth
prior to 34 weeks associated with the use of calcium channel blockers. These
additional data strengthen the beneficial effect of calcium channel blockers
on several neonatal outcomes.
The conclusions of the earlier version of the review remain basically un-
changed. Calcium channel blockers are a safer and more effective tocolytic
agent than betamimetics for mothers and babies
CONTRIBUTIONS OF AUTHORS
James King, Vicki Flenady and Dimitri Papatsonis undertook independent quality assessments, data extraction, resolved differences by
discussion and assembled the review. All authors assisted with the interpretation and final editing.

DECLARATIONS OF INTEREST
B Carbonne, D Papatsonis, and G Dekker were co-authors in a non-Cochrane systematic review of nifedipine and beta-agonists
(Tsatsaris 2001). D Papatsonis and G Dekker were co-authors of a randomised trial of nifedipine and ritodrine for preterm labour
(Papatsonis 1997).
SOURCES OF SUPPORT
Internal sources
Department of Perinatal Medicine, Royal Womens Hospital, Melbourne, Victoria, Australia.
Centre for Clinical Studies-Womens and Childrens Health, Mater Hospital, South Brisbane, Queensland, Australia.
J P Kelly Research Foundation, Mater Hospital, South Brisbane, Queensland, Australia.
External sources
Department of Health and Ageing, Commonwealth Government, Canberra, Supporting Centre for Clinical Studies, Mater
Hospital, Brisbane, Australia.
INDEX TERMS
Medical Subject Headings (MeSH)

Calcium Channel Blockers [ therapeutic use]; Obstetric Labor, Premature [ prevention & control]; Randomized Controlled Trials as
Topic; Tocolytic Agents [ therapeutic use]
MeSH check words

Female; Humans; Pregnancy


Calcium Channel Blockers For Inhibiting Preterm Labour (Review)

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Calcium channel blockers for inhibiting preterm labour

King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B

Calcium channel blockers for inhibiting preterm labour (Review)

Calcium channel blockers for inhibiting preterm labour (Review) i

Calcium channel blockers for inhibiting preterm labour

Hopital Saint Antoine, Saint Antoine, France

Editorial group: Cochrane Pregnancy and Childbirth Group.

PLAIN LANGUAGE SUMMARY

Calcium channel blockers for inhibiting preterm labour

Calcium channel blockers for inhibiting preterm labour (Review) 3

Calcium channel blockers for inhibiting preterm labour (Review) 4

Calcium channel blockers for inhibiting preterm labour (Review) 5

Calcium channel blockers for inhibiting preterm labour (Review) 6

Calcium channel blockers for inhibiting preterm labour (Review) 7

Calcium channel blockers for inhibiting preterm labour (Review) 10

Calcium channel blockers for inhibiting preterm labour (Review) 11

Characteristics of included studies [ordered by study ID]

Methods Blinding of randomisation: Yes, sealed envelopes.

Participants 49 women in preterm labour at 20-36 weeks.

Interventions CCB Group: Nifedipine

Outcomes Delivery < 48 hrs;

Notes No additional data received.

Bias Authors judgement Support for judgement

Allocation concealment? Low risk A - Adequate

Calcium channel blockers for inhibiting preterm labour (Review) 12

Methods Blinding of randomisation: Yes, sealed envelopes.

Participants 66 women in preterm labour at 20-36 weeks gestation.

Interventions CCB Group: Nifedipine

Outcomes Delivery < 37 wks;

Notes Additional data received.

Bias Authors judgement Support for judgement

Allocation concealment? Low risk A - Adequate

Methods Blinding of randomisation: Yes, sealed envelopes.

Participants 52 women in preterm labour at 26-34 weeks.

Interventions CCB Group: Nifedipine

Calcium channel blockers for inhibiting preterm labour (Review) 13

Outcomes Delivery < 48 hrs;

Notes Additional data received.

Bias Authors judgement Support for judgement

Allocation concealment? Low risk A - Adequate

Methods Blinding of randomisation: Yes, sealed envelopes.

Participants 100 women in preterm labour less than 34 wks gestation.

Outcomes Delivery < 48 hrs;

Calcium channel blockers for inhibiting preterm labour (Review) 14

Notes Sample size calculation: No.

Bias Authors judgement Support for judgement

Allocation concealment? Low risk A - Adequate

Methods Blinding of randomisation: Yes, sealed envelopes.

Participants 62 women in preterm labour at 28-36 weeks gestation.

Interventions CCB Group: Nifedipine

Outcomes Pregnancy prolongation;

Notes Additional data received.

Bias Authors judgement Support for judgement

Allocation concealment? Low risk A - Adequate

Calcium channel blockers for inhibiting preterm labour (Review) 15

Methods Blinding of randomisation: Unclear.

Participants 90 women in preterm labour 25 to 35.5 wks.

Outcomes Delivery < 37 hrs;

Notes 4 post randomisation exclusions (2 in each group).

Bias Authors judgement Support for judgement

Allocation concealment? Unclear risk B - Unclear

Methods Blinding of randomisation: Yes, sealed envelopes.

Participants 102 women in preterm labour at 24-34 wks.