Nifedipino Review

Research www. AJOG.
org
OBSTETRICS
Nifedipine in the management of preterm labor:
a systematic review and metaanalysis
Agustín Conde-Agudelo, MD, MPH; Roberto Romero, MD; Juan Pedro Kusanovic, MD
OBJECTIVE: To determine the efficacy and safety of nifedipine as a to- There was no difference between nifedipine and magnesium sulfate in
colytic agent in women with preterm labor. tocolytic efficacy. Nifedipine was associated with significantly fewer
maternal adverse events than ␤2-adrenergic-receptor agonists and
STUDY DESIGN: A systematic review and metaanalysis of randomized
magnesium sulfate. Maintenance nifedipine tocolysis was ineffective in
controlled trials.
prolonging gestation or improving neonatal outcomes when compared
RESULTS: Twenty-six trials (2179 women) were included. Nifedipine with placebo or no treatment.
was associated with a significant reduction in the risk of delivery within
CONCLUSION: Nifedipine is superior to ␤2-adrenergic-receptor ago-
7 days of initiation of treatment and before 34 weeks’ gestation, respi-
nists and magnesium sulfate for tocolysis in women with preterm labor.
ratory distress syndrome, necrotizing enterocolitis, intraventricular
hemorrhage, neonatal jaundice, and admission to the neonatal inten- Key words: calcium channel blocker, neonatal morbidity, pregnancy,
sive care unit when compared with ␤2-adrenergic-receptor agonists. premature birth, preterm birth, tocolysis, uterine contractility
Cite this article as: Conde-Agudelo A, Romero R, Kusanovic JP. Nifedipine in the management of preterm labor: a systematic review and metaanalysis. Am J
Obstet Gynecol 2011;204:134.e1-20.
T he World Health Organization has

estimated that 12.9 million births,
or 9.6% of all births worldwide, were the preterm birth rate has risen over the
mains unclear what the first-line tocolytic
agent should be6: (1) ␤2-adrenergic-recep-
tor agonists reduce the rate of preterm de-
preterm in 2005.1 In the United States, last 2 decades. In 2007, preterm births livery within 48 hours of initiation of treat-
constituted 12.7% of live births, an in- ment.7 Nevertheless, there is no evidence
crease of 20% since 1990, and 36% since that this delay in the timing of birth by itself
From the Perinatology Research Branch, the early 1980s.2 Trends in most other translates into improvements in neonatal
Eunice Kennedy Shriver National Institute of developed countries are similar to those outcomes, and maternal side effects are
Child Health and Human Development, in the United States.3,4 Preterm birth is considerable7; (2) magnesium sulfate has
National Institutes of Health, Department of
the leading cause of perinatal morbidity not been proven to be an effective tocolytic
Health and Human Services, Bethesda, MD,
and Detroit, MI (all authors), and the Center and mortality4 and one of the leading agent, and its use could be associated with
for Molecular Medicine and Genetics (Dr causes of infant mortality.2 Despite the an increased risk of fetal, neonatal, and in-
Romero) and the Department of Obstetrics improvement in survival rates of pre- fant mortality8; (3) there is insufficient ev-
and Gynecology (Drs Romero and term neonates, they are at increased risk idence of whether prostaglandin synthesis
Kusanovic), Wayne State University, of long-term neurodevelopmental dis- inhibitors reduce the risk of preterm
Detroit, MI. abilities and respiratory and gastrointes- birth9; (4) the oxytocin receptor antagonist
Received July 11, 2010; revised Aug. 19, tinal complications.5 atosiban was found to increase the propor-
2010; accepted Nov. 17, 2010. Because uterine contractions are the tion of patients remaining undelivered and
Reprints not available from the authors. most frequently recognized symptom not requiring an alternate tocolytic at 7
This study was supported in part by the and sign of preterm labor, inhibition days when compared with placebo, yet this
Intramural Research Program of the Eunice
Kennedy Shriver National Institute of Child
of uterine contractility with tocolytic was not associated with an improvement
Health and Human Development, National agents to prolong pregnancy and reduce in neonatal outcome, which has been at-
Institutes of Health, Department of Health and neonatal complications continues to be tributed to the complexities of study de-
Human Services. the focus of treatment of preterm labor. sign and interpretation of trials of tocolysis
0002-9378/free Tocolytic agents are intended to arrest that involve a rescue intervention10; bar-
© 2011 Published by Mosby, Inc.
uterine contractions during an episode usiban, a selective oxytocin antagonist, has
doi: 10.1016/j.ajog.2010.11.038
of preterm labor (acute tocolysis) or not been found to be more effective than
maintain uterine quiescence after an placebo in delaying delivery for 48 hours11;
For Editors’ Commentary,
see Table of Contents acute episode has abated (maintenance (5) there is currently insufficient evidence
tocolysis). to support the use of nitric oxide donors as
See related editorial, page 95 Several agents have been used for the in- a tocolytic drug,12 although recent studies
hibition of uterine contractility, but it re- suggest that this option requires further
134.e1 American Journal of Obstetrics & Gynecology FEBRUARY 2011

www.AJOG.org Obstetrics Research
consideration13,14; and (6) maintenance Reporting Items for Systematic reviews tocolysis. Two reviewers independently
tocolysis with ␤2-adrenergic-receptor ago- and Metaanalyses guidelines for meta- evaluated studies for inclusion, and dis-
nists15 and oral magnesium sulfate16 is in- analysis of randomized controlled trials.23 agreements were resolved through con-
effective in prolonging gestation or reduc- sensus among the authors. Investigators
ing adverse neonatal outcomes. Atosiban Search of selected studies were contacted to
maintenance treatment can increase the We searched (without language re- complement data on trial methods
time interval to the next episode of pre- strictions) the following computerized and/or outcomes.
term labor but does not reduce the rate of databases using the terms “nifedipine,”
preterm delivery or improve infant “calcium channel blocker,” “calcium an- Outcome measures
outcomes.17 tagonist,” “tocolysis,” “preterm labor,” The primary outcomes of interest were
Some authors have proposed that “premature,” and their associated medi- delivery within 48 hours and 7 days of
nifedipine, a calcium channel blocker, cal subject headings (MeSH): MED- treatment for acute tocolysis; delivery
could be used as a first-line tocolytic LINE, EMBASE, CINAHL, and LILACS before 34 and 37 weeks’ gestation for
agent.18-20 The most recent substantial (all from inception to December 31, 2010), maintenance tocolysis; and perinatal
update of the Cochrane review regarding the Cochrane Central Register of Controlled death, admission to neonatal intensive
calcium channel blockers for acute toco- Trials (http://www.mrw.interscience. care unit (NICU), neurodevelopmental
lysis in preterm labor included 12 ran- wiley.com/cochrane/cochrane_clcentral_ disability at 2 years of age, and severe ma-
domized controlled trials (10 using ni- articles_fs.html) (1960 to December 31, ternal adverse drug reactions for both
fedipine) involving 1029 patients.21 This 2010), ISI Web of Science (http://www. acute and maintenance tocolysis. Sec-
review concluded that calcium channel isiknowledge.com) (1960 to December 31, ondary outcomes included the interval
blockers (mainly nifedipine) reduce the 2010), Research Registers of Ongoing between trial entry and delivery, gesta-
risk of delivery within 7 days of initiation Trials (www.clinicaltrials.gov, www. tional age at delivery, maternal adverse
of treatment and delivery before 34 controlled-trials.com, www.centerwatch. events, discontinuation of treatment be-
weeks’ gestation with improvements in com, www.anzctr.org.au, and www.umin. cause of adverse events, birthweight,
some clinically important neonatal out- ac.jp/ctr), and Google scholar. To ensure Apgar score at 5 minutes, respiratory dis-
comes such as respiratory distress syn- maximum sensitivity, we placed no limits tress syndrome, intraventricular hemor-
drome, intraventricular hemorrhage, or filters on the searches. Proceedings of rhage, necrotizing enterocolitis, retinop-
necrotizing enterocolitis, and neonatal the Society for Maternal-Fetal Medicine athy of prematurity, neonatal jaundice,
jaundice when compared to other toco- and international meetings on preterm neonatal sepsis, fetal death, neonatal
lytic agents (mainly beta-mimetics). birth and tocolysis, reference lists of iden- death, length of stay in the NICU, long-
A second review from the Cochrane tified studies, textbooks, previously pub- term psychosocial and motor function,
database on maintenance tocolysis re- lished systematic reviews, and review arti- and pregnancy/neonatal outcomes among
ported that nifedipine neither reduces cles were also searched. For studies with women enrolled at less than 32 weeks’
the risk of preterm birth before 37 weeks’ multiple publications, the data from the gestation.
gestation nor improves neonatal out- most complete report were used and sup-
comes, compared with no treatment.22 plemented if additional information ap- Study quality assessment
However, this review included only 1 peared in other publications. We conducted quality assessment ac-
trial of 74 women. The literature cording to a modified scoring system
searches on which these reviews were Study selection proposed by Jadad et al,24 which consid-
based were performed in 2002 and 2004, We included randomized controlled tri- ers 4 items: randomization, blinding,
respectively. Since that time, additional als in which nifedipine was used for to- follow-up, and concealment of alloca-
randomized controlled trials with nifed- colysis in patients with preterm labor tion. We assigned points to each trial as
ipine have been published; therefore, re- compared with alternative tocolytic follows: (1) quality of randomization (2
assessment of the efficacy and safety of agents, placebo, or no treatment. Trials points: computer-generated random
this agent is justified. were excluded if they were quasi-ran- numbers or similar; 1 point: not de-
We conducted a systematic review and domized, if they compared only different scribed; 0 points: quasi-randomized or
metaanalysis of all available randomized doses of nifedipine or other calcium not randomized [we excluded such stud-
controlled trials to determine the efficacy channel blockers, or if nifedipine was ies]); (2) double blinding (2 points: nei-
and safety of nifedipine as a tocolytic given in addition to or following failure ther the person doing the assessments
agent in patients with preterm labor. of another tocolytic drug. Published ab- nor the study participant could identify
stracts alone were excluded if additional the intervention being assessed; 1 point:
information on methodological issues not described; 0 points: no blinding or
M ATERIALS AND M ETHODS and results could not be obtained. We inadequate method); (3) follow-up (2
The systematic review was performed classified trials according to the aim of points: number or reasons for dropouts
following a prospectively prepared pro- the treatment with nifedipine into 2 and withdrawals described and assess-
tocol and reported using the Preferred groups: acute tocolysis and maintenance ment of primary outcomes in 95% or
FEBRUARY 2011 American Journal of Obstetrics & Gynecology 134.e2

Research Obstetrics www.AJOG.org
more of randomized women; 1 point: weeks’ gestation in our data synthesis be- We conducted additional analyses
number or reasons for dropouts and cause of the relatively similar neonatal stratified according to the following
withdrawals described but assessment of outcomes. Disagreements regarding ex- characteristics: definition of preterm la-
primary outcomes in less than 95% of tracted data were resolved by discussion bor (based on uterine contractions plus
randomized women; 0 points: number among the authors. cervical changes vs based on uterine con-
or reasons for dropouts and withdrawals tractions alone); mean or median cervi-
not described); and (4) concealment of Statistical analysis cal dilatation at trial entry (⬍2 vs ⱖ2
allocation (2 points: adequate method Statistical analyses were performed ac- cm); participating patients in true pre-
[central randomization; or drug con- cording to the guidelines of the Co- term labor as judged by the authors (yes
tainers or opaque, sealed envelopes that chrane Collaboration.25 We analyzed vs no/not reported); loading dose of
were sequentially numbered and opened outcomes on an intention-to-treat basis. nifedipine (10 vs 30 mg); membranes
sequentially only after they have been ir- If this was not clear from the original ar- status (intact vs ruptured); plurality (sin-
reversibly assigned to the participant]; 0 ticle, then we carried out reanalysis when gleton vs twin pregnancy); mean gesta-
points: no concealment of allocation or possible. If we found no evidence of a tional age at trial entry (ⱕ30 weeks vs
inadequate method or not described). substantial difference in study popula- ⬎30 weeks); study setting (developed vs
Thus, the total score ranged from 0 (low- tions, interventions, or outcome mea- developing countries); maintenance
est quality) to 8 (highest quality). Studies surements, we performed a metaanaly-
that scored 6 points or more were therapy in studies evaluating acute toco-
sis. We calculated the summary relative lysis (yes vs no/not reported); use of al-
considered to be of high quality. Two risk (RR) for dichotomous data and
investigators (A.C.-A. and J.P.K.) inde- ternative tocolytic therapy (yes vs no/not
weighted mean difference (WMD) for reported); and antenatal corticosteroid
pendently assessed study quality, and continuous data with associated 95%
discrepancies were resolved through therapy (yes vs no/not reported). Meta-
confidence interval (CI). analyses according to plurality of preg-
discussion.
Four prespecified subgroup analyses nancy and membranes status, however,
were performed to compare nifedipine
Data extraction were not undertaken because of insuffi-
with other tocolytic agents (␤2-adrener-
Two reviewers (A.C.-A. and J.P.K.) inde- cient data.
gic-receptor agonists, magnesium sul-
pendently extracted data from each eligi- For the comparison nifedipine vs
fate, atosiban, and nitric oxide donors)
ble study using a standardized data ab- magnesium sulfate, we performed a sub-
for acute tocolysis and 1 to compare ni-
straction form. There was no blinding of group analysis according to dosage of
fedipine with placebo or no treatment
authorship. From each article, we ex- magnesium sulfate used (4 g loading
for maintenance tocolysis. The subgroup
tracted data on study characteristics dose and 2-4 g/h vs 6 g loading dose and
analyses comparing nifedipine vs pla-
(randomization procedure, blinding of 2-4 g/h). Univariable random effects
providers, patient and outcome asses- cebo or no treatment for acute tocolysis
metaregression models25 were used to
sors, follow-up period, intention-to- were not performed because trials ad-
dressing these comparisons were not examine whether effect sizes were af-
treat analysis, losses to follow-up, ex- fected by these study characteristics.
clusions, and concealment allocation identified.
Heterogeneity of the results among We assessed publication and related
method), participants (inclusion and ex- biases visually by examining the symme-
clusion criteria, definition of preterm la- studies was tested with the quantity I2,
which describes the percentage of total try of funnel plots and statistically by us-
bor, cervical dilatation and effacement at ing the Egger test.27 The larger the devi-
trial entry, gestational age at randomiza- variation across studies that is due to het-
erogeneity rather than chance.26 A value ation of the intercept of the regression
tion, number of women randomized,
of 0% indicates no observed heterogene- line from zero, the greater was the asym-
baseline characteristics, and country and
ity whereas I2 values of 50% or more in- metry and the more likely it was that the
date of recruitment), details of interven-
dicate a substantial level of heterogene- metaanalysis would yield a biased esti-
tion (aim, loading and maintenance
dose, route, duration, re-treatment, use ity.26 We planned to pool data across mates of effect. We considered P ⬍ .1 to
of alternative tocolytic therapy, and rou- studies using the fixed-effects models if indicate significant asymmetry, as sug-
tine administration of antenatal cortico- substantial statistical heterogeneity was gested by Egger.
steroids), and outcomes (number of out- no present. We used random-effects We also calculated the number needed
come events and/or mean ⫾ SD for each models to pool data across studies if I2 to treat (NNT) for an additional benefi-
outcome). values were 50% or greater. A predefined cial outcome with its 95% CI for out-
Unpublished additional data used in sensitivity analysis was performed to ex- comes in which the treatment effect was
another metaanalysis21 were included. plore the impact of study quality on the significant at the 5% level (the 95% CI
Studies reporting preterm birth before effect size for the main outcomes. This for the absolute risk difference did not
36 weeks’ gestation as an outcome mea- analysis was performed by excluding include zero).28 NNT was computed
sure were included into the group of trials with a modified Jadad score less from the results of metaanalysis of rela-
studies reporting preterm birth before 37 than 6. tive risks as follows:

FIGURE
R ESULTS
We identified 1527 studies in our litera-
Study selection process
ture search and considered 61 to be po-
1527 studies identified and tentially eligible (Figure). Twenty-six
screened for retrieval studies, including 2179 women, fulfilled
from searches inclusion criteria of which 23 evaluated
acute tocolysis29-51 and 3 evaluated
maintenance tocolysis.52-54 There was
strong agreement among authors on the
1466 excluded after screening inclusion of studies (␬ ⫽ 0.89). Addi-
titles and/or abstracts tional neonatal data and long-term
follow-up data for one trial34 were re-
ported in 2 additional publications.55,56
Of the 23 trials on acute tocolysis, 16
61 retrieved for more detailed evaluation evaluated nifedipine vs ␤2-adrenergic-
42 from electronic searches receptor agonists (11 studies using rito-
7 from reference lists drine,29-36,38,41,44 3 studies using ter-
12 from conference proceedings butaline,39,42,43 and 2 studies using
isoxsuprine37,40), 5 evaluated nifedipine
vs magnesium sulfate,45-49 and one each
35 excluded evaluated nifedipine vs atosiban50 and
nifedipine vs nitric oxide donors.51
12 abstract form and subsequently There were no trials in which nifedipine
published as a full length report
was compared with placebo or no treat-
6 only available in abstract form with
ment in acute tocolysis.
insufficient information
4 quasi-randomized trial Of the 3 trials on maintenance tocoly-
4 outcomes not relevant sis, 2 evaluated nifedipine vs no treat-
3 unclear method of randomization ment52,53 and 1 evaluated nifedipine vs
2 nifedipine added to other tocolytic placebo.54 In the study by Koks et al,35
2 comparison of 2 calcium channel only the subset of patients who were not
blockers or 2 dose regimens of treated with ␤2-adrenergic-receptor
nifedipine agonists before trial entry was included
1 nonrandomized trial (57/102 women). Thirty-five studies
1 women were eligible after failed were excluded for the following reasons:
tocolysis with terbutaline initially available in abstract form and
subsequently published as a full-length
report (n ⫽ 12); available only in ab-
stract form with insufficient information
on methods and results (n ⫽ 6); the
26 studies included
in metaanalysis method of generation of allocation to
treatment was quasi-randomized (n ⫽
Conde-Agudelo. Nifedipine in the management of preterm labor. Am J Obstet Gynecol 2011.
4); an unclear method of randomization
(n ⫽ 3); the study did not report relevant
outcomes (n ⫽ 4); nifedipine was used in
1 delivery within 48 hours or 7 days or combination with other tocolytic agents
NNT ⫽ before 34 or 37 weeks or adverse neo- (n ⫽ 2); comparison of 2 calcium chan-
control group event rate
natal outcome. nel blockers (n ⫽ 1); comparison of 2
⫻ (1 ⫺ relative risk) Analyses were performed with the Re- dose regimens of nifedipine (n ⫽ 1); a
In this review, NNT for an additional view Manager (RevMan) software ver- nonrandomized trial (n ⫽ 1); and
beneficial outcome is the number of sion 5.0.23 (The Nordic Cochrane Cen- women were enrolled only after subcu-
women in preterm labor who need to tre, København, Denmark), StatsDirect taneous terbutaline failed to inhibit con-
be treated with nifedipine rather than version 2.7.8 (StatsDirect Ltd, Cheshire, tractions (n ⫽ 1). The list of excluded
with another tocolytic agent, placebo, UK), and Stata, version 10.0 (StataCorp, studies is available from the authors
or no treatment to prevent 1 case of College Station, TX). upon request.

TABLE 1
Characteristics of studies included in the systematic review
Gestational age (wks), cervical dilatation/
First author, effacement, and frequency of uterine Alternative
year Location Inclusion/exclusion criteria contractions at trial entry Interventions (sample size) tocolytic therapy
Acute tocolysis
................................................................................................................................................................................................................................................................................................................................................................................
Nifedipine compared with ␤2-adrenergic-receptor agonists
................................................................................................................................................................................................................................................................................................................................................................................
Read,29 1986 United Kingdom Inclusion: women with singleton pregnancy 20-35; no data on cervical dilatation and Nifedipine (n ⫽ 20): 30 mg orally, Ritodrine in
in preterm labor (at least 1 uterine effacement, and frequency of uterine then 20 mg orally every 8 hours nifedipine group
contraction every 10 min) and intact contractions at trial entry. for 3 days.
membranes. Ritodrine (n ⫽ 20): 50 ␮g/min
Exclusion: multiple pregnancy, intravenously, increasing by 50
polyhydramnios, premature rupture of ␮g every 10 minutes to a
membranes, history of cervical surgery, maximum of 300 ␮g for 24
history of midtrimester abortion or previous hours, then 10 mg orally oral
preterm delivery, history of any medical every 4 hours for 48 hours.
condition that would contraindicate the use
of either of the drugs, chorioamnionitis,
any irregularity of the fetal heart rate, and
cervical dilatation greater than 4 cm.
................................................................................................................................................................................................................................................................................................................................................................................
Ferguson,30 United States Inclusion: women with singleton pregnancy 20-36; mean cervical effacement at trial Nifedipine (n ⫽ 33): 10 mg Alternate regimen
1990 in preterm labor (uterine contractions at a entry was 60 ⫾ 22% and 67 ⫾ 25% for sublingually. If uterine and terbutaline
frequency of 8 or more per hour with a nifedipine and ritodrine groups, respectively; contractions persisted after 20
documented change in cervical dilatation 82% of women had a cervical dilatation less minutes, a similar dose was
or effacement) irrespective of the than 2 cm and 18% had 2-3.9 cm at trial repeated at intervals of 20
membranes status. entry. minutes, up to a maximal total
Exclusion: previous treatment with dose of 40 mg during the first
tocolytics in current pregnancy, diabetes, hour of treatment, then 20 mg
hyperthyroidism, cardiac disease, severe orally every 4-6 hours.
preeclampsia, eclampsia, placental Ritodrine (n ⫽ 33): 50 ␮g/min
abruption, chorioamnionitis, multiple intravenously increasing by 50 ␮g
pregnancy, polyhydramnios, cervical every 15-30 minutes up to a
dilatation greater than 4 cm, fetal distress, maximum of 350 ␮g/min, then
severe intrauterine growth retardation, fetal 10-20 mg orally every 4-6 hours.
death, and fetal anomaly incompatible with
life.
................................................................................................................................................................................................................................................................................................................................................................................
Janky,31 1990 France Inclusion: women with singleton pregnancy 28-36; 76% of women had a Baumgarten Nifedipine (n ⫽ 30): 10 mg Permitted but
in preterm labor (at least 2 uterine tocolytic score of 3-6 and 24% had a score sublingually, then 20 mg orally unspecified
contractions every 10 minutes with cervical less than 3 (true labor defined as a every 8 hours for 7 days.
modifications). Baumgarten tocolytic score of ⱖ2.5). Mean Ritodrine (n ⫽ 32): 200-300 ␮g/
Exclusion: chorioamnionitis, fetal death, number of uterine contractions in 20 min intravenously until
fetal anomaly incompatible with life, minutes was 7 (range, 4–12). contractions ceased, then 100
medical condition contraindicating the use ␮g/min for 24 hours, thereafter
of betamimetics, cervix greater than 4 cm, 20 mg orally every 4-6 hours for
and premature rupture of membranes after 6 days.
34 weeks.
................................................................................................................................................................................................................................................................................................................................................................................
Bracero,32 1991 United States Inclusion: women with singleton pregnancy 20-36; mean Bishop score at trial entry was Nifedipine (n ⫽ 26): 30 mg orally, Ritodrine and
in preterm labor (cervical dilatation ⱖ2 cm 6.6 ⫾ 1.8 and 5.9 ⫾ 2.4, for nifedipine and then 20 mg orally every 6 hours magnesium
or effacement ⱖ80%, or ⱖ2 contractions ritodrine groups, respectively. for 24 hours, then decreased to 8 sulfate in
lasting more than 30 seconds with cervical hour intervals for an additional 24 nifedipine group
changes) and intact membranes. hours, thenceforth 20 mg every and magnesium
Exclusion: multiple pregnancy, premature 8-12 hours. No data on duration sulfate in ritodrine
rupture of membranes of treatment. group
Ritodrine (n ⫽ 23): 100 ␮g/min
intravenously increasing by 50
␮g/min every 10 minutes to a
maximum of 350 ␮g/min. Thirty
minutes prior to discontinuation of
intravenous ritodrine, 10 mg
orally every 2 hours for 24 hours,
then 10 mg every 4 hours for 24
hours, then 20 mg every 8-12
hours, thereafter 10-20 mg orally
every 4-6 hours. No data on
duration of treatment.
................................................................................................................................................................................................................................................................................................................................................................................
Conde-Agudelo. Nifedipine in the management of preterm labor. Am J Obstet Gynecol 2011. (continued )
Characteristics of the studies in- 7 in European countries,29,31,34-36,41,44 with evidence of cervical changes
cluded in the review are summarized in and 1 in Brazil.51 The sample size in 18 trials.30-33,38-40,42,43,45,46,48-54 Eight
Table 1. Seven studies were conducted ranged from 4029,42 to 19249 (median, studies did not include cervical
in the United States,30,32,45,46,49,52,54 11 74). Preterm labor was defined as changes in the diagnosis of preterm
in Asian countries,33,37-40,42,43,47,48,50,53 the presence of uterine contractions labor.29,34-37,41,44,47

TABLE 1
Characteristics of studies included in the systematic review (continued)
Kupferminc,33 Israel Inclusion: women with singleton or twin 26-34; mean cervical dilatation and Nifedipine (n ⫽ 36): 30 mg orally, Ritodrine in
1993 pregnancy in preterm labor (uterine effacement at trial entry was 1.8 ⫾ 0.6 and then 20 mg after 90 minutes if nifedipine group
contractions at least every 6 minutes with 1.9 ⫾ 0.7 cm and 42 ⫾ 17% and contractions persisted, thereafter
evidence of change in cervical dilatation or 43 ⫾ 14% for nifedipine and ritodrine 20 mg every 8 hours until 34-35
effacement between consecutive digital groups, respectively. weeks.
examinations) and intact membranes. Ritodrine (n ⫽ 35): 50 ␮g/min
Exclusion: polyhydramnios, placental intravenously increasing by 15 ␮g/
abruption, hypertension, infection, any min every 15 minutes to a
medical condition that would contraindicate maximum of 300 ␮g/min for 12
tocolytic therapy, cervical dilatation greater hours, then 10 mg orally every 3
than 4 cm, and premature rupture of hours until 34-35 weeks.
membranes.
................................................................................................................................................................................................................................................................................................................................................................................
Papatsonis,34 The Inclusion: women with singleton pregnancy 20-33 4/7; mean cervical dilatation in Nifedipine (n ⫽ 95): 10 mg Nifedipine in
1997 Netherlands in preterm labor (at least 1 uterine women with intact membranes at trial entry sublingually. If contractions ritodrine group;
contraction every 10 minutes during at was 1.5 ⫾ 2.1 and 1.8 ⫾ 2.2 cm for persisted, this dose was repeated Indomethacin in
least 1 hour; cervical changes were not nifedipine and ritodrine groups, respectively. every 15 minutes to maximum of both groups
obligatory for inclusion) irrespective of the 40 mg during the first hour of
membranes status. treatment, then 60-160 mg/day of
Exclusion: multiple pregnancy, intrauterine slow-release nifedipine until 34
infection, fetal congenital anomalies, weeks.
abruption placenta, severe fetal growth Ritodrine (n ⫽ 90): 383 ␮g/min
restriction, and any contraindication for the intravenously after which the
use of beta-adrenergic drugs. infusion rate was determined by
the time lag after which tocolysis
is established (minimum 100 ␮g/
min) for at least 3 days. Then
ritodrine 40 mg orally every 8
hours until 34 weeks in 2 of the 3
participating hospitals.
................................................................................................................................................................................................................................................................................................................................................................................
Koks,35 1998a The Inclusion: women with singleton or twin 24-34; 86% of women had a cervical Nifedipine (n ⫽ 32): 30 mg Indomethacin in
Netherlands pregnancy in preterm labor (ⱖ6 uterine dilatation 2 cm or less and 14% had greater sublingually, then 20 mg orally both groups
contractions per hour with a duration of than 2 cm at trial entry. every 6-12 hours, which was
ⱖ30 seconds with and without cervical reduced to 20 mg every 8 hours
dilatation or effacement) irrespective of the until 34 weeks.
membranes status. Ritodrine (n ⫽ 25): 200 ␮g/min
Exclusion: any contraindication for the use intravenously up to maximum of
of nifedipine or betamimetic, intrauterine 400 ␮g/min, then 80 mg orally
infection, irregular fetal heart rate, every 8 hours until 34 weeks.
antepartum hemorrhage, and
polyhydramnios.
................................................................................................................................................................................................................................................................................................................................................................................
García- Spain Inclusion: women with singleton pregnancy 26-34; mean Bishop score at trial entry was Nifedipine (n ⫽ 26): 30 mg (20 Indomethacin in
Velasco,36 1998 in preterm labor (ⱖ4 uterine contractions 2.9 ⫾ 0.9 and 2.6 ⫾ 0.9 for nifedipine and mg orally and 10 mg both groups
in 30 minutes, irrespective of cervical ritodrine groups, respectively. sublingually), then 10-20 mg
changes) and intact membranes. every 4-6 hours. No data on
Exclusion: previous tocolytic treatment, duration of treatment or
cervical dilatation 3 cm or greater, maintenance therapy.
maternal infection, vaginal bleeding, and Ritodrine (n ⫽ 26): 50 ␮g/min
any medical or obstetrical condition intravenously increasing by 50
contraindicating tocolytic therapy. ␮g/min every 20 minutes to a
maximum of 350 ␮g/min for 12
hours, then 5 mg orally every 3
hours. No data on duration of
treatment or maintenance
therapy.
................................................................................................................................................................................................................................................................................................................................................................................
Ganla,37 1999 India Inclusion: women with singleton pregnancy 26-36; no data on cervical dilatation and Nifedipine (n ⫽ 50): 5 mg Not reported
in preterm labor (uterine contractions effacement, and frequency of uterine sublingually. If contractions persisted,
occurring at interval of ⬍10 minutes contractions at trial entry. this dose was repeated every 15
recorded for at least 30 minutes). No data minutes to maximum of 40 mg
on membranes status. during the first 2 hours of treatment,
Exclusion: diabetes, hyperthyroidism, then 10 mg orally every 8 hours for
cardiac disease, severe preeclampsia, 48 hours, thereafter 10-20 mg orally
eclampsia, placental abruption, every 12 hours until 36 weeks.
chorioamnionitis, cervical dilatation greater Isoxsuprine (n ⫽ 50): 0.5 mg/min
than 3 cm, severe fetal growth restriction, intravenously increasing to a
and lethal fetal anomalies. maximum of 10 mg/min for 12
hours, then 10 mg intramuscularly
every 8 hours for 48 hours,
thereafter 10-20 mg orally every 8
hours until 36 weeks.
................................................................................................................................................................................................................................................................................................................................................................................

TABLE 1
Al-Qattan,38 Kuwait Inclusion: women with singleton pregnancy 24-34; 9% of women had a closed cervix, Nifedipine (n ⫽ 30): 30 mg orally. Not reported
2000 in preterm labor (uterine contractions at a 72% had a cervical dilatation of 1-2 cm, and If contractions persisted after 2
frequency of 2-3 per 10 minute interval 19% had greater than 2 cm at trial entry. hours, a second dose of 20 mg
with a documented change in cervical was given, then 20 mg orally
dilatation or effacement) and intact every 6 hours until 34 weeks.
membranes. Ritodrine (n ⫽ 30): 50 ␮g/min
Exclusion: multiple pregnancy, cardiac intravenously, then 10 mg orally
disease, placental abruption, every 4-6 hours until 34 weeks.
hyperthyroidism, severe preeclampsia,
eclampsia, infection, cervical dilatation 4
cm or greater, polyhydramnios, fetal
pathology, premature rupture of
membranes, breech presentation, fetal
death, fetal distress, and congenital
malformation.
................................................................................................................................................................................................................................................................................................................................................................................
Weerakul,39 Thailand Inclusion: women with singleton pregnancy 28-34; mean Bishop score at trial entry was Nifedipine (n ⫽ 45): 10 mg Not reported
2002 in preterm labor (definition not provided) 6.2 ⫾ 2.8 and 5.2 ⫾ 2.6 for nifedipine and sublingually. If contractions
and intact membranes. terbutaline groups, respectively. persisted after 15 minutes, a
Exclusion: multiple pregnancy, premature second dose of 10 mg was given,
rupture of membranes, previous tocolytics, then 20 mg after 30 minutes to a
cervical dilatation greater than 3 cm, maximum in the first hour of 40
chorioamnionitis, infection, fetal distress, mg, then 60-120 mg orally per
fetal anomalies, and medical or obstetrical day for 3 days. No data on
complications. maintenance therapy.
Terbutaline (n ⫽ 44): 0.25 mg
intravenously followed by
continuous intravenous infusion
started at 5 ␮g/min and
increased by 5 ␮g/min every 15
minutes up to a maximum of 15
␮g/min. Then the infusion was
maintained at the same rate for
2 h, after which the treatment
was continued with subcutaneous
injection of 0.25 mg every 4
hours for 24 hours. No data on
maintenance therapy.
................................................................................................................................................................................................................................................................................................................................................................................
Rayamahji,40 Nepal Inclusion: women with singleton or twin 28-36; 39% had a cervical dilatation less Nifedipine (n ⫽ 32): 10 mg Not reported
2003 pregnancy in preterm labor (uterine than 1.5 cm and 61% had 1.5-3 cm at trial sublingually. This dose was
contractions at least 1 every 10 minutes, entry. repeated every 20 minutes to
with even minimal cervical changes) and maximum of 40 mg during the
intact membranes. first hour of treatment, then 10-
Exclusion: premature rupture of 20 mg orally every 6-8 hours for
membranes, advanced labor, up to 7 days.
preeclampsia, eclampsia, cardiac disease, Isoxsuprine (n ⫽ 30): 0.08 mg/
thyroid disorder, antepartum hemorrhage, min intravenously increasing to a
polyhydramnios, chorioamnionitis, severe maximum of 0.24 mg/min, then
fetal growth restriction, fetal death, 10 mg orally every 8 hours for up
oligoamnios, fetal anomalies incompatible to 7 days.
with life.
................................................................................................................................................................................................................................................................................................................................................................................
Cararach,41 Spain Inclusion: women with singleton pregnancy 22-35; mean Bishop score at trial entry was Nifedipine (n ⫽ 40): 30 mg (20 Alternate regimen
2006 in preterm labor (at least 2 uterine 2.7 ⫾ 1.8 and 2.9 ⫾ 1.9 for nifedipine and mg orally and 10 mg and indomethacin
contractions within a 10 minutes period ritodrine groups, respectively. sublingually), then 20 mg orally
during 60 minutes) and intact membranes. every 6 hours for 48 hours. There
Exclusion: cervical dilatation greater than 5 was no maintenance therapy.
cm, polyhydramnios, fetal anomalies, fetal Ritodrine (n ⫽ 40): 100 ␮g/min
distress, intrauterine infection, fetal growth intravenously increasing by 50
restriction, contraindication for the use of ␮g/min every 20 min to a
betamimetic drugs, and previous treatment maximum of 350 ␮g/min for 48
with tocolytics in current pregnancy. hours followed by 10 mg orally
every 6 hours until discharge.
There was no maintenance
therapy.
................................................................................................................................................................................................................................................................................................................................................................................
According to the widely used diag- bor.”30-36,38-42,45,46,48,49,51-54 Nineteen membranes,30,31,34,35,42,44,49 and 8 in-
nostic criteria for preterm labor,57 we studies were limited to women with included women with a twin preg-
considered that participating women tact membranes,29,32,33,36-41,43,45-48,50-54 nancy.33,35,40,43,49,50,53,54 Standard ma-
in 20 trials were in “true preterm la- 7 also included women with ruptured ternal and fetal contraindications to toco-

TABLE 1
Laohapojanart,42 Thailand Inclusion: women with singleton pregnancy 24-36; mean cervical dilatation and Nifedipine (n ⫽ 20): 10 mg orally. Alternate regimen
2007 in preterm labor (ⱖ4 uterine contractions effacement at trial entry was 1.4 ⫾ 0.7 and If contractions persisted, 10 mg and indomethacin
per 20 minutes with cervical dilatation of 1.4 ⫾ 0.6 cm and 59 ⫾ 17% and orally every 4 hours to a
1-4 cm and/or documented changing in 64 ⫾ 14% for nifedipine and terbutaline maximum in the first hour of 40
cervical effacement) irrespective of the groups, respectively. mg. Then 20 mg every 4 hours
membranes status. for 3 days. No data on
Exclusion: multiple pregnancy, heart or maintenance therapy.
renal disease, hypertension, Terbutaline (n ⫽ 20): 10 ␮g/min
chorioamnionitis, placental abruption, intravenously followed by
placenta previa, preeclampsia, diabetes, continuous intravenous infusion
and thyrotoxicosis. with an increment 5 ␮g/min
every 10 minutes until 25 ␮g/min
was reached, then subcutaneous
injection of 0.25 mg every 4
hours for 24 hours. No data on
................................................................................................................................................................................................................................................................................................................................................................................
Mawaldi,43 2008 Saudi Arabia Inclusion: women with singleton or twin 24-34; no data on cervical dilatation and Nifedipine (n ⫽ 79): 30 mg orally Not reported
pregnancy in preterm labor (1-3 uterine effacement, and frequency of uterine followed by 20 mg after 90 min. If
contractions within a 10 minute period contractions at trial entry. contractions persisted, 20 mg
during 60 minutes with cervical dilatation orally every 8 h for 48 h. No data
of 0-3 cm in primigravidas and 1-3 cm in on maintenance therapy.
multigravidas and cervical effacement Terbutaline (n ⫽ 95): 0.25 mg
⬍50%) and intact membranes. subcutaneous repeated every 45
Exclusion: women carrying more than 2 minutes if the uterine contractions
fetuses, major antepartum hemorrhage, persisted. No data on
premature rupture of membranes, major maintenance therapy.
medical disorder, temperature higher than
37.5°C, blood pressure less than 90/50
mm Hg, compromised fetus, and lethal
fetal anomalies
................................................................................................................................................................................................................................................................................................................................................................................
Van De Water,44 The Inclusion: women with singleton pregnancy 24-34; no data on cervical dilatation and Nifedipine (n ⫽ 48): 20 mg orally. Indomethacin
2008 Netherlands in preterm labor (⬎1 uterine contraction effacement, and frequency of uterine If contractions persisted after 30
every 10 minutes for at least 60 minutes) contractions at trial entry. minutes, a second dose of 20 mg
irrespective of the membranes status. was given, then 90-120 mg orally
Exclusion: multiple pregnancy, intrauterine per day for 48 hours, thereafter
infection, fetal congenital defects, placental 90 mg/day for 7 days.
abruption, diabetes mellitus, cardiovascular Ritodrine (n ⫽ 43): 200 ␮g/min
diseases, hyperthyroidism, and intravenously increasing by 50
preeclampsia. ␮g/min every 30 minutes until
quiescence was achieved for 48
hours, then 80 mg orally every 8
hours for a total duration of 7
days.
................................................................................................................................................................................................................................................................................................................................................................................
Nifedipine compared with magnesium sulfate
................................................................................................................................................................................................................................................................................................................................................................................
Glock,45 1993 United States Inclusion: primigravid women with 20-34; mean cervical dilatation and Nifedipine (n ⫽ 39): 10 mg Intravenous
singleton pregnancy in preterm labor effacement, and uterine contraction sublingually. If contractions ritodrine
(regular uterine contractions less than 10 frequency at trial entry was 2.0 ⫾ 0.8 and persisted, this dose was repeated
minutes apart with documented cervical 2.0 ⫾ 0.9 cm, 43 ⫾ 7% and 44 ⫾ 8%, and every 20 minutes to maximum of
change or cervical dilatation 2 cm or 4.4 ⫾ 1.0 and 4.4 ⫾ 1.1 for nifedipine and 40 mg during the first hour of
greater) and intact membranes. magnesium sulfate groups, respectively. treatment. Once contractions
Exclusion: multiple pregnancy, premature ceased, 20 mg orally every 4
rupture of membranes, known tocolytic hours for 48 hours, then 10 mg
drug exposure during the study pregnancy, orally every 8 hours until 34
diabetes, hyperthyroidism, cardiac disease, weeks.
preeclampsia, abruptio placentae, Magnesium sulfate (n ⫽ 41): 6 g
chorioamnionitis, hydramnios, renal failure, bolus, then 2 g/h, increased to
cervical dilatation 4 cm or greater, fetal maximum of 4 g/h until
distress, severe intrauterine growth quiescence for 24 hours, then
restriction, and fetal anomaly incompatible weaned at 0.5 g every 4-6 hours,
with life thereafter terbutaline 5 mg orally
every 6 hours until 34 weeks.
................................................................................................................................................................................................................................................................................................................................................................................
lysis were reported as exclusion criteria in to 28 weeks, and the maximum ranged For studies evaluating acute tocolysis,
the great majority of included studies. from 33 to 36 weeks. Most trials included nifedipine dosing regimens were similar
The gestational age at inclusion varied women between 24 and 34 weeks’ gesta- across the trials with loading doses of
from 20 to 36 weeks. The minimum ges- tion. Mean gestational age at each trial’s 10-30 mg administered orally or sublin-
tational age at trial entry ranged from 20 entry varied from 29.1 to 32.4 weeks. gually, followed by 10-20 mg orally every

TABLE 1
Floyd,46 1995 United States Inclusion: women with singleton pregnancy 20-34; mean cervical dilatation and Nifedipine (n ⫽ 50): 30 mg orally Not reported
in preterm labor (at least 1 uterine effacement and number of uterine followed by 20 mg every 8 hours
contractions every 10 minutes with contractions per hour at trial entry was 1.8 until quiescence, then 20 mg
documented cervical change or cervical ⫾ 1.0 and 1.5 ⫾ 1.2 cm, 46 ⫾ 27% and 51 orally every 8 h until 37 weeks or
dilatation ⱖ2 cm) and intact membranes. ⫾ 21%, and 18 ⫾ 6 and 17 ⫾ 0.6 for delivery, whichever occurred first.
Exclusion: Previous tocolytic therapy in nifedipine and magnesium sulfate groups, Magnesium sulfate (n ⫽ 40): 4-g
current pregnancy, allergy to either study respectively. bolus then 4-6 g/h continued for
drug, medical or obstetric complications 6 hours after quiescence, then
precluding treatment with either drug, and magnesium gluconate 2 g orally
chorioamnionitis. every 4 hours until 37 weeks or
delivery, whichever occurred first.
................................................................................................................................................................................................................................................................................................................................................................................
Haghighi,47 Iran Inclusion: women with singleton pregnancy 23-36; no data on cervical dilatation and Nifedipine (n ⫽ 34): 10 mg Not reported
1999 in preterm labor (regular uterine effacement, and frequency of uterine sublingually. If contractions
contractions less than 10 minutes apart) contractions at trial entry. persisted, this dose was repeated
and intact membranes. every 20 minutes to maximum of
Exclusion: known tocolytic drug exposure 40 mg during the first hour of
during the study pregnancy, diabetes, treatment. Once contractions
hyperthyroidism, cardiac disease, ceased, 20 mg orally every 6
preeclampsia, placental abruption, hours during the first 24 hours
chorioamnionitis, polyhydramnios, renal and 20 mg every 8 hours the
failure, cervical dilatation 4 cm or greater, second day. No data on
fetal distress, severe intrauterine growth maintenance therapy.
restriction, and fetal anomaly incompatible Magnesium sulfate (n ⫽ 40): 6 g
with life. bolus, then 2 g/h, increased to
maximum of 4 g/h until quiescence
for up to 48 hours. Then terbutaline
5 mg orally every 6 h. No data on
................................................................................................................................................................................................................................................................................................................................................................................
Taherian,48 Iran Inclusion: women with singleton pregnancy 26-36; mean cervical dilatation and Nifedipine (n ⫽ 57): 10 mg orally Ritodrine or
2007 in preterm labor (ⱖ4 uterine contractions effacement at trial entry was 1.5 ⫾ 1.1 and every 20 minutes (maximal dose indomethacin
per 10 minutes with duration of at least 30 1.6 ⫾ 1.1 cm and 53 ⫾ 25% and of 40 mg in first hour). Once (18% in nifedipine
seconds and progressive cervical dilatation 54 ⫾ 22% for nifedipine and magnesium contractions ceased, 10-20 mg group and 13% in
and effacement) and intact membranes. sulfate groups, respectively. orally every 6 hours. No data on magnesium
Exclusion: taking other tocolytic agents, duration of treatment or sulfate group)
cervical dilatation 5 cm or greater or maintenance therapy.
obstetrical contraindications for tocolysis Magnesium sulfate (n ⫽ 63): 4 g
such as severe preeclampsia, lethal fetal bolus, then 2-3 g/h. No data on
anomalies, chorioamnionitis, significant duration of treatment or
antepartum hemorrhage, and maternal maintenance therapy.
cardiac or liver diseases.
................................................................................................................................................................................................................................................................................................................................................................................
Lyell,49 2007 United States Inclusion: women with singleton or twin 24-33; mean cervical dilatation and Nifedipine (n ⫽ 100): 10 mg Permitted but
pregnancy in preterm labor (ⱖ2 uterine effacement and uterine contraction sublingually every 20 minutes for unspecified
contractions every 10 minutes with cervical frequency at trial entry was 1.8 ⫾ 0.9 and three doses total, followed by 20
change or cervical dilatation ⱖ2 cm and 1.9 ⫾ 1.0 cm, 2.2 ⫾ 1.2 and 2.2 ⫾ 1.1 cm, mg orally every 4-6 hours until at
80% effacement) irrespective of the and 3.5 ⫾ 1.2 and 3.6 ⫾ 1.5 for nifedipine least 12 hours of uterine
membranes status. and magnesium sulfate groups, respectively. quiescence occurred within the
Exclusion: placental abruption, placenta previa, first 48 hours. Maintenance
nonreassuring fetal status, intrauterine growth therapy with nifedipine in 42% of
restriction, chorioamnionitis, and maternal women.
medical disease. Magnesium sulfate (n ⫽ 92): 4 g
bolus, then 2 g/h, increased to
maximum of 4 g/h, until at least
12 hours of uterine quiescence
occurred within the first 48 hours.
Maintenance therapy with
nifedipine in 38% of women.
................................................................................................................................................................................................................................................................................................................................................................................
4-8 hours for 24-72 hours. Twelve stud- treatment if contractions persisted. Eleven als32,36,38 reported the total duration of
ies used a 30 mg loading dose of nifedi- trials31-35,37,38,44-46,49 reported mainte- treatment.
pine, 30,31,34,39,40,42,45,47-51 9 used 10 nance therapy, 929,30,36,39,42,43,47,48,51 All studies evaluating maintenance
mg,29,32,33,35,36,38,41,43,46 and 1 each used did not, and 340,41,50 stated there was tocolysis52-54 used nifedipine 20 mg
5 mg 37 and 20 mg. 44 Twelve stud- no maintenance therapy. Seven stud- orally every 4-6 hours until 37 weeks’
ies 30,34,37,39,40,42,44,45,47-50 repeated a ies33-35,37,38,45,46 used oral maintenance gestation or delivery, whichever oc-
loading dose every 15-20 minutes to a therapy in both treatment groups until curred first. Use of alternative toco-
maximum of 40 mg during the first hour of 34-37 weeks’ gestation. All but 3 tri- lytic therapy was explicitly mentioned

TABLE 1
Nifedipine compared with atosiban
................................................................................................................................................................................................................................................................................................................................................................................
Kashanian,50 Iran Inclusion: women with singleton or twin 26-34; no data on cervical dilatation and Nifedipine (n ⫽ 40): 10 mg Not reported
2005 pregnancy in preterm labor (ⱖ4 uterine effacement, and frequency of uterine sublingually every 20 minutes to a
contractions in 20 minutes or ⱖ8 in 60 contractions at trial entry. maximum in the first hour of 40
minutes and cervical dilatation and mg. Then 20 mg orally every 6
effacement ⱖ1 cm and ⱖ50%, hours for the first 24 hours, then
respectively) and intact membranes. every 8 h for the following 24 h,
Exclusion: premature rupture of thereafter 10 mg orally every 8
membranes, vaginal bleeding, fetal death, hours for the last 24 hours. There
fetal distress, fetal growth restriction, was no maintenance therapy.
history of trauma, cervical dilatation Atosiban (n ⫽ 40): 300 ␮g/min
greater than 3 cm, maternal systemic intravenously, continued for a
disorders, uterine anomaly, and blood maximum of 12 hours, or 6 hours
pressure less than 90/50 mm Hg. after contractions were inhibited.
There was no maintenance
therapy.
................................................................................................................................................................................................................................................................................................................................................................................
Nifedipine compared with nitric oxide donors
................................................................................................................................................................................................................................................................................................................................................................................
Amorim,51 2009 Brazil Inclusion: women with singleton pregnancy 24-34; median (range) cervical dilatation and Nifedipine (n ⫽ 24): 10 mg Terbutaline
in preterm labor (ⱖ4 uterine contractions number of uterine contractions per 10 sublingually repeated after 30
in 30 minutes with duration of at least 30 minutes at trial entry was 2 (2–4) cm and 3 minutes, then 20 mg orally every
seconds and cervical changes) and intact (2–4) cm, respectively. 6 hours for at least 24 hours. No
membranes. data on maintenance therapy.
Exclusion: premature rupture of Nitroglycerin (n ⫽ 26): 10 mg
membranes, preeclampsia, diabetes, transdermal patch. If contractions
placental abruption, fetal malformation, persisted after 6 hours, a second
and previous treatment with tocolytics. patch of 10 mg was placed
(maximum dose of 20 mg per 24
hours). No data on maintenance
therapy.
................................................................................................................................................................................................................................................................................................................................................................................
Maintenance tocolysis
................................................................................................................................................................................................................................................................................................................................................................................
Nifedipine compared with placebo/no treatment
................................................................................................................................................................................................................................................................................................................................................................................
Carr,52 1999 United States Inclusion: women with singleton pregnancy 24-33; median (range) cervical dilatation and Nifedipine (n ⫽ 37): 20 mg orally Magnesium
who had been in active preterm labor (ⱖ6 effacement at trial entry was 2 (1–4) cm and every 4-6 hours until 37 weeks. It sulfate or
uterine contractions per hour for ⱖ2 hours, 50% (0–100%), respectively was initiated after discontinuation terbutaline
cervical dilatation of 2-4 cm, ⱖ75% of acute intravenous tocolysis.
effacement, or evidence of cervical Control (n ⫽ 37): no treatment
change) successfully arrested with
intravenous magnesium sulfate.
Exclusion: cervical dilatation 5 cm or
greater, obstetric contraindications to
tocolysis (severe preeclampsia, lethal fetal
anomalies, chorioamnionitis, significant
antepartum hemorrhage), or maternal
cardiac or liver disease.
................................................................................................................................................................................................................................................................................................................................................................................
Sayin,53 2004 Turkey Inclusion: women with singleton or twin Not stated; mean Bishop score at trial entry Nifedipine (n ⫽ 37): 20 mg orally Ritodrine and
pregnancy and intact membranes who had was 2.4 ⫾ 0.8 and 2.6 ⫾ 0.8 for nifedipine every 6 hours until 37 weeks. It verapamil
been in active preterm labor (ⱖ4 uterine and no treatment groups, respectively. was initiated after discontinuation
contractions per hour with evidence of of acute intravenous tocolysis.
cervical change on serial digital Control (n ⫽ 36): no treatment
examinations) successfully arrested with
intravenous ritodrine and verapamil.
Exclusion: cervical dilatation ⱖ4 cm or
greater, triple or higher-order pregnancy,
intrauterine infection, fetal congenital
anomalies, fetal growth restriction, and any
contraindication to betamimetics such as
diabetes mellitus, cardiac disease, or
hyperthyroidism.
................................................................................................................................................................................................................................................................................................................................................................................
in 18 studies29-36,41,42,44,45,48,49,51-54 natal corticosteroids use was not tion of allocation sequence. Sixteen stud-
Twenty trials30,33-40,42-45,48-54 reported reported. ies30-32,34-36,39,41,43-46,49,51,52,54 reported
administration of antenatal cortico- Table 2 shows quality assessment of adequate concealment of allocation. For
steroids for all women enrolled. In the included studies. All but 5 stud- all of the 23 studies evaluating acute toco-
remaining 6 trials,29,31,32,41,46,47 ante- ies37,40,45,47,53 had an adequate genera- lysis, blinding of the intervention was not

TABLE 1
Lyell,54 2008 United States Inclusion: women with singleton or twin 24-34; mean cervical dilatation and length Nifedipine (n ⫽ 33): 20 mg orally Magnesium
pregnancy and intact membranes who had by digital examination at trial entry was every 6 hours until 37 weeks. It sulfate
been in active preterm labor (uterine 2.0 ⫾ 0.9 and 2.5 ⫾ 0.9 cm and 2.2 ⫾ 1.2 was initiated after discontinuation
contractions with cervical change) and 1.6 ⫾ 1.1 cm for nifedipine and of acute intravenous tocolysis.
successfully arrested with intravenous magnesium sulfate groups, respectively. Control (n ⫽ 35): placebo
magnesium sulfate or oral nifedipine.
Exclusion: placental abruption, placenta
previa, fetal anomaly incompatible with life,
triple or higher-order multiple pregnancies,
intrauterine infection, or a maternal
medical contraindication to ongoing
tocolysis.
................................................................................................................................................................................................................................................................................................................................................................................
a
Women receiving ␤2-agonists immediately before randomization (n ⫽ 45) were excluded from analyses.
performed and blinding assessment of NNT for benefit, 13; 95% CI, 12–21). A Nifedipine vs magnesium sulfate
outcomes was not reported. Only 1 study54 significant increase in gestational age at Five trials contributed data that included
evaluating maintenance tocolysis was birth (WMD, 0.7 weeks; 95% CI, 0.3– 556 women. There was no overall differ-
double blinded. Eighteen trials reported 1.2; I2 ⫽ 0.0%), interval between trial en- ence between nifedipine and magnesium
the assessment of primary outcomes try and delivery (WMD, 5.8 days; 95% sulfate for delivery within 48 hours of
in 95% or more of the randomized CI, 1.4 –10.2; I2 ⫽ 63.0%), and birth- treatment or before 34 or 37 weeks’ ges-
women.29-37,39,41,43,44,46,47,49,53,54 Thirteen weight (WMD, 178.8 g; 95% CI, 84.1– tation, gestational age at birth, or in time
trials (50%) had a modified Jadad score of 273.6; I2 ⫽ 31.0%) was also shown. No from trial entry to delivery (Table 4). Ni-
6 or more.30-32,34-36,39,41,43,44,46,49,54 differences were seen in the risk of deliv- fedipine was associated with a significant
ery within 48 hours of initiation of treat- reduction in maternal adverse events
Acute tocolysis
ment or before 37 weeks’ gestation. (23.5% vs 35.6%; RR, 0.63; 95% CI,
Nifedipine vs ␤2-adrenergic-
Treatment with nifedipine was associ- 0.48 – 0.82; I2 ⫽ 48.0%; NNT for benefit,
receptor agonists
ated with an overall reduction in respira- 8; 95% CI, 5–19). In addition, 1 trial49
This subgroup analysis included data
tory distress syndrome (10.9% vs 16.8%; reported that severe maternal adverse ef-
from 16 trials with a total of 1278
women. Compared with women receiv- RR, 0.63; 95% CI, 0.46 – 0.86; I2 ⫽ 0.0%; fects were significantly less frequent
NNT for benefit, 16; 95% CI, 11–51), ne- among women receiving nifedipine than
ing ␤2-adrenergic-receptor agonists,
crotizing enterocolitis (0.4% vs 3.4%; among women receiving magnesium
those using nifedipine had a statistically
RR, 0.21; 95% CI, 0.05– 0.94; I2 ⫽ 0.0%; sulfate (10.0% vs 21.7%; RR, 0.46; 95%
significant reduction in the risk of deliv-
NNT for benefit, 37; 95% CI, 31–514), CI, 0.23– 0.93).
ery within 7 days of initiation of treat-
intraventricular hemorrhage (8.5% vs There were no significant differences
ment (37.1% vs 45.0%; RR, 0.82; 95%
16.5%; RR, 0.53; 95% CI, 0.34 – 0.84; I2 between the groups in the risk of major
CI, 0.70 – 0.97; I2 ⫽ 0.0%) (Table 3).
⫽ 0.0%; NNT for benefit, 13; 95% CI, adverse neonatal outcomes, although a
Twelve women with preterm labor need
9 – 42), neonatal jaundice (43.2% vs significant reduction was seen in the risk
to be treated (NNT) with nifedipine
60.6%; RR, 0.73; 95% CI, 0.57– 0.93; I2 ⫽ of admission to the NICU (37.3% vs
rather than with ␤2-adrenergic-receptor
48.0%; NNT for benefit, 6; 95% CI, 51.9%; RR, 0.72; 95% CI, 0.53– 0.97;
agonists to prevent 1 case of delivery
4 –30), admission to the NICU (26.6% vs NNT for benefit, 7; 95% CI, 4 – 69) and
within 7 days of treatment (95% CI,
34.3%; RR, 0.76; 95% CI, 0.62– 0.93; I2 ⫽ NICU length of stay (WMD, ⫺2.2 days;
7– 63).
0.0%; NNT for benefit, 12; 95% CI, 95% CI, ⫺3.4 to ⫺1.1; I2 ⫽ 42.0%) in the
Nifedipine was also associated with a
7– 48), and NICU length of stay (WMD, nifedipine group compared with the
decreased risk of delivery before 34
⫺7.2 days; 95% CI, ⫺11.2 to ⫺3.3; I2 ⫽ magnesium sulfate group.
weeks’ gestation (48.4% vs 62.2%; RR,
0.77; 95% CI, 0.66 – 0.91; I2 ⫽ 0.0%; 0.0%). No statistically significant differ-
NNT for benefit, 7; 95% CI, 5–24), ma- ences were seen in perinatal mortality, Nifedipine vs atosiban
ternal adverse events (19.5% vs 56.1%; fetal and neonatal death, neonatal sepsis, This comparison included 1 trial50 in-
RR, 0.31; 95% CI, 0.18 – 0.54; I2 ⫽ Apgar score less than 7 at 5 minutes, ret- volving only 40 women in each group.
86.0%; NNT for benefit, 3; 95% CI, 2–5), inopathy of prematurity, neurodevelop- No difference was shown for the fre-
and discontinuation of treatment be- mental delay at 2 years of age, and psy- quency of delivery within 48 hours of
cause of adverse events (0.6% vs 8.8%; chosocial and motor function at 9-12 treatment (25.0% vs 17.5%; RR, 1.43;
RR, 0.14; 95% CI, 0.06 – 0.31; I2 ⫽ 0.0%; years of age. 95% CI, 0.60 –3.38) or within 7 days

TABLE 2
Methodological quality assessment (modified Jadad scoring system24) of included studies
Study Randomization Blinding Follow-up Allocation concealment Total score
29
Read and Wellby 2 0 2 0 4
................................................................................................................................................................................................................................................................................................................................................................................
30
Ferguson et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
31
Janky et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
32
Bracero et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
33
Kupferminc et al 2 0 2 0 4
................................................................................................................................................................................................................................................................................................................................................................................
34
Papatsonis et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
35
Koks et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
36
García-Velasco and González González 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
37
Ganla et al 1 0 2 0 3
................................................................................................................................................................................................................................................................................................................................................................................
38
Al-Qattan et al 2 0 1 0 3
................................................................................................................................................................................................................................................................................................................................................................................
39
Weerakul et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
40
Rayamahji and Pratap 1 0 1 0 2
................................................................................................................................................................................................................................................................................................................................................................................
41
Cararach et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
42
Laohapojanart et al 2 0 1 0 3
................................................................................................................................................................................................................................................................................................................................................................................
43
Mawaldi et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
44
Van De Water et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
45
Glock and Morales 1 0 1 2 4
................................................................................................................................................................................................................................................................................................................................................................................
46
Floyd et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
47
Haghighi 1 0 2 0 3
................................................................................................................................................................................................................................................................................................................................................................................
48
Taherian and Dehdar 2 0 1 0 3
................................................................................................................................................................................................................................................................................................................................................................................
49
Lyell et al 2 0 2 2 6
................................................................................................................................................................................................................................................................................................................................................................................
50
Kashanian et al 2 0 0 0 2
................................................................................................................................................................................................................................................................................................................................................................................
51
Amorim et al 2 0 1 2 5
................................................................................................................................................................................................................................................................................................................................................................................
52
Carr et al 2 0 1 2 5
................................................................................................................................................................................................................................................................................................................................................................................
53
Sayin et al 1 0 2 0 3
................................................................................................................................................................................................................................................................................................................................................................................
54
Lyell et al 2 2 2 2 8
................................................................................................................................................................................................................................................................................................................................................................................
Scores: 0, lowest quality, to 8, highest quality.
(35.0% vs 25.0%; RR, 1.40; 95% CI, ery within 48 hours of treatment or ma- ventricular hemorrhage, neonatal jaun-
0.71–2.77) for women receiving nifedi- ternal adverse drug reaction. dice, admission to the NICU, and NICU
pine compared with atosiban. Maternal length of stay did not change after sensi-
side effects secondary to study medica- Sensitivity analysis tivity analysis limited to trials with high
tion were significantly more common methodological quality (modified Jadad
Table 5 displays the sensitivity analysis
among women allocated to nifedipine score 6 or greater). However, the in-
for the comparison of nifedipine with
rather than atosiban (40% vs 17.5%; RR, crease in gestational age at birth for
␤2-adrenergic-receptor agonists and
2.29; 95% CI, 1.06 – 4.95). women receiving nifedipine compared
magnesium sulfate in acute tocolysis.
The effects of nifedipine on reduction of with ␤2-adrenergic-receptor agonists
Nifedipine vs nitric oxide donors delivery within 7 days of initiation of was not demonstrated after the sensitiv-
There was only 1 trial51 that compared treatment and before 34 weeks’ gesta- ity analysis (WMD, 0.6 weeks; 95% CI,
these 2 agents, involving a total of 50 tion, maternal adverse drug reaction, 0.0 –1.2; I2 ⫽ 0.0%).
women. No statistically significant dif- discontinuation of treatment because of The subgroup analyses according to
ferences were found between nifedipine adverse effects, respiratory distress syn- loading dose revealed that, compared
and transdermal nitroglycerin for deliv- drome, necrotizing enterocolitis, intra- with ␤2-adrenergic-receptor agonists,

TABLE 3
Acute tocolysis: nifedipine compared with ␤2-adrenergic-receptor agonists
Number of events/total
number or total number
Relative risk or mean
Outcome Number of trials Nifedipine ␤2-Agonists difference (95% CI) I 2 (%)
Pregnancy outcomes
.......................................................................................................................................................................................................................................................................................................................................................................
29,30,33-36,38-44
Delivery within 48 hours of treatment 13 114/535 126/524 0.84 (0.68–1.05) 35
.......................................................................................................................................................................................................................................................................................................................................................................
30,33-35,38-42,44
Delivery within 7 days of treatment 10 153/410 171/380 0.82 (0.70–0.97) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍34 weeks’ gestation 5 34,35,38,39,44
121/250 140/225 0.77 (0.66–0.91) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍37 weeks’ gestation 9 30,33,34,36,38-42
214/356 206/336 0.97 (0.87–1.08) 3
.......................................................................................................................................................................................................................................................................................................................................................................
29,31,32,34,36,37,39-41
Pregnancy prolongation, d 9 360 350 5.8 (1.4–10.2) 63
.......................................................................................................................................................................................................................................................................................................................................................................
32,34,35,38-42
Gestational age at birth, wks 8 319 291 0.7 (0.3–1.2) 0
.......................................................................................................................................................................................................................................................................................................................................................................
29,30,33,34,39,41-44
Maternal adverse drug reaction 9 81/415 235/419 0.31 (0.18–0.54) 86
.......................................................................................................................................................................................................................................................................................................................................................................
30-41,44
Discontinuation of treatment because 13 3/522 44/498 0.14 (0.06–0.31) 0
of adverse effects
................................................................................................................................................................................................................................................................................................................................................................................
Perinatal and neonatal outcomes
.......................................................................................................................................................................................................................................................................................................................................................................
29,32,34-36,38-42
Birthweight, g 10 365 335 178.8 (84.1–273.6) 31
.......................................................................................................................................................................................................................................................................................................................................................................
Apgar score ⬍7 at 5 minutes 2 33,34
6/137 10/130 0.6 (0.2–1.5) 0
.......................................................................................................................................................................................................................................................................................................................................................................
30-39,41,42,44
Respiratory distress syndrome 13 56/516 81/483 0.63 (0.46–0.86) 0
.......................................................................................................................................................................................................................................................................................................................................................................
32,34,39,41,44
Necrotizing enterocolitis 5 1/250 8/235 0.21 (0.05–0.94) 0
.......................................................................................................................................................................................................................................................................................................................................................................
30,34,38,39,42,44
Intraventricular hemorrhage 6 23/271 41/249 0.53 (0.34–0.84) 0
.......................................................................................................................................................................................................................................................................................................................................................................
34,44
Retinopathy of prematurity 2 0/143 5/133 0.15 (0.02–1.28) 0
.......................................................................................................................................................................................................................................................................................................................................................................
32,34
Neonatal jaundice 2 51/118 66/109 0.73 (0.57–0.93) 48
.......................................................................................................................................................................................................................................................................................................................................................................
31,32,34,39,41,44
Neonatal sepsis 6 27/280 37/267 0.70 (0.45–1.09) 0
.......................................................................................................................................................................................................................................................................................................................................................................
29-34,36,38-41
Perinatal mortality 11 12/415 11/396 1.02 (0.49–2.14) 0
.......................................................................................................................................................................................................................................................................................................................................................................
29-34,36,38-41
Fetal death 11 1/415 1/396 1.00 (0.14–6.96) 0
.......................................................................................................................................................................................................................................................................................................................................................................
29-36,38-42,44
Neonatal death 14 15/518 13/483 1.03 (0.53–2.02) 0
.......................................................................................................................................................................................................................................................................................................................................................................
31-36,39,42,44
Admission to NICU 9 97/364 116/338 0.76 (0.62–0.93) 0
.......................................................................................................................................................................................................................................................................................................................................................................
NICU stay, d 2 32,44
71 62 ⫺7.2 (⫺11.2 to ⫺3.3) 0
.......................................................................................................................................................................................................................................................................................................................................................................
44
Any mental retardation at 2 y of age 1 9/28 12/35 0.94 (0.46–1.90) NA
.......................................................................................................................................................................................................................................................................................................................................................................
Behavioral-emotional functioning score 1 34
45 51 ⫺1.5 (⫺4.7 to 1.8) NA
at age 9-12 y
.......................................................................................................................................................................................................................................................................................................................................................................
Quality of life score at age 9-12 y 1 34
44 50 ⫺0.3 (⫺0.7 to 0.1) NA
................................................................................................................................................................................................................................................................................................................................................................................
CI, confidence interval; NA, not applicable; NICU, neonatal intensive care unit.
use of 10 mg of nifedipine was associated ceptor agonists and magnesium sulfate nifedipine with ␤2-adrenergic-receptor
with a significant reduction in the risk of in delivery within 48 hours or 7 days of agonists and magnesium sulfate in acute
delivery within 48 hours (RR, 0.72; 95% initiation of treatment and before 34 or tocolysis showed that estimates of effect
CI, 0.52– 0.99) or 7 days (RR, 0.74; 95% 37 weeks. sizes varied to some degree depending on
CI, 0.59 – 0.93) of initiation of treatment There were no significant differences the definition of preterm labor used,
and before 34 weeks (RR, 0.77; 95 CI, between nifedipine and magnesium sul- judgment of the presence of true preterm
0.62– 0.95). No difference was seen for fate (either 4 g loading dose and mainte- labor, dosage of magnesium sulfate used,
the risk of delivery before 37 weeks’ ges- nance dose of 2-4 g/h or 6 g loading dose and use of maintenance therapy, but the
tation (RR, 0.98; 95% CI, 0.87–1.11). and maintenance dose of 2-4 g/h of mag- CIs were wide and tests for interaction
There were no significant differences nesium sulfate) for any of the outcomes were not statistically significant (data not
between the 30 mg loading dose of ni- evaluated. Additional sensitivity and shown). In addition, univariable meta-
fedipine and both ␤2-adrenergic-re- subgroup analyses for the comparison of regression analyses indicated no associa-

TABLE 4
Acute tocolysis: nifedipine compared with magnesium sulfate, atosiban, and nitric oxide donors
Number Relative risk or mean
Outcome of trials Nifedipine Other tocolytic difference (95% CI) I 2 (%)
................................................................................................................................................................................................................................................................................................................................................................................
Pregnancy outcomes
.......................................................................................................................................................................................................................................................................................................................................................................
45,47-49
Delivery within 48 h of treatment 4 41/230 53/236 0.84 (0.60–1.18) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍34 weeks’ gestation 3 45,46,48
57/146 60/144 0.99 (0.76–1.29) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍37 weeks’ gestation 3 45,46,49
93/189 92/173 0.94 (0.77–1.14) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Pregnancy prolongation, d 1 46
50 40 ⫺5.8 (⫺18.6 to 7.0) NA
.......................................................................................................................................................................................................................................................................................................................................................................
Gestational age at birth, wks 2 45,49
139 133 ⫺0.1 (⫺0.9 to 0.7) 19
.......................................................................................................................................................................................................................................................................................................................................................................
45,47-49
.......................................................................................................................................................................................................................................................................................................................................................................
49
Severe maternal adverse drug reaction 1 10/100 20/92 0.46 (0.23–0.93) NA
.......................................................................................................................................................................................................................................................................................................................................................................
45,47
Discontinuation of treatment because of adverse effects 2 0/73 4/81 0.12 (0.01–2.10) NA
................................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Birthweight, g 4 45,47-49
240 250 ⫺5.6 (⫺67.5 to 56.4) 0
.......................................................................................................................................................................................................................................................................................................................................................................
45,47,48
Apgar score at 5 min 3 130 144 0.0 (⫺0.4 to 0.4) 0
.......................................................................................................................................................................................................................................................................................................................................................................
46
Apgar score less than 7 at 5 min 1 7/50 6/40 0.93 (0.34–2.56) NA
.......................................................................................................................................................................................................................................................................................................................................................................
46,49
.......................................................................................................................................................................................................................................................................................................................................................................
49
Intraventricular hemorrhage 1 2/110 3/106 0.64 (0.11–3.77) NA
.......................................................................................................................................................................................................................................................................................................................................................................
49
Neonatal sepsis 1 3/110 5/106 0.58 (0.14–2.36) NA
.......................................................................................................................................................................................................................................................................................................................................................................
45,46,49
Perinatal mortality 3 3/199 1/187 1.71 (0.37–7.88) 0
.......................................................................................................................................................................................................................................................................................................................................................................
45,46,49
Fetal death 3 1/199 0/187 2.41 (0.10–57.65) NA
.......................................................................................................................................................................................................................................................................................................................................................................
45,46,49
Neonatal death 3 2/199 1/187 1.51 (0.26–8.74) 36
.......................................................................................................................................................................................................................................................................................................................................................................
49
Admission to NICU 1 41/110 55/106 0.72 (0.53–0.97) NA
.......................................................................................................................................................................................................................................................................................................................................................................
144 146 ⫺2.2 (⫺3.4 to ⫺1.1) 42
................................................................................................................................................................................................................................................................................................................................................................................
Nifedipine compared with atosiban
.......................................................................................................................................................................................................................................................................................................................................................................
50
Delivery within 48 h of treatment 1 10/40 7/40 1.43 (0.60–3.38) NA
.......................................................................................................................................................................................................................................................................................................................................................................
50
Delivery within 7 d of treatment 1 14/40 10/40 1.40 (0.71–2.77) NA
.......................................................................................................................................................................................................................................................................................................................................................................
50
Maternal adverse drug reaction 1 16/40 7/40 2.29 (1.06–4.95) NA
................................................................................................................................................................................................................................................................................................................................................................................
Nifedipine compared with oxide nitric donors (nitroglycerin)
.......................................................................................................................................................................................................................................................................................................................................................................
51
Delivery within 48 h of treatment 1 3/24 4/26 0.81 (0.20–3.26) NA
.......................................................................................................................................................................................................................................................................................................................................................................
51
................................................................................................................................................................................................................................................................................................................................................................................
tion between effect sizes and study char- 37 weeks’ gestation, gestational age at All funnel plots showed no asymme-
acteristics considered. birth, episodes of recurrent preterm la- try, either visually or in terms of statisti-
Maintenance tocolysis bor, and adverse neonatal outcomes. Ni- cal significance (P ⬎ .10 for all, by Egger
Nifedipine vs placebo or no treatment fedipine was associated with a significant test).
Three trials, which recruited 215 increase in pregnancy prolongation
women, were included. No significant (WMD, 6.3 days; 95% CI, 1.2–11.4; I2 ⫽ C OMMENT
differences were seen between nifedipine 22.0%) (Table 6). Outcomes were simi- Principal findings of this study
maintenance therapy and placebo or no lar for the subgroup of women enrolled The principal findings of this study in-
treatment for preterm birth before 34 or at less than 32 weeks’ gestation. cluded the following: (1) there were no

TABLE 5
Acute tocolysis: sensitivity analysis including only studies with
high methodological quality (modified Jadad score >6)
Relative risk or mean
Outcome Number of trials Nifedipine ␤2-Agonists difference (95% CI) I 2 (%)
Nifedipine compared with ␤2-adrenergic-receptor agonists
.......................................................................................................................................................................................................................................................................................................................................................................
30,34-36,39,41,43,44
Delivery within 48 h of treatment 8 83/397 78/394 1.00 (0.76–1.31) 48
.......................................................................................................................................................................................................................................................................................................................................................................
30,34,35,39,41,44
Delivery within 7 d of treatment 6 106/292 122/274 0.81 (0.66–0.98) 31
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍34 weeks’ gestation 4 34,35,39,44
106/220 122/202 0.79 (0.67–0.94) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍37 weeks’ gestation 5 30,34,36,39,41
137/238 131/232 1.01 (0.88–1.17) 26
.......................................................................................................................................................................................................................................................................................................................................................................
31,32,34,36,39,41
.......................................................................................................................................................................................................................................................................................................................................................................
32,34,35,39,41
Gestational age at birth, wks 5 237 220 0.6 (0.0–1.2) 0
.......................................................................................................................................................................................................................................................................................................................................................................
30,34,39,41,43,44
.......................................................................................................................................................................................................................................................................................................................................................................
30-32,34-36,39,41,44
Discontinuation of treatment because 9 1/374 31/355 0.11 (0.04–0.31) 0
of adverse effects
.......................................................................................................................................................................................................................................................................................................................................................................
32,34,35,36,39,41
Birthweight, g 6 263 246 139.9 (13.9–265.8) 48
.......................................................................................................................................................................................................................................................................................................................................................................
30-32,34-36,39,41,44
.......................................................................................................................................................................................................................................................................................................................................................................
32,34,39,41,44
.......................................................................................................................................................................................................................................................................................................................................................................
30,34,39,44
.......................................................................................................................................................................................................................................................................................................................................................................
32,34
Neonatal jaundice 2 51/118 66/109 0.73 (0.57–0.93) 48
.......................................................................................................................................................................................................................................................................................................................................................................
31,32,34-36,39,44
.......................................................................................................................................................................................................................................................................................................................................................................
71 62 ⫺7.2 (⫺11.2 to ⫺3.3) 0
................................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
49
Delivery within 48 hours of treatment 1 8/100 7/92 1.05 (0.40–2.78) NA
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍34 weeks’ gestation 1 46
10/50 8/40 1.00 (0.44–2.30) NA
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍37 weeks’ gestation 2 46,49
70/150 68/132 0.91 (0.72–1.16) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Pregnancy prolongation, d 1 46
50 40 ⫺5.8 (⫺18.6 to 7.0) NA
.......................................................................................................................................................................................................................................................................................................................................................................
49
Gestational age at birth, wks 1 100 92 0.2 (⫺0.7 to 1.1) NA
.......................................................................................................................................................................................................................................................................................................................................................................
49
.......................................................................................................................................................................................................................................................................................................................................................................
49
Severe maternal adverse drug reaction 1 10/100 20/92 0.46 (0.23–0.93) NA
.......................................................................................................................................................................................................................................................................................................................................................................
49
Admission to NICU 1 41/110 55/106 0.72 (0.53–0.97) NA
.......................................................................................................................................................................................................................................................................................................................................................................
NICU stay, d 1 49
110 106 ⫺4.6 (⫺8.3 to ⫺0.9) NA
................................................................................................................................................................................................................................................................................................................................................................................
significant differences in the rate of de- improvement in clinically important when compared with ␤2-adrenergic-re-
livery within 48 hours of initiation of neonatal outcomes such as respiratory ceptor agonists; (4) there were no signif-
treatment and before 37 weeks’ gestation distress syndrome, necrotizing entero- icant differences between children
between nifedipine and both ␤2-adren- colitis, intraventricular hemorrhage, exposed in utero to either nifedipine or
ergic-receptor agonists and magnesium neonatal jaundice, admission to the ␤2-adrenergic-receptor agonists in neu-
sulfate; (2) however, nifedipine was su- NICU, and length of stay in the NICU; rodevelopmental status at 2 years of age
perior to ␤2-adrenergic-receptor ago- (3) nifedipine was less likely than ␤2-ad- or psychosocial and motor functioning
nists because its use was associated with a renergic-receptor agonists and magne- at 9-12 years of age; (5) conclusions
significant reduction in preterm birth sium sulfate to cause maternal side ef- about the comparative efficacy of atosi-
within 7 days of initiation of treatment fects, and its use was associated with a ban or nitric oxide donors vs nifedipine
and delivery before 34 weeks’ gestation significant decrease in discontinuation could not be drawn because of the pau-
(approximately 20%) and significant of treatment because of adverse effects city of randomized controlled trials with

TABLE 6
Maintenance tocolysis: nifedipine compared with placebo/no treatment
Number Placebo/no Relative risk or mean
Outcome of trials Nifedipine treatment difference (95% CI) I 2 (%)
Pregnancy outcomes
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍34 weeks’ gestation 1 52
12/37 9/37 1.33 (0.64–2.78) NA
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍37 weeks’ gestation 3 52-54
59/107 69/108 0.87 (0.69–1.08) 32
.......................................................................................................................................................................................................................................................................................................................................................................
52-54
.......................................................................................................................................................................................................................................................................................................................................................................
52-54
Gestational age at birth, wks 3 107 108 0.7 (⫺0.7 to 2.1) 66
.......................................................................................................................................................................................................................................................................................................................................................................
52,53
At least 1 episode of recurrent preterm labor 2 16/69 20/68 1.19 (0.19–7.30) 66
.......................................................................................................................................................................................................................................................................................................................................................................
53,54
More than 1 episode of recurrent preterm labor 2 21/70 18/71 1.21 (0.72–2.03) 15
................................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Birthweight, g 3 52-54
125 120 ⫺29.4 (⫺209.1 to 150.4) 0
.......................................................................................................................................................................................................................................................................................................................................................................
52,53
.......................................................................................................................................................................................................................................................................................................................................................................
52,53
.......................................................................................................................................................................................................................................................................................................................................................................
52,53
.......................................................................................................................................................................................................................................................................................................................................................................
53
Neonatal sepsis 1 2/40 1/40 2.00 (0.19–21.18) NA
.......................................................................................................................................................................................................................................................................................................................................................................
53
Neonatal death 1 0/40 2/40 0.20 (0.01–4.04) NA
.......................................................................................................................................................................................................................................................................................................................................................................
52,53
.......................................................................................................................................................................................................................................................................................................................................................................
NICU stay, d 3 52-54
125 120 ⫺0.3 (⫺2.1 to 1.4) 0
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍34 weeks’ gestation among 1 52
8/25 8/24 0.96 (0.43–2.15) NA
women enrolled at ⬍32 weeks’ gestation
.......................................................................................................................................................................................................................................................................................................................................................................
Preterm birth ⬍37 weeks’ gestation among 2 52,54
34/50 38/52 0.93 (0.72–1.20) 0
women enrolled at ⬍32 weeks’ gestation
.......................................................................................................................................................................................................................................................................................................................................................................
52-54
Pregnancy prolongation among women 3 66 75 11.0 (⫺2.1 to 24.2) 73
enrolled at ⬍32 weeks’ gestation, d
.......................................................................................................................................................................................................................................................................................................................................................................
52,54
Gestational age at birth among women enrolled 2 50 52 0.2 (⫺1.2 to 1.6) 0
at ⬍32 weeks’ gestation, wks
.......................................................................................................................................................................................................................................................................................................................................................................
Birthweight among women enrolled at ⬍32 1 52
25 24 122.0 (⫺308.0 to 552.0) NA
weeks’ gestation
.......................................................................................................................................................................................................................................................................................................................................................................
52
Admission to NICU among women enrolled at 1 5/25 6/24 0.80 (0.28–2.28) NA
⬍32 weeks’ gestation
................................................................................................................................................................................................................................................................................................................................................................................
these agents; and (6) maintenance toco- relatively large number of studies in the overall findings; (8) the subgroup
lysis with nifedipine was ineffective in metaanalyses; (4) the quality assessment and metaregression analyses that did not
prolonging gestation or reducing any ad- of trials included in the review was based show any significant influence of study
verse neonatal outcomes when com- on a widely used and validated scale; (5) characteristics on effect size; and (9) the
pared with placebo or no treatment. the relatively narrow confidence inter- symmetrical funnel plots suggesting ab-
vals obtained making our estimates of ef- sence of publication and related biases in
Strengths of this study
fect size; (6) the evidence of clinical and our metaanalyses.
Strengths of the study include: (1) the
use of rigorous methodology for the per- statistical homogeneity in the results of Limitations of this study
formance of a systematic review of ran- the trials for most of the outcomes evalu- It must be stressed that there are no pla-
domized controlled trials; (2) a compre- ated; (7) the sensitivity analyses re- cebo-controlled trial comparing the effi-
hensive literature search to identify stricted to high-quality trials that were cacy and safety of nifedipine for acute to-
relevant studies; (3) the inclusion of a consistent with (and thus supportive of) colysis in preterm labor. Therefore, most

of the evidence generated is based on We were unable to determine the effi- Recently Khan et al65 published a sys-
comparative trials of 2 apparently active cacy of nifedipine for acute tocolysis in tematic review and metaregression anal-
tocolytic agents. Randomized controlled women with twin pregnancies or with ysis of randomized controlled trials,
trials in which ␤2-adrenergic-receptor preterm premature rupture of mem- observational studies, and case series,
agonists were compared with placebo in- branes because of the paucity of data. which evaluated the feto-maternal safety
dicated that these drugs reduced the risk Two studies33,35 reported data for of calcium channel blockers when used
of delivery within 48 hours of initiation women with twin pregnancies (n ⫽ 35), in pregnancy, not just for the treatment
of treatment (RR, 0.63; 95% CI, 0.53– and 230,35 reported data for women with of preterm labor but also for use in the
0.75) and within 7 days of treatment premature rupture of membranes (n ⫽ treatment of hypertension in pregnancy.
(RR, 0.78; 95% CI, 0.68 – 0.90).7 58). There were no statistically signifi- These authors reported that adverse
Because the metaanalysis reported cant differences between nifedipine- events were highest among women who
here showed that nifedipine is as effec- treated and ritodrine-treated groups for received more than 60 mg total dose of
tive as ␤2-adrenergic-receptor agonists delivery within 48 hours and 7 days of nifedipine (odds ratio, 3.78; 95% CI,
in reducing the rate of delivery within 48 initiation of treatment and preterm birth 1.27–11.2) and in case series compared
hours and more effective in reducing the before 34 and 36 weeks’ gestation. with controlled studies (odds ratio, 2.45;
rate of delivery within 7 days of treat- Some serious adverse effects such as 95% CI, 1.17–5.15).
ment with a significantly better adverse- myocardial infarction,58,59 severe mater-
event profile, it is unlikely that a placebo- nal dyspnea,60 maternal hypoxia,61 se- Implications of the study
controlled trial involving nifedipine for vere maternal hypotension with fetal Inhibition of uterine contractions has
acute tocolysis will be undertaken. In- death,62 and atrial fibrillation63 have been a major component of the therapy
deed, randomized controlled trials of to- been reported during tocolytic therapy of patients with preterm labor with the
colysis have become difficult to perform with nifedipine. A case series study re- hope that inhibiting uterine contractility
ported that 6 of 7 cases of nifedipine-as- would prevent preterm delivery and the
because many clinicians reason that pro-
sociated severe maternal dyspnea oc- neonatal complications associated with
longation of pregnancy for 48 hours is
curred in women with twin pregnancies the unscheduled onset of labor. Despite
desirable to allow steroids to exert their
and recommended caution when ad- decades of basic and clinical research in
beneficial effects.
ministering nifedipine to patients with tocolytic agents, it is unclear whether in-
Another potential limitation of this
compromised cardiovascular condition, hibition of uterine contractions can sub-
metaanalysis is that only half of the trials
mainly those with a twin gestation, car- stantially change the prognosis of pre-
included herein were considered to be of
diac disease, maternal hypertension, and term labor. It seems that tocolysis can
high quality and just one was double-
intrauterine infection.60 achieve a slight prolongation of preg-
blinded. Nevertheless, sensitivity analy-
A recent multicenter prospective co- nancy and sometimes a reduction in
ses restricted to high-quality trials hort study from The Netherlands and neonatal morbidity, particularly when
showed no significant differences in the Belgium, in which an independent panel used in combination with steroids.
results obtained with overall metaanaly- evaluated the recorded adverse events The fundamental problem of preterm
ses. In addition, assessment and mea- without knowledge of the type of toco- labor appears to be not only the untimely
surement of most outcomes included in lytic used, reported that among 542 activation of the common pathway of
our review are considered objective in women treated with nifedipine, 5 (0.9%) parturition (uterine contractility, cervi-
nature and thereby not likely to be influ- had a serious adverse side effect and 6 cal ripening, and membrane/decidual
enced by lack of blinding. (1.1%) had a mild adverse side effect.64 activation)66 but also the cause of such
It is noteworthy that several studies In our systematic review, nifedipine was activation. Moreover, it remains to be
did not report results that are the subject associated with a significantly decreased proven that treatment of one of the com-
of our metaanalysis; thus, our study may risk in maternal adverse effects when ponents (ie, in the case of tocolysis, uter-
be underpowered for some outcomes. It compared with ␤2-adrenergic-receptor ine contractility) may deactivate other
is possible that if these results were re- agonists and magnesium sulfate and a components that have been subclinically
ported more consistently, effect sizes significant reduction in the rate of dis- recruited into the process of parturition.
might be different. continuation of treatment because of ad- Indeed, the onset of preterm labor has
Finally, we could not fully address the verse effects when compared to ␤2-ad- been proposed to have survival value
potential for performance biases by ex- renergic-receptor agonists. Moreover, when the mother and fetus are at risk be-
tracting consistent data on concomitant nifedipine had no effect on the rate of cause of intrauterine infection/inflam-
cointerventions. The difference in fre- fetal and neonatal death. However, con- mation.67-69 However, the onset of pre-
quency of use and/or type of alternative sideration of randomized control trials term labor may also have survival value
tocolytic therapy between groups could alone is insufficient to determine the in cases in which there is no infection,
have increased the apparent benefit of range and severity of adverse events and but an immunological insult (ie, fetal in-
nifedipine compared with ␤2-adrener- both observational studies and case re- flammatory response syndrome, type
gic-receptor agonists. ports must be used to assess safety data. II).70

We have recently identified that on equivalence trials in which a low pro- ple gestations, preterm prelabor rupture
chronic chorioamnionitis/villitis of un- file of adverse events has been observed of membranes, and very low gestational
known etiology is the hallmark of im- with similar efficacy to that of beta-ad- ages; its effectiveness as maintenance
mune rejection of the fetal semiallograft, renergic agents. We are unable to render therapy after preterm labor has been ar-
and this is a frequent lesion in late pre- any opinion about the comparison be- rested; the cost-effectiveness of this in-
term births.70,71 The role of tocolysis tween calcium channel blockers and ato- tervention; and the long-term conse-
when subclinical pathology (eg, acute siban because of the lack of adequate quences of exposure of infants to this
chorioamnionitis, chronic chorioam- randomized clinical trials. calcium channel blocker. f
nionitis, vascular disease, and other dis- A recent randomized controlled
orders) are present needs to be examined trial,79 published in abstract form, eval-
(it is possible that patients in which there uated maintenance tocolysis with nifed- REFERENCES
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