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OBSTETRICS

Nifedipine in the management of preterm labor:

a systematic review and metaanalysisAgustn Conde-Agudelo, MD, MPH; Roberto Romero, MD; Juan Pedro Kusanovic, MD

OBJECTIVE:To determine the efficacy and safety of nifedipine as a to-

colytic agent in women with preterm labor.

STUDY DESIGN:A systematic review and metaanalysis of randomized

controlled trials.

RESULTS:Twenty-six trials (2179 women) were included. Nifedipine

was associated with a significant reduction in the risk of delivery within

7 days of initiation of treatment and before 34 weeks gestation, respi-

ratory distress syndrome, necrotizing enterocolitis, intraventricular

hemorrhage, neonatal jaundice, and admission to the neonatal inten-

sive care unit when compared with2-adrenergic-receptor agonists.

There was no difference between nifedipine and magnesium sulfate in

tocolytic efficacy. Nifedipine was associated with significantly fewer

maternal adverse events than 2-adrenergic-receptor agonists and

magnesium sulfate. Maintenance nifedipine tocolysis was ineffective in

prolonging gestation or improving neonatal outcomes when compared

with placebo or no treatment.

CONCLUSION:Nifedipine is superior to 2-adrenergic-receptor ago-

nists and magnesium sulfate for tocolysis in women with preterm labor.

Key words:calcium channel blocker, neonatal morbidity, pregnancy,

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.

The World Health Organization hasestimated that 12.9 million births,or 9.6% of all births worldwide, were

preterm in 2005.1 In the United States,

the preterm birth rate has risen over the

last 2 decades. In 2007, preterm births

constituted 12.7% of live births, an in-

crease of 20% since 1990, and 36% since

the early 1980s.2 Trends in most other

developed countries are similar to thosein the United States.3,4 Preterm birth is

the leading cause of perinatal morbidity

and mortality4 and one of the leading

causes of infant mortality.2 Despite the

improvement in survival rates of pre-

term neonates, they are at increased risk

of long-term neurodevelopmental dis-

abilities and respiratory and gastrointes-

tinal complications.5

Because uterine contractions are the

most frequently recognized symptom

and sign of preterm labor, inhibition

of uterine contractility with tocolytic

agents to prolong pregnancy and reduce

neonatal complications continues to be

the focus of treatment of preterm labor.

Tocolytic agents are intended to arrest

uterine contractions during an episode

of preterm labor (acute tocolysis) or

maintain uterine quiescence after an

acute episode has abated (maintenance

tocolysis).

Several agents have been used forthe in-hibition of uterine contractility, but it re-

mains unclear what the first-line tocolytic

agent should be6:(1)2-adrenergic-recep-

tor agonists reduce the rate of preterm de-

livery within 48hours of initiation of treat-

ment.7 Nevertheless, there is no evidence

thatthisdelayinthetimingofbirthbyitself

translates into improvements in neonatal

outcomes, and maternal side effects areconsiderable7; (2) magnesium sulfate has

not been proven to be aneffective tocolytic

agent, and its use could be associated with

an increased risk of fetal, neonatal, and in-

fant mortality8; (3) there is insufficient ev-

idence of whether prostaglandin synthesis

inhibitors reduce the risk of preterm

birth9;(4)theoxytocinreceptorantagonist

atosiban wasfound to increase the propor-

tionof patients remainingundeliveredand

not requiring an alternate tocolytic at 7

days when compared withplacebo, yet this

was not associated with an improvement

in neonatal outcome, which has been at-

tributed to the complexities of study de-

signandinterpretationof trials of tocolysis

that involve a rescue intervention10; bar-

usiban, a selective oxytocin antagonist, has

not been found to be more effective than

placeboin delaying delivery for48 hours11;

(5) there is currently insufficient evidence

to support theuse of nitric oxide donors as

a tocolytic drug,12

although recent studiessuggest that this option requires further

From the Perinatology Research Branch,

Eunice Kennedy ShriverNational Institute ofChild Health and Human Development,

National Institutes of Health, Department of

Health and Human Services, Bethesda, MD,

and Detroit, MI (all authors), and the Center

for Molecular Medicine and Genetics (Dr

Romero) and the Department of Obstetrics

and Gynecology (Drs Romero and

Kusanovic), Wayne State University,

Detroit, MI.

Received July 11, 2010; revised Aug. 19,

2010; accepted Nov. 17, 2010.

Reprints not available from the authors.

This study was supported in part by the

Intramural Research Program of theEunice

Kennedy ShriverNational Institute of Child

Health and Human Development, National

Institutes of Health, Department of Health and

Human Services.

0002-9378/free

2011 Published by Mosby, Inc.

doi: 10.1016/j.ajog.2010.11.038

For Editors Commentary,

see Table of Contents

See related editorial, page 95

Research www.AJOG.org

134.e1 American Journal of Obstetrics &Gynecology FEBRUARY 2011


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consideration13,14; and (6) maintenancetocolysis with2-adrenergic-receptorago-nists15 and oral magnesium sulfate16 is in-effective in prolonging gestation or reduc-ing adverse neonatal outcomes. Atosibanmaintenance treatment can increase the

time interval to the next episode of pre-term labor but does not reduce the rate ofpreterm delivery or improve infantoutcomes.17

Some authors have proposed thatnifedipine, a calcium channel blocker,could be used as a first-line tocolyticagent.18-20 The most recent substantialupdate of the Cochrane review regardingcalcium channel blockers for acute toco-lysis in preterm labor included 12 ran-domized controlled trials (10 using ni-

fedipine) involving 1029 patients.

21

Thisreview concluded that calcium channelblockers (mainly nifedipine) reduce therisk of delivery within 7 days of initiationof treatment and delivery before 34weeks gestation with improvements insome clinically important neonatal out-comes such as respiratory distress syn-drome, intraventricular hemorrhage,necrotizing enterocolitis, and neonataljaundice when compared to other toco-lytic agents (mainly beta-mimetics).

A second review from the Cochranedatabase on maintenance tocolysis re-ported that nifedipine neither reducesthe risk of preterm birth before 37 weeksgestation nor improves neonatal out-comes, compared with no treatment.22

However, this review included only 1trial of 74 women. The literaturesearches on which these reviews werebased were performed in 2002 and 2004,respectively. Since that time, additionalrandomized controlled trials with nifed-

ipine have been published; therefore, re-assessment of the efficacy and safety ofthis agent is justified.

We conducted a systematic review andmetaanalysis of all available randomizedcontrolledtrials to determinethe efficacyand safety of nifedipine as a tocolyticagent in patients with preterm labor.

MATERIALS ANDMETHODSThe systematic review was performed

following a prospectively prepared pro-tocol and reported using the Preferred

Reporting Items for Systematic reviewsand Metaanalyses guidelines for meta-analysis of randomized controlled trials.23

Search

We searched (without language re-

strictions) the following computerizeddatabases using the terms nifedipine,calcium channel blocker, calcium an-tagonist, tocolysis, preterm labor,premature, and their associated medi-cal subject headings (MeSH): MED-LINE, EMBASE, CINAHL, and LILACS(all frominceptionto December 31,2010),theCochrane Central Register of ControlledTrials (http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html)(1960 to December 31,

2010), ISI Web of Science (http://www.isiknowledge.com) (1960 to December 31,2010), Research Registers of OngoingTrials (www.clinicaltrials.gov, www.controlled-trials.com,www.centerwatch.com,www.anzctr.org.au,andwww.umin.ac.jp/ctr), and Google scholar. To ensuremaximum sensitivity, we placed no limitsor filters on the searches. Proceedings ofthe Society for Maternal-Fetal Medicineand international meetings on pretermbirth and tocolysis, reference lists of iden-

tified studies, textbooks, previously pub-lished systematic reviews, and review arti-cles were also searched. For studies withmultiple publications, the data from themost complete report were used and sup-plemented if additional information ap-peared in other publications.

Study selection

We included randomized controlled tri-als in which nifedipine was used for to-colysis in patients with preterm labor

compared with alternative tocolyticagents, placebo, or no treatment. Trialswere excluded if they were quasi-ran-domized,if they comparedonlydifferentdoses of nifedipine or other calciumchannel blockers, or if nifedipine wasgiven in addition to or following failureof another tocolytic drug. Published ab-stracts alone were excluded if additionalinformation on methodological issuesand results could not be obtained. Weclassified trials according to the aim of

the treatment with nifedipine into 2groups: acute tocolysis and maintenance

tocolysis. Two reviewers independentlyevaluated studies for inclusion, and dis-agreements were resolved through con-sensus among the authors. Investigatorsof selected studies were contacted tocomplement data on trial methods

and/or outcomes.

Outcome measures

The primary outcomes of interest weredelivery within 48 hours and 7 days oftreatment for acute tocolysis; deliverybefore 34 and 37 weeks gestation formaintenance tocolysis; and perinataldeath, admission to neonatal intensivecare unit (NICU), neurodevelopmentaldisabilityat2yearsofage,andseverema-ternal adverse drug reactions for both

acute and maintenance tocolysis. Sec-ondary outcomes included the intervalbetween trial entry and delivery, gesta-tional age at delivery, maternal adverseevents, discontinuation of treatment be-cause of adverse events, birthweight,Apgar score at 5 minutes, respiratory dis-tress syndrome, intraventricular hemor-rhage, necrotizing enterocolitis, retinop-athy of prematurity, neonatal jaundice,neonatal sepsis, fetal death, neonataldeath, length of stay in the NICU, long-

term psychosocial and motor function,and pregnancy/neonatal outcomes amongwomen enrolled at less than 32 weeksgestation.

Study quality assessment

We conducted quality assessment ac-cording to a modified scoring systemproposed by Jadad et al,24 which consid-ers 4 items: randomization, blinding,follow-up, and concealment of alloca-tion. We assigned points to each trial as

follows: (1) quality of randomization (2points: computer-generated randomnumbers or similar; 1 point: not de-scribed; 0 points: quasi-randomized ornot randomized [weexcluded such stud-ies]); (2) double blinding (2 points: nei-ther the person doing the assessmentsnor the study participant could identifythe intervention being assessed; 1 point:not described; 0 points: no blinding orinadequate method); (3) follow-up (2points: number or reasons for dropouts

and withdrawals described and assess-ment of primary outcomes in 95% or

www.AJOG.org Obstetrics Research

FEBRUARY 2011 American Journal of Obstetrics&Gynecology 134.e2
http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.isiknowledge.com/http://www.isiknowledge.com/http://www.isiknowledge.com/http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/http://www.controlled-trials.com/http://www.controlled-trials.com/http://www.controlled-trials.com/http://www.centerwatch.com/http://www.centerwatch.com/http://www.centerwatch.com/http://www.anzctr.org.au/http://www.anzctr.org.au/http://www.umin.ac.jp/ctrhttp://www.umin.ac.jp/ctrhttp://www.umin.ac.jp/ctrhttp://www.umin.ac.jp/ctrhttp://www.umin.ac.jp/ctrhttp://www.anzctr.org.au/http://www.centerwatch.com/http://www.centerwatch.com/http://www.controlled-trials.com/http://www.controlled-trials.com/http://www.clinicaltrials.gov/http://www.isiknowledge.com/http://www.isiknowledge.com/http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html


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more of randomized women; 1 point:number or reasons for dropouts andwithdrawals described but assessment ofprimary outcomes in less than 95% ofrandomized women; 0 points: numberor reasons for dropouts and withdrawals

not described); and (4) concealment ofallocation (2 points: adequate method[central randomization; or drug con-tainers or opaque, sealed envelopes thatwere sequentially numbered and openedsequentially only after they have been ir-reversibly assigned to the participant]; 0points: no concealment of allocation orinadequate method or not described).Thus, the total score rangedfrom 0 (low-est quality) to 8 (highest quality). Studiesthat scored 6 points or more were

considered to be of high quality. Twoinvestigators (A.C.-A. and J.P.K.) inde-pendently assessed study quality, anddiscrepancies were resolved throughdiscussion.

Data extraction

Two reviewers(A.C.-A. and J.P.K.) inde-pendently extracted datafrom each eligi-ble study using a standardized data ab-straction form. There was no blinding ofauthorship. From each article, we ex-

tracted data on study characteristics(randomization procedure, blinding ofproviders, patient and outcome asses-sors, follow-up period, intention-to-treat analysis, losses to follow-up, ex-clusions, and concealment allocationmethod), participants (inclusionand ex-clusion criteria, definition of preterm la-bor, cervical dilatation and effacement attrial entry, gestational age at randomiza-tion, number of women randomized,baseline characteristics, and country and

date of recruitment), details of interven-tion (aim, loading and maintenancedose, route, duration, re-treatment, useof alternative tocolytic therapy, and rou-tine administration of antenatal cortico-steroids),and outcomes (number of out-come events and/or mean SD for eachoutcome).

Unpublished additional data used inanother metaanalysis21 were included.Studies reporting preterm birth before36 weeks gestation as an outcome mea-

sure were included into the group ofstudiesreportingpretermbirthbefore37

weeks gestationin ourdata synthesis be-

cause of the relatively similar neonatal

outcomes. Disagreements regarding ex-

tracted data were resolved by discussion

among the authors.

Statistical analysisStatistical analyses were performed ac-

cording to the guidelines of the Co-

chrane Collaboration.25 We analyzed

outcomes on an intention-to-treat basis.

If this was not clear from the original ar-

ticle, then we carried outreanalysis when

possible. If we found no evidence of a

substantial difference in study popula-

tions, interventions, or outcome mea-

surements, we performed a metaanaly-

sis. We calculated the summary relative

risk (RR) for dichotomous data andweighted mean difference (WMD) for

continuous data with associated 95%

confidence interval (CI).

Four prespecified subgroup analyses

were performed to compare nifedipine

with other tocolytic agents (2-adrener-

gic-receptor agonists, magnesium sul-

fate, atosiban, and nitric oxide donors)

for acute tocolysis and 1 to compare ni-

fedipine with placebo or no treatment

for maintenance tocolysis.The subgroup

analyses comparing nifedipine vs pla-cebo or no treatment for acute tocolysis

were not performed because trials ad-

dressing these comparisons were not

identified.

Heterogeneity of the results among

studies was tested with the quantityI2,

which describes the percentage of total

variationacross studies that is due to het-

erogeneity rather than chance.26 A value

of 0% indicates no observed heterogene-

ity whereasI2 values of 50% or more in-

dicate a substantial level of heterogene-

ity.26 We planned to pool data across

studies using the fixed-effects models if

substantial statistical heterogeneity was

no present. We used random-effects

models to pool data across studies ifI2

values were 50%or greater. A predefined

sensitivity analysis was performed to ex-

plore the impact of study quality on the

effect size for the main outcomes. This

analysis was performed by excluding

trials with a modified Jadad score lessthan 6.

We conducted additional analyses

stratified according to the following

characteristics: definition of preterm la-

bor (based on uterine contractions plus

cervical changes vs based on uterine con-

tractions alone); mean or median cervi-

cal dilatation at trial entry (2 vs 2cm); participating patients in true pre-

term labor as judged by the authors (yes

vs no/not reported); loading dose of

nifedipine (10 vs 30 mg); membranes

status (intact vs ruptured); plurality(sin-

gleton vs twin pregnancy); mean gesta-

tional age at trial entry (30 weeks vs

30 weeks); study setting (developed vs

developing countries); maintenance

therapy in studies evaluating acute toco-

lysis (yes vs no/not reported); use of al-

ternative tocolytic therapy (yes vs no/not

reported); and antenatal corticosteroid

therapy (yes vs no/not reported). Meta-

analyses according to plurality of preg-

nancy and membranes status, however,

were not undertaken because of insuffi-

cient data.

For the comparison nifedipine vs

magnesium sulfate, we performed a sub-

group analysis according to dosage of

magnesium sulfate used (4 g loading

dose and 2-4 g/h vs 6 g loading dose and2-4 g/h). Univariable random effects

metaregression models25 were used to

examine whether effect sizes were af-

fected by these study characteristics.

We assessed publication and related

biases visually by examining the symme-

try of funnel plots and statistically by us-

ing the Egger test.27 The larger the devi-

ation of the intercept of the regression

line from zero, the greater was the asym-

metry and the more likely it was that the

metaanalysis would yield a biased esti-mates of effect. We consideredP .1 to

indicate significant asymmetry, as sug-

gested by Egger.

We also calculated the number needed

to treat (NNT) for an additional benefi-

cial outcome with its 95% CI for out-

comes in which the treatment effect was

significant at the 5% level (the 95% CI

for the absolute risk difference did not

include zero).28 NNT was computed

from the results of metaanalysis of rela-tive risks as follows:

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NNT1

control group event rate

(1 relative risk)

In this review, NNT foran additionalbeneficial outcome is the number ofwomen in preterm labor who need tobe treated with nifedipine rather than

with another tocolytic agent, placebo,or no treatment to prevent 1 case of

delivery within 48 hours or 7 days or

before 34 or 37 weeks or adverse neo-

natal outcome.

Analyses were performed with the Re-

view Manager (RevMan) software ver-

sion 5.0.23 (The Nordic Cochrane Cen-

tre, Kbenhavn, Denmark), StatsDirect

version 2.7.8 (StatsDirect Ltd, Cheshire,

UK), and Stata, version 10.0 (StataCorp,College Station, TX).

RESULTSWe identified 1527 studies in our litera-

ture search and considered 61 to be po-

tentially eligible (Figure). Twenty-six

studies, including 2179 women, fulfilled

inclusion criteria of which 23 evaluated

acute tocolysis29-51

and 3 evaluatedmaintenance tocolysis.52-54 There was

strong agreement among authors on the

inclusion of studies ( 0.89). Addi-

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

evaluated nifedipine vs 2-adrenergic-

receptor agonists (11 studies using rito-

drine,29-36,38,41,44 3 studies using ter-

butaline,39,42,43 and 2 studies using

isoxsuprine37,40), 5 evaluated nifedipine

vs magnesium sulfate,45-49 and one each

evaluated nifedipine vs atosiban50 and

nifedipine vs nitric oxide donors.51

There were no trials in which nifedipine

was compared with placebo or no treat-

ment in acute tocolysis.

Of the 3 trials on maintenance tocoly-

sis, 2 evaluated nifedipine vs no treat-

ment52,53 and 1 evaluated nifedipine vs

placebo.54 In the study by Koks et al,35

only the subset of patients who were nottreated with 2-adrenergic-receptor

agonists before trial entry was included

(57/102 women). Thirty-five studies

were excluded for the following reasons:

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

method of generation of allocation to

treatment was quasi-randomized (n

4); an unclear method of randomization(n 3); the study didnot report relevant

outcomes (n4);nifedipine was used in

combination with other tocolytic agents

(n 2); comparison of 2 calcium chan-

nel blockers (n 1); comparison of 2

dose regimens of nifedipine (n 1); a

nonrandomized trial (n 1); and

women were enrolled only after subcu-

taneous terbutaline failed to inhibit con-

tractions (n 1). The list of excluded

studies is available from the authorsupon request.

FIGURE

Study selection process

1466 excluded after screeningtitles and/or abstracts

35 excluded

12 abstract form and subsequentlypublished as a full length report

6 only available in abstract form withinsufficient information

4 quasi-randomized trial4 outcomes not relevant3 unclear method of randomization2 nifedipine added to other tocolytic

2 comparison of 2 calcium channelblockers or 2 dose regimens ofnifedipine

1 nonrandomized trial1 women were eligible after failed

tocolysis with terbutaline

26 studies included

in metaanalysis

61 retrieved for more detailed evaluation42 from electronic searches

7 from reference lists12 from conference proceedings

1527 studies identified andscreened for retrievalfrom searches

Conde-Agudelo.Nifedipine in the managementof preterm labor. Am J Obstet Gynecol 2011.




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Characteristics of the studies in-cluded in the revieware summarized inTable 1.Seven studies were conducted

in the United States,30,32,45,46,49,52,54

11in Asian countries,33,37-40,42,43,47,48,50,53

7 in European countries,29,31,34-36,41,44

and 1 in Brazil.51 The sample sizeranged from 4029,42 to 19249 (median,

74). Preterm labor was defined asthe presence of uterine contractions

with evidence of cervical changesin 18 trials.30-33,38-40,42,43,45,46,48-54 Eightstudies did not include cervical

changes in the diagnosis of pretermlabor.29,34-37,41,44,47

TABLE 1

Characteristics of studies included in the systematic review

First author,

year Location Inclusion/exclusion criteria

Gestational age (wks), cervical dilatation/

effacement, and frequency of uterine

contractions at trial entry Interventions (sample size)

Alternative

tocolytic therapy

Acute tocolysis................................................................................................................................................................................................................................................................................................................................................................................

Nifedipine compared with2-adrenergic-receptor agonists................................................................................................................................................................................................................................................................................................................................................................................

Read,29 1986 United Kingdom Inclusion: women with singleton pregnancyin preterm labor (at least 1 uterinecontraction every 10 min) and intactmembranes.Exclusion: multiple pregnancy,polyhydramnios, premature rupture ofmembranes, history of cervical surgery,history of midtrimester abortion or previouspreterm delivery, history of any medicalcondition that would contraindicate the useof either of the drugs, chorioamnionitis,any irregularity of the fetal heart rate, andcervical dilatation greater than 4 cm.

20-35; no data on cervical dilatation andeffacement, and frequency of uterinecontractions at trial entry.

Nifedipine (n 20): 30 mg orally,then 20 mg orally every 8 hoursfor 3 days.Ritodrine (n 20): 50g/minintravenously, increasing by 50g every 10 minutes to amaximum of 300g for 24hours, then 10 mg orally oralevery 4 hours for 48 hours.

Ritodrine innifedipine group

................................................................................................................................................................................................................................................................................................................................................................................

Ferguson,30

1990United States Inclusion: women with singleton pregnancy

in preterm labor (uterine contractions at a

frequency of 8 or more per hour with adocumented change in cervical dilatationor effacement) irrespective of themembranes status.Exclusion: previous treatment withtocolytics in current pregnancy, diabetes,hyperthyroidism, cardiac disease, severepreeclampsia, eclampsia, placentalabruption, chorioamnionitis, multiplepregnancy, polyhydramnios, cervicaldilatation greater than 4 cm, fetal distress,severe intrauterine growth retardation, fetaldeath, and fetal anomaly incompatible withlife.

20-36; mean cervical effacement at trialentry was 60 22% and 67 25% for

nifedipine and ritodrine groups, respectively;82% of women had a cervical dilatation lessthan 2 cm and 18% had 2-3.9 cm at trialentry.

Nifedipine (n 33): 10 mgsublingually. If uterine

contractions persisted after 20minutes, a similar dose wasrepeated at intervals of 20minutes, up to a maximal totaldose of 40 mg during the firsthour of treatment, then 20 mgorally every 4-6 hours.Ritodrine (n 33): 50g/minintravenously increasing by 50 gevery 15-30 minutes up to amaximum of 350g/min, then10-20 mg orally every 4-6 hours.

Alternate regimenand terbutaline

................................................................................................................................................................................................................................................................................................................................................................................

Janky,31 1990 France Inclusion: women with singleton pregnancyin preterm labor (at least 2 uterinecontractions every 10 minutes with cervical

modifications).Exclusion: chorioamnionitis, fetal death,fetal anomaly incompatible with life,medical condition contraindicating the useof betamimetics, cervix greater than 4 cm,and premature rupture of membranes after34 weeks.

28-36; 76% of women had a Baumgartentocolytic score of 3-6 and 24% had a scoreless than 3 (true labor defined as a

Baumgarten tocolytic score of 2.5). Meannumber of uterine contractions in 20minutes was 7 (range, 412).

Nifedipine (n 30): 10 mgsublingually, then 20 mg orallyevery 8 hours for 7 days.

Ritodrine (n 32): 200-300g/min intravenously untilcontractions ceased, then 100g/min for 24 hours, thereafter20 mg orally every 4-6 hours for6 days.

Permitted butunspecified

................................................................................................................................................................................................................................................................................................................................................................................

Bracero,32 1991 United States Inclusion: women with singleton pregnancyin preterm labor (cervical dilatation 2 cmor effacement 80%, or 2 contractionslasting more than 30 seconds with cervicalchanges) and intact membranes.Exclusion: multiple pregnancy, prematurerupture of membranes

20-36; mean Bishop score at trial entry was6.6 1.8 and 5.9 2.4, for nifedipine andritodrine groups, respectively.

Nifedipine (n 26): 30 mg orally,then 20 mg orally every 6 hoursfor 24 hours, then decreased to 8hour intervals for an additional 24hours, thenceforth 20 mg every8-12 hours. No data on durationof treatment.Ritodrine (n 23): 100g/minintravenously increasing by 50g/min every 10 minutes to a

maximum of 350g/min. Thirtyminutes prior to discontinuation ofintravenous ritodrine, 10 mgorally every 2 hours for 24 hours,then 10 mg every 4 hours for 24hours, then 20 mg every 8-12hours, thereafter 10-20 mg orallyevery 4-6 hours. No data onduration of treatment.

Ritodrine andmagnesiumsulfate innifedipine groupand magnesiumsulfate in ritodrinegroup

................................................................................................................................................................................................................................................................................................................................................................................

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TABLE 1

Characteristics of studies included in the systematic review (continued)

First author,





Alternative

tocolytic therapy

Kupferminc,33

1993

Israel Inclusion: women with singleton or twin

pregnancy in preterm labor (uterinecontractions at least every 6 minutes withevidence of change in cervical dilatation oreffacement between consecutive digitalexaminations) and intact membranes.Exclusion: polyhydramnios, placentalabruption, hypertension, infection, anymedical condition that would contraindicatetocolytic therapy, cervical dilatation greaterthan 4 cm, and premature rupture ofmembranes.

26-34; mean cervical dilatation and

effacement at trial entry was 1.8

0.6 and1.9 0.7 cm and 42 17% and43 14% for nifedipine and ritodrinegroups, respectively.

Nifedipine (n 36): 30 mg orally,

then 20 mg after 90 minutes ifcontractions persisted, thereafter20 mg every 8 hours until 34-35weeks.Ritodrine (n 35): 50 g/minintravenously increasing by 15 g/min every 15 minutes to amaximum of 300 g/min for 12hours, then 10 mg orally every 3hours until 34-35 weeks.

Ritodrine in

nifedipine group

................................................................................................................................................................................................................................................................................................................................................................................

Papatsonis,34

1997TheNetherlands

Inclusion: women with singleton pregnancyin preterm labor (at least 1 uterinecontraction every 10 minutes during atleast 1 hour; cervical changes were notobligatory for inclusion) irrespective of themembranes status.Exclusion: multiple pregnancy, intrauterineinfection, fetal congenital anomalies,abruption placenta, severe fetal growthrestriction, and any contraindication for theuse of beta-adrenergic drugs.

20-33 4/7; mean cervical dilatation inwomen with intact membranes at trial entrywas 1.5 2.1 and 1.8 2.2 cm fornifedipine and ritodrine groups, respectively.

Nifedipine (n 95): 10 mgsublingually. If contractionspersisted, this dose was repeatedevery 15 minutes to maximum of40 mg during the first hour oftreatment, then 60-160 mg/day ofslow-release nifedipine until 34weeks.Ritodrine (n 90): 383g/minintravenously after which theinfusion rate was determined bythe time lag after which tocolysisis established (minimum 100 g/min) for at least 3 days. Thenritodrine 40 mg orally every 8hours until 34 weeks in 2 of the 3participating hospitals.

Nifedipine inritodrine group;Indomethacin inboth groups

................................................................................................................................................................................................................................................................................................................................................................................

Koks,35 1998a TheNetherlands

Inclusion: women with singleton or twinpregnancy in preterm labor (6 uterinecontractions per hour with a duration of30 seconds with and without cervicaldilatation or effacement) irrespective of themembranes status.Exclusion: any contraindication for the use

of nifedipine or betamimetic, intrauterineinfection, irregular fetal heart rate,antepartum hemorrhage, andpolyhydramnios.

24-34; 86% of women had a cervicaldilatation 2 cm or less and 14% had greaterthan 2 cm at trial entry.

Nifedipine (n 32): 30 mgsublingually, then 20 mg orallyevery 6-12 hours, which wasreduced to 20 mg every 8 hoursuntil 34 weeks.Ritodrine (n 25): 200g/minintravenously up to maximum of

400g/min, then 80 mg orallyevery 8 hours until 34 weeks.

Indomethacin inboth groups

................................................................................................................................................................................................................................................................................................................................................................................

Garca-Velasco,36 1998

Spain Inclusion: women with singleton pregnancyin preterm labor (4 uterine contractionsin 30 minutes, irrespective of cervicalchanges) and intact membranes.Exclusion: previous tocolytic treatment,cervical dilatation 3 cm or greater,maternal infection, vaginal bleeding, andany medical or obstetrical conditioncontraindicating tocolytic therapy.

26-34; mean Bishop score at trial entry was2.9 0.9 and 2.6 0.9 for nifedipine andritodrine groups, respectively.

Nifedipine (n 26): 30 mg (20mg orally and 10 mgsublingually), then 10-20 mgevery 4-6 hours. No data onduration of treatment ormaintenance therapy.Ritodrine (n 26): 50g/minintravenously increasing by 50g/min every 20 minutes to amaximum of 350g/min for 12hours, then 5 mg orally every 3hours. No data on duration oftreatment or maintenance

therapy.

Indomethacin inboth groups

................................................................................................................................................................................................................................................................................................................................................................................

Ganla,37 1999 India Inclusion: women with singleton pregnancyin preterm labor (uterine contractionsoccurring at interval of 10 minutesrecorded for at least 30 minutes). No dataon membranes status.Exclusion: diabetes, hyperthyroidism,cardiac disease, severe preeclampsia,eclampsia, placental abruption,chorioamnionitis, cervical dilatation greaterthan 3 cm, severe fetal growth restriction,and lethal fetal anomalies.


Nifedipine (n 50): 5 mgsublingually. If contractions persisted,this dose was repeated every 15minutes to maximum of 40 mgduring the first 2 hours of treatment,then 10 mg orally every 8 hours for48 hours, thereafter 10-20 mg orallyevery 12 hours until 36 weeks.Isoxsuprine (n 50): 0.5 mg/minintravenously increasing to amaximum of 10 mg/min for 12hours, then 10 mg intramuscularlyevery 8 hours for 48 hours,thereafter 10-20 mg orally every 8hours until 36 weeks.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................





7/20

According to the widely used diag-nostic criteria for preterm labor,57 we

considered that participating womenin 20 trials were in true preterm la-

bor.30-36,38-42,45,46,48,49,51-54 Nineteenstudies were limited to women with in-

tact membranes,29,32,33,36-41,43,45-48,50-54

7 also included women with ruptured

membranes,30,31,34,35,42,44,49 and 8 in-cluded women with a twin preg-

nancy.33,35,40,43,49,50,53,54

Standard ma-ternal and fetal contraindications to toco-

TABLE 1


First author,





Alternative

tocolytic therapy

Al-Qattan,38

2000

Kuwait Inclusion: women with singleton pregnancy

in preterm labor (uterine contractions at afrequency of 2-3 per 10 minute intervalwith a documented change in cervicaldilatation or effacement) and intactmembranes.Exclusion: multiple pregnancy, cardiacdisease, placental abruption,hyperthyroidism, severe preeclampsia,eclampsia, infection, cervical dilatation 4cm or greater, polyhydramnios, fetalpathology, premature rupture ofmembranes, breech presentation, fetaldeath, fetal distress, and congenitalmalformation.

24-34; 9% of women had a closed cervix,

72% had a cervical dilatation of 1-2 cm, and19% had greater than 2 cm at trial entry.

Nifedipine (n 30): 30 mg orally.

If contractions persisted after 2hours, a second dose of 20 mgwas given, then 20 mg orallyevery 6 hours until 34 weeks.Ritodrine (n 30): 50g/minintravenously, then 10 mg orallyevery 4-6 hours until 34 weeks.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................

Weerakul,39

2002Thailand Inclusion: women with singleton pregnancy

in preterm labor (definition not provided)and intact membranes.Exclusion: multiple pregnancy, prematurerupture of membranes, previous tocolytics,cervical dilatation greater than 3 cm,chorioamnionitis, infection, fetal distress,fetal anomalies, and medical or obstetricalcomplications.

28-34; mean Bishop score at trial entry was6.2 2.8 and 5.2 2.6 for nifedipine andterbutaline groups, respectively.

Nifedipine (n 45): 10 mgsublingually. If contractionspersisted after 15 minutes, asecond dose of 10 mg was given,then 20 mg after 30 minutes to amaximum in the first hour of 40mg, then 60-120 mg orally perday for 3 days. No data onmaintenance therapy.Terbutaline (n 44): 0.25 mgintravenously followed bycontinuous intravenous infusionstarted at 5g/min andincreased by 5 g/min every 15minutes up to a maximum of 15g/min. Then the infusion wasmaintained at the same rate for2 h, after which the treatmentwas continued with subcutaneousinjection of 0.25 mg every 4hours for 24 hours. No data onmaintenance therapy.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................

Rayamahji,40

2003Nepal Inclusion: women with singleton or twin

pregnancy in preterm labor (uterinecontractions at least 1 every 10 minutes,with even minimal cervical changes) andintact membranes.Exclusion: premature rupture ofmembranes, advanced labor,preeclampsia, eclampsia, cardiac disease,thyroid disorder, antepartum hemorrhage,polyhydramnios, chorioamnionitis, severefetal growth restriction, fetal death,oligoamnios, fetal anomalies incompatiblewith life.

28-36; 39% had a cervical dilatation lessthan 1.5 cm and 61% had 1.5-3 cm at trialentry.

Nifedipine (n 32): 10 mgsublingually. This dose wasrepeated every 20 minutes tomaximum of 40 mg during thefirst hour of treatment, then 10-20 mg orally every 6-8 hours forup to 7 days.Isoxsuprine (n 30): 0.08 mg/min intravenously increasing to amaximum of 0.24 mg/min, then10 mg orally every 8 hours for upto 7 days.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................

Cararach,41

2006Spain Inclusion: women with singleton pregnancy

in preterm labor (at least 2 uterinecontractions within a 10 minutes period

during 60 minutes) and intact membranes.Exclusion: cervical dilatation greater than 5cm, polyhydramnios, fetal anomalies, fetaldistress, intrauterine infection, fetal growthrestriction, contraindication for the use ofbetamimetic drugs, and previous treatmentwith tocolytics in current pregnancy.

22-35; mean Bishop score at trial entry was2.7 1.8 and 2.9 1.9 for nifedipine andritodrine groups, respectively.

Nifedipine (n 40): 30 mg (20mg orally and 10 mgsublingually), then 20 mg orally

every 6 hours for 48 hours. Therewas no maintenance therapy.Ritodrine (n 40): 100g/minintravenously increasing by 50g/min every 20 min to amaximum of 350g/min for 48hours followed by 10 mg orallyevery 6 hours until discharge.There was no maintenancetherapy.

Alternate regimenand indomethacin

................................................................................................................................................................................................................................................................................................................................................................................





8/20

lysis were reported as exclusion criteria inthe great majority of included studies.

The gestational age at inclusion varied

from 20 to 36 weeks. The minimum ges-tational age at trial entry ranged from 20

to 28 weeks, and the maximum rangedfrom 33 to 36 weeks.Most trialsincludedwomen between 24 and 34 weeks gesta-

tion. Mean gestational age at each trialsentry varied from 29.1 to 32.4 weeks.

For studies evaluating acute tocolysis,nifedipine dosing regimens were similaracross the trials with loading doses of

10-30 mg administered orally or sublin-gually, followed by 10-20 mg orally every

TABLE 1


First author,





Alternative

tocolytic therapy

Laohapojanart,42

2007

Thailand Inclusion: women with singleton pregnancy

in preterm labor (

4 uterine contractionsper 20 minutes with cervical dilatation of1-4 cm and/or documented changing incervical effacement) irrespective of themembranes status.Exclusion: multiple pregnancy, heart orrenal disease, hypertension,chorioamnionitis, placental abruption,placenta previa, preeclampsia, diabetes,and thyrotoxicosis.


effacement at trial entry was 1.4

0.7 and1.4 0.6 cm and 59 17% and64 14% for nifedipine and terbutalinegroups, respectively.

Nifedipine (n 20): 10 mg orally.

If contractions persisted, 10 mgorally every 4 hours to amaximum in the first hour of 40mg. Then 20 mg every 4 hoursfor 3 days. No data onmaintenance therapy.Terbutaline (n 20): 10g/minintravenously followed bycontinuous intravenous infusionwith an increment 5g/minevery 10 minutes until 25 g/minwas reached, then subcutaneousinjection of 0.25 mg every 4hours for 24 hours. No data onmaintenance therapy.

Alternate regimen

and indomethacin

................................................................................................................................................................................................................................................................................................................................................................................

Mawaldi,43 2008 Saudi Arabia Inclusion: women with singleton or twinpregnancy in preterm labor (1-3 uterinecontractions within a 10 minute periodduring 60 minutes with cervical dilatationof 0-3 cm in primigravidas and 1-3 cm inmultigravidas and cervical effacement50%) and intact membranes.Exclusion: women carrying more than 2fetuses, major antepartum hemorrhage,premature rupture of membranes, majormedical disorder, temperature higher than37.5C, blood pressure less than 90/50mm Hg, compromised fetus, and lethalfetal anomalies


Nifedipine (n 79): 30 mg orallyfollowed by 20 mg after 90 min. Ifcontractions persisted, 20 mgorally every 8 h for 48 h. No dataon maintenance therapy.Terbutaline (n 95): 0.25 mgsubcutaneous repeated every 45minutes if the uterine contractionspersisted. No data onmaintenance therapy.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................

Van De Water,44

2008TheNetherlands

Inclusion: women with singleton pregnancyin preterm labor (1 uterine contractionevery 10 minutes for at least 60 minutes)irrespective of the membranes status.Exclusion: multiple pregnancy, intrauterineinfection, fetal congenital defects, placental

abruption, diabetes mellitus, cardiovasculardiseases, hyperthyroidism, andpreeclampsia.


Nifedipine (n 48): 20 mg orally.If contractions persisted after 30minutes, a second dose of 20 mgwas given, then 90-120 mg orallyper day for 48 hours, thereafter90 mg/day for 7 days.

Ritodrine (n 43): 200g/minintravenously increasing by 50g/min every 30 minutes untilquiescence was achieved for 48hours, then 80 mg orally every 8hours for a total duration of 7days.

Indomethacin

................................................................................................................................................................................................................................................................................................................................................................................

Nifedipine compared with magnesium sulfate................................................................................................................................................................................................................................................................................................................................................................................

Glock,45 1993 United States Inclusion: primigravid women withsingleton pregnancy in preterm labor(regular uterine contractions less than 10minutes apart with documented cervicalchange or cervical dilatation 2 cm orgreater) and intact membranes.Exclusion: multiple pregnancy, prematurerupture of membranes, known tocolytic

drug exposure during the study pregnancy,diabetes, hyperthyroidism, cardiac disease,preeclampsia, abruptio placentae,chorioamnionitis, hydramnios, renal failure,cervical dilatation 4 cm or greater, fetaldistress, severe intrauterine growthrestriction, and fetal anomaly incompatiblewith life

20-34; mean cervical dilatation andeffacement, and uterine contractionfrequency at trial entry was 2.0 0.8 and2.0 0.9 cm, 43 7% and 44 8%, and4.4 1.0 and 4.4 1.1 for nifedipine andmagnesium sulfate groups, respectively.

Nifedipine (n 39): 10 mgsublingually. If contractionspersisted, this dose was repeatedevery 20 minutes to maximum of40 mg during the first hour oftreatment. Once contractionsceased, 20 mg orally every 4hours for 48 hours, then 10 mg

orally every 8 hours until 34weeks.Magnesium sulfate (n 41): 6 gbolus, then 2 g/h, increased tomaximum of 4 g/h untilquiescence for 24 hours, thenweaned at 0.5 g every 4-6 hours,thereafter terbutaline 5 mg orallyevery 6 hours until 34 weeks.

Intravenousritodrine

................................................................................................................................................................................................................................................................................................................................................................................





9/20

4-8 hours for 24-72 hours. Twelve stud-ies used a 30 mg loading dose of nifedi-pine,30,31,34,39,40,42,45,47-51 9 used 10mg,29,32,33,35,36,38,41,43,46 and 1 each used5 mg37 and 20 mg.44 Twelve stud-ies30,34,37,39,40,42,44,45,47-50 repeated a

loading dose every 15-20 minutes to amaximumof40mgduringthefirsthourof

treatment if contractions persisted. Eleventrials31-35,37,38,44-46,49 reported mainte-nance therapy, 929,30,36,39,42,43,47,48,51

did not, and 340,41,50 stated there wasno maintenance therapy. Seven stud-ies33-35,37,38,45,46 used oral maintenance

therapy in both treatment groups until34-37 weeks gestation. All but 3 tri-

als32,36,38 reported the total duration oftreatment.

All studies evaluating maintenancetocolysis52-54 used nifedipine 20 mgorally every 4-6 hours until 37 weeksgestation or delivery, whichever oc-

curred first. Use of alternative toco-lytic therapy was explicitly mentioned

TABLE 1


First author,





Alternative

tocolytic therapy

Floyd,46 1995 United States Inclusion: women with singleton pregnancy

in preterm labor (at least 1 uterinecontractions every 10 minutes withdocumented cervical change or cervicaldilatation 2 cm) and intact membranes.Exclusion: Previous tocolytic therapy incurrent pregnancy, allergy to either studydrug, medical or obstetric complicationsprecluding treatment with either drug, andchorioamnionitis.


effacement and number of uterinecontractions per hour at trial entry was 1.8 1.0 and 1.5 1.2 cm, 46 27% and 51 21%, and 18 6 and 17 0.6 fornifedipine and magnesium sulfate groups,respectively.

Nifedipine (n 50): 30 mg orally

followed by 20 mg every 8 hoursuntil quiescence, then 20 mgorally every 8 h until 37 weeks ordelivery, whichever occurred first.Magnesium sulfate (n 40): 4-gbolus then 4-6 g/h continued for6 hours after quiescence, thenmagnesium gluconate 2 g orallyevery 4 hours until 37 weeks ordelivery, whichever occurred first.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................

Haghighi,47

1999Iran Inclusion: women with singleton pregnancy

in preterm labor (regular uterinecontractions less than 10 minutes apart)and intact membranes.Exclusion: known tocolytic drug exposureduring the study pregnancy, diabetes,hyperthyroidism, cardiac disease,preeclampsia, placental abruption,chorioamnionitis, polyhydramnios, renalfailure, cervical dilatation 4 cm or greater,fetal distress, severe intrauterine growthrestriction, and fetal anomaly incompatiblewith life.


Nifedipine (n 34): 10 mgsublingually. If contractionspersisted, this dose was repeatedevery 20 minutes to maximum of40 mg during the first hour oftreatment. Once contractionsceased, 20 mg orally every 6hours during the first 24 hoursand 20 mg every 8 hours thesecond day. No data onmaintenance therapy.Magnesium sulfate (n 40): 6 gbolus, then 2 g/h, increased tomaximum of 4 g/h until quiescencefor up to 48 hours. Then terbutaline5 mg orally every 6 h. No data onmaintenance therapy.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................

Taherian,48

2007Iran Inclusion: women with singleton pregnancy

in preterm labor (4 uterine contractionsper 10 minutes with duration of at least 30seconds and progressive cervical dilatationand effacement) and intact membranes.Exclusion: taking other tocolytic agents,cervical dilatation 5 cm or greater orobstetrical contraindications for tocolysis

such as severe preeclampsia, lethal fetalanomalies, chorioamnionitis, significantantepartum hemorrhage, and maternalcardiac or liver diseases.

26-36; mean cervical dilatation andeffacement at trial entry was 1.5 1.1 and1.6 1.1 cm and 53 25% and54 22% for nifedipine and magnesiumsulfate groups, respectively.

Nifedipine (n 57): 10 mg orallyevery 20 minutes (maximal doseof 40 mg in first hour). Oncecontractions ceased, 10-20 mgorally every 6 hours. No data onduration of treatment ormaintenance therapy.Magnesium sulfate (n 63): 4 g

bolus, then 2-3 g/h. No data onduration of treatment ormaintenance therapy.

Ritodrine orindomethacin(18% in nifedipinegroup and 13% inmagnesiumsulfate group)

................................................................................................................................................................................................................................................................................................................................................................................

Lyell,49 2007 United States Inclusion: women with singleton or twinpregnancy in preterm labor (2 uterinecontractions every 10 minutes with cervicalchange or cervical dilatation 2 cm and80% effacement) irrespective of themembranes status.Exclusion: placental abruption, placenta previa,nonreassuring fetal status, intrauterine growthrestriction, chorioamnionitis, and maternalmedical disease.

24-33; mean cervical dilatation andeffacement and uterine contractionfrequency at trial entry was 1.8 0.9 and1.9 1.0 cm, 2.2 1.2 and 2.2 1.1 cm,and 3.5 1.2 and 3.6 1.5 for nifedipineand magnesium sulfate groups, respectively.

Nifedipine (n 100): 10 mgsublingually every 20 minutes forthree doses total, followed by 20mg orally every 4-6 hours until atleast 12 hours of uterinequiescence occurred within thefirst 48 hours. Maintenancetherapy with nifedipine in 42% ofwomen.Magnesium sulfate (n 92): 4 gbolus, then 2 g/h, increased tomaximum of 4 g/h, until at least12 hours of uterine quiescence

occurred within the first 48 hours.Maintenance therapy withnifedipine in 38% of women.

Permitted butunspecified

................................................................................................................................................................................................................................................................................................................................................................................





10/20

in 18 studies29-36,41,42,44,45,48,49,51-54

Twenty trials30,33-40,42-45,48-54 reported

administration of antenatal cortico-

steroids for all women enrolled. In theremaining 6 trials,29,31,32,41,46,47 ante-

natal corticosteroids use was not

reported.

Table 2 shows quality assessment of

included studies. All but 5 stud-ies37,40,45,47,53 had an adequate genera-

tion of allocation sequence.Sixteen stud-

ies30-32,34-36,39,41,43-46,49,51,52,54 reported

adequate concealment of allocation. For

all of the 23 studies evaluating acute toco-lysis, blinding of the intervention was not

TABLE 1


First author,





Alternative

tocolytic therapy

Nifedipine compared with atosiban................................................................................................................................................................................................................................................................................................................................................................................

Kashanian,50

2005Iran Inclusion: women with singleton or twin

pregnancy in preterm labor (4 uterinecontractions in 20 minutes or 8 in 60minutes and cervical dilatation andeffacement1 cm and 50%,respectively) and intact membranes.Exclusion: premature rupture ofmembranes, vaginal bleeding, fetal death,fetal distress, fetal growth restriction,history of trauma, cervical dilatationgreater than 3 cm, maternal systemicdisorders, uterine anomaly, and bloodpressure less than 90/50 mm Hg.


Nifedipine (n 40): 10 mgsublingually every 20 minutes to amaximum in the first hour of 40mg. Then 20 mg orally every 6hours for the first 24 hours, thenevery 8 h for the following 24 h,thereafter 10 mg orally every 8hours for the last 24 hours. Therewas no maintenance therapy.Atosiban (n 40): 300g/minintravenously, continued for amaximum of 12 hours, or 6 hoursafter contractions were inhibited.There was no maintenancetherapy.

Not reported

................................................................................................................................................................................................................................................................................................................................................................................

Nifedipine compared with nitric oxide donors................................................................................................................................................................................................................................................................................................................................................................................

Amorim,51 2009 Brazil Inclusion: women with singleton pregnancyin preterm labor (4 uterine contractionsin 30 minutes with duration of at least 30seconds and cervical changes) and intactmembranes.Exclusion: premature rupture ofmembranes, preeclampsia, diabetes,placental abruption, fetal malformation,and previous treatment with tocolytics.

24-34; median (range) cervical dilatation andnumber of uterine contractions per 10minutes at trial entry was 2 (24) cm and 3(24) cm, respectively.

Nifedipine (n 24): 10 mgsublingually repeated after 30minutes, then 20 mg orally every6 hours for at least 24 hours. Nodata on maintenance therapy.Nitroglycerin (n 26): 10 mgtransdermal patch. If contractionspersisted after 6 hours, a secondpatch of 10 mg was placed(maximum dose of 20 mg per 24hours). No data on maintenancetherapy.

Terbutaline

................................................................................................................................................................................................................................................................................................................................................................................

Maintenance tocolysis................................................................................................................................................................................................................................................................................................................................................................................

Nifedipine compared with placebo/no treatment................................................................................................................................................................................................................................................................................................................................................................................

Carr,52 1999 United States Inclusion: women with singleton pregnancywho had been in active preterm labor (6

uterine contractions per hour for 2 hours,cervical dilatation of 2-4 cm, 75%effacement, or evidence of cervicalchange) successfully arrested withintravenous magnesium sulfate.Exclusion: cervical dilatation 5 cm orgreater, obstetric contraindications totocolysis (severe preeclampsia, lethal fetalanomalies, chorioamnionitis, significantantepartum hemorrhage), or maternalcardiac or liver disease.

24-33; median (range) cervical dilatation andeffacement at trial entry was 2 (14) cm and

50% (0100%), respectively

Nifedipine (n 37): 20 mg orallyevery 4-6 hours until 37 weeks. It

was initiated after discontinuationof acute intravenous tocolysis.Control (n 37): no treatment

Magnesiumsulfate or

terbutaline

................................................................................................................................................................................................................................................................................................................................................................................

Sayin,53 2004 Turkey Inclusion: women with singleton or twinpregnancy and intact membranes who hadbeen in active preterm labor (4 uterinecontractions per hour with evidence ofcervical change on serial digitalexaminations) successfully arrested with

intravenous ritodrine and verapamil.Exclusion: cervical dilatation 4 cm orgreater, triple or higher-order pregnancy,intrauterine infection, fetal congenitalanomalies, fetal growth restriction, and anycontraindication to betamimetics such asdiabetes mellitus, cardiac disease, orhyperthyroidism.

Not stated; mean Bishop score at trial entrywas 2.4 0.8 and 2.6 0.8 for nifedipineand no treatment groups, respectively.

Nifedipine (n 37): 20 mg orallyevery 6 hours until 37 weeks. Itwas initiated after discontinuationof acute intravenous tocolysis.Control (n 36): no treatment

Ritodrine andverapamil

................................................................................................................................................................................................................................................................................................................................................................................





11/20

performed and blinding assessment of

outcomes wasnot reported. Only 1 study54

evaluating maintenance tocolysis wasdouble blinded. Eighteen trials reportedthe assessment of primary outcomesin 95% or more of the randomizedwomen.29-37,39,41,43,44,46,47,49,53,54 Thirteentrials (50%) had a modified Jadad score of6 or more.30-32,34-36,39,41,43,44,46,49,54

Acute tocolysisNifedipine vs

2-adrenergic-

receptor agonists

This subgroup analysis included datafrom 16 trials with a total of 1278women. Compared with women receiv-ing 2-adrenergic-receptor agonists,those using nifedipine had a statisticallysignificant reduction in the risk of deliv-ery within 7 days of initiation of treat-ment (37.1% vs 45.0%; RR, 0.82; 95%CI, 0.700.97; I2 0.0%) (Table 3).Twelve women with preterm labor needto be treated (NNT) with nifedipinerather than with 2-adrenergic-receptor

agonists to prevent 1 case of deliverywithin 7 days of treatment (95% CI,763).

Nifedipine was also associated with adecreased risk of delivery before 34weeks gestation (48.4% vs 62.2%; RR,0.77; 95% CI, 0.66 0.91; I2 0.0%;NNT for benefit, 7; 95% CI, 524), ma-ternal adverse events (19.5% vs 56.1%;RR, 0.31; 95% CI, 0.18 0.54; I2 86.0%; NNT for benefit, 3; 95% CI, 25),and discontinuation of treatment be-

cause of adverse events (0.6% vs 8.8%;RR, 0.14; 95% CI, 0.060.31;I2 0.0%;

NNT for benefit, 13; 95% CI, 1221). A

significant increase in gestational age atbirth (WMD, 0.7 weeks; 95% CI, 0.3

1.2; I20.0%), interval between trial en-

try and delivery (WMD, 5.8 days; 95%

CI, 1.410.2; I2 63.0%), and birth-

weight (WMD, 178.8 g; 95% CI, 84.1

273.6;I2 31.0%) was also shown. No

differences were seen in the risk of deliv-

ery within 48 hours of initiation of treat-

ment or before 37 weeks gestation.

Treatment with nifedipine was associ-

ated with an overall reduction in respira-

tory distress syndrome (10.9% vs 16.8%;

RR, 0.63; 95% CI, 0.46 0.86;I2 0.0%;

NNT for benefit, 16; 95% CI, 1151), ne-

crotizing enterocolitis (0.4% vs 3.4%;

RR, 0.21; 95% CI, 0.050.94;I2 0.0%;

NNT for benefit, 37; 95% CI, 31514),

intraventricular hemorrhage (8.5% vs

16.5%; RR, 0.53; 95% CI, 0.340.84; I2

0.0%; NNT for benefit, 13; 95% CI,

9 42), neonatal jaundice (43.2% vs

60.6%;RR, 0.73; 95%CI, 0.570.93;I2


4 30), admission to the NICU (26.6%vs

34.3%;RR, 0.76; 95%CI, 0.620.93;I2


748), and NICU length of stay (WMD,

7.2 days; 95% CI, 11.2 to3.3;I2

0.0%). No statistically significant differ-

ences were seen in perinatal mortality,

fetal and neonatal death, neonatal sepsis,

Apgar score less than 7 at 5 minutes, ret-

inopathy of prematurity, neurodevelop-

mental delay at 2 years of age, and psy-

chosocial and motor function at 9-12years of age.

Nifedipinevs magnesium sulfate

Five trials contributed data that included556 women. There was no overall differ-ence between nifedipineand magnesiumsulfate for delivery within 48 hours oftreatment or before 34 or 37 weeks ges-tation, gestational age at birth, or in timefrom trial entry to delivery (Table 4). Ni-fedipine was associated with a significantreduction in maternal adverse events(23.5% vs 35.6%; RR, 0.63; 95% CI,0.480.82; I2 48.0%; NNT for benefit,8; 95% CI, 519). In addition, 1 trial49

reported that severe maternal adverse ef-fects were significantly less frequentamong women receiving nifedipine thanamong women receiving magnesiumsulfate (10.0% vs 21.7%; RR, 0.46; 95%CI, 0.230.93).

There were no significant differencesbetween the groups in the risk of majoradverse neonatal outcomes, although asignificant reduction was seen in the riskof admission to the NICU (37.3% vs51.9%; RR, 0.72; 95% CI, 0.530.97;

NNT for benefit, 7; 95% CI, 469) andNICU length of stay (WMD, 2.2 days;95%CI,3.4to1.1; I242.0%) in thenifedipine group compared with themagnesium sulfate group.

Nifedipinevs atosiban

This comparison included 1 trial50 in-volving only 40 women in each group.No difference was shown for the fre-quency of delivery within 48 hours of

treatment (25.0% vs 17.5%; RR, 1.43;95% CI, 0.603.38) or within 7 days

TABLE 1


First author,





Alternative

tocolytic therapy

Lyell,54 2008 United States Inclusion: women with singleton or twin

pregnancy and intact membranes who hadbeen in active preterm labor (uterinecontractions with cervical change)successfully arrested with intravenousmagnesium sulfate or oral nifedipine.Exclusion: placental abruption, placentaprevia, fetal anomaly incompatible with life,triple or higher-order multiple pregnancies,intrauterine infection, or a maternalmedical contraindication to ongoingtocolysis.

24-34; mean cervical dilatation and length

by digital examination at trial entry was2.0 0.9 and 2.5 0.9 cm and 2.2 1.2and 1.6 1.1 cm for nifedipine andmagnesium sulfate groups, respectively.

Nifedipine (n 33): 20 mg orally

every 6 hours until 37 weeks. Itwas initiated after discontinuationof acute intravenous tocolysis.Control (n 35): placebo

Magnesium

sulfate

................................................................................................................................................................................................................................................................................................................................................................................a Women receiving 2-agonists immediately before randomization (n 45) were excluded from analyses.

Conde-Agudelo. Nifedipinein the managementof preterm labor. Am J Obstet Gynecol 2011.




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13/20

use of 10 mg of nifedipine was associatedwith a significant reduction in the risk ofdelivery within 48 hours (RR, 0.72; 95%CI, 0.520.99) or 7 days (RR, 0.74; 95%CI, 0.590.93) of initiation of treatmentand before 34 weeks (RR, 0.77; 95 CI,0.620.95). No difference was seen forthe risk of delivery before 37 weeks ges-tation (RR, 0.98; 95% CI, 0.871.11).There were no significant differences

between the 30 mg loading dose of ni-fedipine and both 2-adrenergic-re-

ceptor agonists and magnesium sulfatein delivery within 48 hours or 7 days ofinitiation of treatmentand before 34 or37 weeks.

There were no significant differencesbetween nifedipine and magnesium sul-fate (either 4 g loading dose and mainte-nance dose of 2-4 g/h or 6 g loading doseand maintenance dose of 2-4 g/h of mag-nesium sulfate) for any of the outcomes

evaluated. Additional sensitivity andsubgroup analyses for the comparison of

nifedipine with 2-adrenergic-receptoragonists and magnesium sulfate in acutetocolysis showed that estimates of effectsizes variedto some degreedepending onthe definition of preterm labor used,judgment of the presence of true pretermlabor, dosage of magnesiumsulfate used,and use of maintenance therapy, but theCIs were wide and tests for interactionwerenot statistically significant (datanot

shown). In addition, univariable meta-regression analyses indicated no associa-

TABLE 3

Acute tocolysis: nifedipine compared with 2-adrenergic-receptor agonists

Outcome Number of trials

Number of events/totalnumber or total number

Relative risk or meandifference (95% CI) I2 (%)Nifedipine 2-Agonists

Pregnancy outcomes...................................................................................................................... ........................................ .........................................................................................................................................................................................................

Delivery within 48 hours of treatment 1329,30,33-36,38-44 114/535 126/524 0.84 (0.681.05) 35...................................................................................................................... ........................................ .........................................................................................................................................................................................................

Delivery within 7 days of treatment 1030,33-35,38-42,44 153/410 171/380 0.82 (0.700.97) 0...................................................................................................................... ................................ .................................................................................................................................................................................................................

Preterm birth 34 weeks gestation 534,35,38,39,44 121/250 140/225 0.77 (0.660.91) 0...................................................................................................................... ........................................ .........................................................................................................................................................................................................

Preterm birth 37 weeks gestation 930,33,34,36,38-42 214/356 206/336 0.97 (0.871.08) 3...................................................................................................................... .................................................... .............................................................................................................................................................................................

Pregnancy prolongation, d 929,31,32,34,36,37,39-41 360 350 5.8 (1.410.2) 63...................................................................................................................... ................................. ................................................................................................................................................................................................................

Gestational age at birth, wks 832,34,35,38-42 319 291 0.7 (0.31.2) 0...................................................................................................................... .............................................. ...................................................................................................................................................................................................

Maternal adverse drug reaction 929,30,33,34,39,41-44 81/415 235/419 0.31 (0.180.54) 86...................................................................................................................... .................... .............................................................................................................................................................................................................................

Discontinuation of treatment becauseof adverse effects

1330-41,44 3/522 44/498 0.14 (0.060.31) 0

................................................................................................................................................................................................................................................................................................................................................................................

Perinatal and neonatal outcomes...................................................................................................................... ........................................ .........................................................................................................................................................................................................

Birthweight, g 1029,32,34-36,38-42 365 335 178.8 (84.1273.6) 31...................................................................................................................... .............. ...................................................................................................................................................................................................................................

Apgar score 7 at 5 minutes 233,34 6/137 10/130 0.6 (0.21.5) 0...................................................................................................................... ................................. ................................................................................................................................................................................................................

Respiratory distress syndrome 1330-39,41,42,44 56/516 81/483 0.63 (0.460.86) 0...................................................................................................................... ................................ .................................................................................................................................................................................................................

Necrotizing enterocolitis 532,34,39,41,44 1/250 8/235 0.21 (0.050.94) 0...................................................................................................................... ....................................... ..........................................................................................................................................................................................................

Intraventricular hemorrhage 630,34,38,39,42,44 23/271 41/249 0.53 (0.340.84) 0...................................................................................................................... .............. ...................................................................................................................................................................................................................................

Retinopathy of prematurity 234,44 0/143 5/133 0.15 (0.021.28) 0...................................................................................................................... .............. ...................................................................................................................................................................................................................................

Neonatal jaundice 232,34 51/118 66/109 0.73 (0.570.93) 48...................................................................................................................... ....................................... ..........................................................................................................................................................................................................

Neonatal sepsis 631,32,34,39,41,44 27/280 37/267 0.70 (0.451.09) 0...................................................................................................................... .................................. ...............................................................................................................................................................................................................

Perinatal mortality 1129-34,36,38-41 12/415 11/396 1.02 (0.492.14) 0...................................................................................................................... .................................. ...............................................................................................................................................................................................................

Fetal death 1129-34,36,38-41 1/415 1/396 1.00 (0.146.96) 0...................................................................................................................... .................................. ...............................................................................................................................................................................................................

Neonatal death 1429-36,38-42,44 15/518 13/483 1.03 (0.532.02) 0...................................................................................................................... ................................. ................................................................................................................................................................................................................

Admission to NICU 931-36,39,42,44 97/364 116/338 0.76 (0.620.93) 0...................................................................................................................... .............. ...................................................................................................................................................................................................................................

NICU stay, d 232,44 71 62 7.2 (11.2 to 3.3) 0...................................................................................................................... .................................................................................................................................................................................................................................................

Any mental retardation at 2 y of age 144 9/28 12/35 0.94 (0.461.90) NA ...................................................................................................................... .................................................................................................................................................................................................................................................

Behavioral-emotional functioning scoreat age 9-12 y

134 45 51 1.5 (4.7 to 1.8) NA

...................................................................................................................... .................................................................................................................................................................................................................................................

Quali ty of life score at age 9-12 y 134 44 50 0.3 (0.7 to 0.1) NA ................................................................................................................................................................................................................................................................................................................................................................................

CI, confidence interval;NA, not applicable;NICU, neonatal intensive care unit.

Conde-Agudelo.Nifedipine in the managementof preterm labor. Am J Obstet Gynecol 2011.



nifedipine in management preterm labor

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