tocolytics for preterm labor: a systematic review

Robinson HP. Correlation between nuchal thickness and abnormalkaryotype in first trimester fetuses. Med J Aust 1996;165:365–8.

26. Pajkrt E, Mol BWJ, Van Lith JMM, Bleker OP, Bilardo CM.Screening for Down syndrome by fetal nuchal translucency mea-surement in a high-risk population. Ultrasound Obstet Gynecol1998;12:156–62.

27. Scott F, Boogert A, Sinosich M, Anderson J. Establishment andapplication of a normal range for nuchal translucency across thefirst trimester. Prenat Diagn 1996;16:629–34.

28. Zimmerman R, Hucha A, Salvodelli G, Blinkert F, Achermann,Grudzinskas JG. Serum parameters and nuchal translucency infirst trimester screening for fetal chromosomal abnormalities. Br JObstet Gynaecol 1996;103:1009–14.

29. Biagiotti R, Periti E, Brizzi L, Vanzi E, Cariatti E. Comparisonbetween two methods for standardization for gestational agedifferences in fetal nuchal translucency measurement in first-trimester screening for trisomy 21. Ultrasound Obstet Gynecol1997;9:248–52.

30. Martinez JM, Borrell A, Antolin E, Puerto B, Casals E, Ojuel J, et al.Combining nuchal translucency with umbilical Doppler velocim-etry for detecting fetal trisomies in the first trimester of pregnancy.Br J Obstet Gynaecol 1997;104:11–4.

31. Borrell A, Costa D, Martinez JM, Delgado RD, Farguell T, FortunyA. Criteria for fetal nuchal thickness cutoff: A re-evaluation. PrenatDiagn 1997;17:23–9.

32. Orlandi F, Daminai G, Hallahan TW, Krantz DA, Macri JN.First-trimester screening for fetal aneuploidy: Biochemistry andnuchal translucency. Ultrasound Obstet Gynecol 1997;10:381–6.

33. Hafner E, Schuchter K, Liebhart E, Phillipp K. Results of routinefetal nuchal translucency measurement at weeks 10–13 in 4223unselected pregnant women. Prenat Diagn 1998;18:29–34.

34. Schuchter K, Wald NJ, Hacksaw AK, Hafner E, Liebhardt E. Thedistribution of nuchal translucency in 10–13 weeks pregnancy.Prenat Diagn 1998;18:281–6.

35. Snijders RJ, Noble P, Sebire NJ, Souka A, Nicolaides KH. UKmulticentre project on the assessment of risk of trisomy 21 bymaternal age and fetal nuchal-translucency thickness at 10–14weeks gestation. Lancet 1998;351:343–6.

36. Haddow JE. Antenatal screening for Down syndrome: Where arewe and where next? [editorial]. Lancet 1998;352:366–7.

Address reprint requests to:Ben W. J. Mol, MDDepartment of Clinical Epidemiology and BiostatisticsAcademic Medical CenterUniversity of Amsterdam, PO Box 22700Amsterdam, 1100 DEThe NetherlandsE-mail: [email protected]

Received December 14, 1998.Received in revised form June 3, 1999.Accepted June 10, 1999.

Copyright © 1999 by The American College of Obstetricians andGynecologists. Published by Elsevier Science Inc.

Tocolytics for preterm labor:A systematic review

Kristen Gyetvai, Mary E. Hannah, MDCM,Ellen D. Hodnett, PhD, and Arne Ohlsson, MD

Objective: To examine the effectiveness of any tocolyticcompared with a placebo or no tocolytic for preterm labor.

Data Sources: We checked MEDLINE (1966–1998) and theCochrane Controlled Trials Register for articles, using thesearch terms “randomized controlled trial” (RCT), “pretermlabor,” “tocolysis,” “betamimetics,” “ritodrine,” “terbuta-line,” “hexaprenaline,” “isoxuprine,” “prostaglandin syn-thetase inhibitors,” “indomethacin,” “sulindac,” “calciumchannel blockers,” “nifedipine,” “oxytocin receptor block-ers,” “atosiban,” “nitroglceride,” and “magnesium sulfate.”

Methods of Study Selection: We included all RCTs thatcompared effect of a tocolytic with a placebo or no tocolyticin women in preterm labor, and reported perinatal, neonatal,or maternal outcomes. Studies were excluded if loss tofollow-up exceeded 20% of those originally enrolled, or ifdata were not reported on a per-patient-treated basis. Eigh-teen of 76 articles retrieved met the inclusion criteria.

Tabulation, Integration, and Results: Two authors inde-pendently reviewed the articles and abstracted the data.Discrepancies were resolved by consensus. Meta-analyses(odds ratio [OR] and 95% confidence interval [CI]) were donefor each outcome for all trials and for specific types oftocolytic therapy when possible. Tocolytics decreased therisk of delivery within 7 days (OR 0.60, 95% CI 0.38, 0.95).Betamimetics, indomethacin, atosiban, and ethanol, but notmagnesium sulfate, were associated with significant prolon-gations in pregnancy. Tocolytics were not associated withimproved perinatal outcomes. Maternal side effects signifi-cantly associated with tocolytic use were palpitations, nau-sea, tremor, chorioamnionitis, hyperglycemia, hypokalemia,and need to discontinue treatment.

Conclusion: Although tocolytics prolong pregnancy, theyhave not been shown to improve perinatal or neonataloutcomes and have adverse effects on women in pretermlabor. (Obstet Gynecol 1999;94:869–77. © 1999 by TheAmerican College of Obstetricians and Gynecologists.)

From the Department of Obstetrics and Gynaecology, Sunnybrook andWomen’s College Health Sciences Centre; Faculty of Nursing, Depart-ment of Paediatrics, Mount Sinai Hospital; and the Maternal and InfantReproductive Health Research Unit at the Centre for Research inWomen’s Health, University of Toronto, Toronto, Ontario, Canada.

Kristen Gyetvai was supported by a Medical Research Council ofCanada Summer Studentship.

869VOL. 94, NO. 5, PART 2, NOVEMBER 1999 0029-7844/99/$20.00PII S0029-7844(99)00329-4

Preterm birth significantly contributes to infant morbid-ity and mortality,1 and although treatment of it hasreceived considerable attention, the rate of pretermbirth has not declined in the past 15 years.2 Mostpreterm births result from preterm labor.3 Tocolytics,drugs that inhibit uterine contractions, are used fre-quently in clinical practice despite limited evidence ofbenefit.4

The purpose of this review was to evaluate theeffectiveness of any tocolytic compared with a placeboor no treatment for preterm labor on prolongation ofpregnancy, perinatal outcomes, and maternal side ef-fects.

Sources

We searched MEDLINE and the Cochrane Library forstudies involving human subjects, published in Englishbetween 1966 and 1998, using the search terms “ran-domized controlled trial” (RCT), “preterm labor,” “to-colysis,” “betamimetics,” “ritodrine,” “terbutaline,”“hexaprenaline,” “isoxuprine,” “prostaglandin syn-thetase inhibitors,” “indomethacin,” “sulindac,” “calci-um channel blockers,” “nifedipine,” “oxytocin receptorblockers,” “atosiban,” “nitroglyceride,” and “magne-sium sulfate.”

Study Selection

We included all RCTs that compared a tocolytic with aplacebo or no tocolytic for women in preterm labor andreported on perinatal or maternal outcomes, or both.Studies were excluded if loss to follow-up exceeded20% of those originally enrolled, or if data were notreported on a per-patient-treated basis. All articles werereviewed and data abstracted independently by two ofthe authors (KG, MEH). Discrepancies were resolved byconsensus. The method of randomization and use ofplacebo controls were evaluated in each study.5

Baseline information and data on cointerventions (eg,antenatal corticosteroids, antibiotics) were analyzed de-scriptively. Heterogeneity among trials was assessedusing simple x2 analysis. Meta-analyses of data for eachoutcome were done for all trials and for specific types oftocolytic therapy when possible. A fixed-effects model(Peto) was used if there was no significant heterogene-ity among trials. Otherwise, a random-effects model(DerSimonian and Laird) was used. A fixed-effectsmodel ignores between-study variation and gives nar-rower confidence intervals than a random-effectsmodel, which incorporates between-study variation inestimating the confidence interval (CI). For each meta-analysis, an odds ratio (OR) and 95% CI were calcu-lated. P , .05 was considered statistically significant.

Results

We retrieved 76 articles from the literature search. Ofthose, 58 were excluded for the following reasons: dualpublication (n 5 2),6,7 data not reported by enrollee butby episode of preterm labor (n 5 1),8 use of tocolytics totreat other conditions (n 5 7) (Kulier R, GulmezogluAM, Hofmeyr GJ. Betamimetics for fetal distress: Arandomized trial. Proceedings of the Fourteenth Con-ference on Priorities in Perinatal Care in South Africa1995;190–3; Renaud R, Brettes P, Irrmann M, Boog G,Schumacher J, Gandar R. A double-blind crossover trialto assess the effect of ritodrine on uterine blood flow innormal and pathologic pregnancies. A preliminary re-port. Proceedings of International Symposium on theTreatment of Fetal Risks; Baden, Austria 1972;53–4),9–13

loss to follow-up exceeding 20% (n 5 5),14–18 tocolyticsnot evaluated for treatment but prevention or recur-rence of preterm labor (n 5 12) (Carlan S, Jones M,Schorr S, McNeill T, Rawji H, Clark K. Oral sulindac toprevent recurrence of preterm labor [abstract]. Am JObstet Gynecol 1994;170:381; Sanchez-Ramos L, Valen-zuela G, Romero R, Silver H, Koltun W, Millar L, et al.A double-blind placebo-controlled trial of oxytocin re-ceptor antagonist (antocin) maintenance therapy in pa-tients with preterm labor [abstract]. Am J Obstet Gy-necol 1997;176:S30),19–28 assignment not clearly random(n 5 5) (Sivasamboo R. Premature labour. Proceedingsof the International Symposium on the Treatment ofFetal Risks; Baden Austria 1972;16–20),29–32 tocolyticnot evaluated (n 5 22) (McCaul JF, Perry KG, MartinRW, Morrison JC. Treatment of idiopathic pretermrupture of membranes or labor with adjunctive ampi-cillin [abstract]. Am J Obstet Gynecol 1991;164:376;Blanco J, Iams J, Artal R, Baker D, Hibbard J, McGregorJ, et al. Multicenter double-blind prospective randomtrial of ceftizoxime vs. placebo in women with pretermpremature ruptured membranes (PPROM) [abstract].Am J Obstet Gynecol 1993;168:378),33–52 study being areview article (n 5 1),53 or study not reporting anyuseable outcomes (n 5 3) (Cavalle-Garrido T, Panter K,Smallhorn JF, Seaward G, Farine D. A RCT of indo-methacin for preterm labor: Effects on fetal heart andductus arteriosus [abstract]. Am J Obstet Gynecol 1997;176:S46).54,55

The characteristics of the remaining 17 studies (18articles) are listed in Table 1 (Sibai BM, Romero R,Sanchez-Ramos L, Valenzuela G, Veille JC, Tabor B, etal. A double-blind placebo-controlled trial of an oxyto-cin-receptor antagonist (antocin) in the treatment ofpreterm labor [abstract]. Am J Obstet Gynecol 1997;176:S2; Silver H, Valenzuela G, Sanchez-Ramos L, RomeroR, Sibai B, Goodwin T, et al. Maternal side effects andsafety of the oxytocin receptor antagonist antocin [ab-stract]. Am J Obstet Gynecol 1997;176:S45; Panter K,

870 Gyetvai et al Tocolytics for Preterm Labor Obstetrics & Gynecology

Hannah M, Farine D, Amankwah K, Jefferies A, Ohls-son A. The effect of indomethacin tocolysis of pretermlabor on perinatal outcome: A RCT [abstract]. Am JObstet Gynecol 1997;176:S46).56–70 One study was re-ported twice (Sibai BM, et al. Am J Obstet Gynecol

1997;176:S2; Silver H, et al. Am J Obstet Gynecol 1997;176:S45).

Three of 17 studies included women with rupturedmembranes.59,61,63 The definition of preterm labor var-ied between studies (Table 1). The most frequently

Table 1. Randomized Controlled Trials Included in the Review

TrialDefinition of preterm

labor Use of ACS & antibioticsMethod of

randomization

Tocolytic Control

Type Women Infants Type Women Infants

Adam,66 1966 Moderate–strong UC N/S N/S Isoxuprine 22 28 Placebo 22 24Zlatnik and Fuchs,67

1972Threatened preterm

laborN/S Sealed

envelopesEthanol 21 25 Control 21 23

Ingemarsson,68 1976 Painful/regular UC 1dilated & effacedcervix

N/S Centrallycontrolled

Terbutaline 15 15 Placebo 15 15

Spellacy et al,63 1979 Regular UC 1 changein cervix

N/S N/S Ritodrine 14 14 Placebo 15 15

Larsen et al,65 1980 Regular UC or UC 1change in cervix

N/S N/S Ritodrine 131 131 Placebo 45 45

Niebyl et al,*58 1980 Painful or regular UC1 change in cervix

N/S Sealedenvelopes

Indomethacin 15 16 Placebo 15 15

Cotton et al,62 1984 Regular UC 1 dilatedor effaced cervix,change in cervix, orSROM

14 women received ACS,evenly dividedbetween groups

N/S MgSO4

Terbutaline1619

1619

Control 19 19

Zuckerman et al,*57

1984Regular painful UC or

UC 1 dilated oreffaced cervix

N/S N/S Indomethacin 18 18 Placebo 18 18

Leveno et al,64 1986 Regular UC 1 dilatedcervix

N/S Sealedenvelopes

Ritodrine 54 56 Control 52 55

Garite et al,61 1987 Regular UC 1 SROM Neither used N/S Ritodrine 39 39 Control 40 40Cox et al,69 1990 Regular UC 1 dilated

cervixN/S Sealed

envelopesMgSO4 76 78 Control 80 89

CPLIG,59 1992 Regular UC or UC 1SROM, dilated oreffaced cervix, orchange in cervix

34.6% of ritodrine group& 36.0% of placebogroup received a fullcourse of ACS

Centrallycontrolled

Ritodrine 352 380 Placebo 356 391

Fox et al,60 1993 UC 1 change incervix

No ACS given Centrallycontrolled

MgSO4 45 45 Control 45 45

Goodwin et al,56

1994Regular UC 1 dilated

or effaced cervix orchange in cervix

N/S Centrallycontrolled

Atosiban 56 57 Placebo 56 57

Panter et al,† 1997 Regular UC 1 dilatedor effaced cervix

81% of indomethacingroup & 83% ofplacebo group receiveda complete course ofACS

Centrallycontrolled

Indomethacin 16 19 Placebo 18 20

Mittendorf et al,70

1997UC 1 dilated cervix N/S N/S MgSO4 29 30 Placebo 28 29

Sibai et al,*‡ 1997 UC 1 dilated oreffaced cervix orchange in cervix

N/S N/S Atosiban 246 246 Placebo 255 255

Silver et al,*§ 1997* UC 1 dilated oreffaced cervix orchange in cervix

N/S N/S Atosiban 250 250 Placebo 251 251

ACS 5 antenatal corticosteroids; UC 5 uterine contractions; N/S 5 not specified; MgSO4 5 magnesium sulfate; SROM 5 spontaneous ruptureof membranes; CPLIG 5 Canadian Preterm Labor Investigators Group.

* Denotes that over 20% of treatment or control group received a tocolytic in addition to the study drug.† Panter K, Hannah M, Farine D, Amankwah K, Jeffries A, Ohlsson A. The effect of indomethacin tocolysis of preterm labor on perinatal outcome:

A RCT [abstract]. Am J Obstet Gynecol 1997;176:S46.‡ Sibai BM, Romero R, Sanchez-Ramos L, Valenzuela G, Veille JC, Tabor B, et al. A double-blind, placebo-controlled trial of an oxytocin-receptor

antagonist (antocin) in the treatment of preterm labor [abstract]. Am J Obstet Gynecol 1997;176:S2.§ Silver H, Valenzuela G, Sanchez-Ramos L, Romero R, Sibai B, Goodwin T, et al. Maternal side effects and safety of the oxytocin receptor

antagonist antocin [abstract]. Am J Obstet Gynecol 1997;176:S45.

VOL. 94, NO. 5, PART 2, NOVEMBER 1999 Gyetvai et al Tocolytics for Preterm Labor 871

evaluated tocolytic was ritodrine (n 5 5).59,61,63–65 Theother tocolytics evaluated were isoxuprine (n 5 1),66

ethanol (n 5 1),67 terbutaline (n 5 2),62,68 magnesiumsulfate (n 5 4),60,62,69,70 indomethacin (n 5 3) (Panter K,

et al. Am J Obstet Gynecol 1997;176:S46),57,58 and atosi-ban (n 5 2) (Sibai BM, et al. Am J Obstet Gynecol1997;176:S2; Silver H, et al. Am J Obstet Gynecol 1997;176:S45).56 Four studies allowed more than 20% ofwomen enrolled in either arm to receive additionaltocolytics if study drugs failed (Sibai BM, et al. Am JObstet Gynecol 1997;176:S2; Silver H, et al. Am J ObstetGynecol 1997;176:S45).56–58 The methodologic quality ofthe studies varied (Table 1). Only five used a centrallycontrolled randomization method (Panter K, et al. Am JObstet Gynecol 1997;176:S46).56,59,60,68 Nine studies at-tempted masking (Panter K, et al. Am J Obstet Gynecol1997;176:S46; Sibai BM, et al. Am J Obstet Gynecol1997;176:S2; Silver H, et al. Am J Obstet Gynecol 1997;176:S45).56–59,63,68,70

Tocolytics were associated with significant decreasesin the likelihood of delivery within 24 hours (OR 0.47,95% CI 0.29, 0.77), 48 hours (OR 0.57, 95% CI 0.38, 0.83),and 7 days (OR 0.60, 95% CI 0.38, 0.95). For specifictypes of tocolytics, significant effects on prolongation ofpregnancy were found with betamimetics, indometha-cin, atosiban, and ethanol but not with magnesiumsulfate (Table 2). Tocolytics were not associated withsignificant reduction in births before 30 weeks’ gesta-tion (OR 1.33, 95% CI 0.53, 3.33), before 32 weeks’gestation (OR 0.81, 95% CI 0.61, 1.07), or before 37weeks’ gestation (OR 0.17, 95% CI 0.02, 1.62). Only onestudy of indomethacin showed a significant decrease inpreterm births (Table 2).

Tocolytics were not associated with significantly re-duced rates of perinatal death (OR 1.22, 95% CI 0.84,1.78), respiratory distress syndrome (RDS) (OR 0.82,95% CI 0.64, 1.07), intraventricular hemorrhage (OR0.73, 95% CI 0.46, 1.15), necrotizing enterocolitis (OR0.96, 95% CI 0.35, 2.65), patent ductus arteriosus (OR0.82, 95% CI 0.52, 1.30), neonatal sepsis (OR 1.09, 95% CI0.70, 1.68), seizures (OR 1.05, 95% CI 0.35, 3.14), hypo-glycemia (OR 1.36, 95% CI 0.87, 2.14), or birth weightunder 2500 g (OR 0.62, 95% CI 0.35, 1.09) when data forall tocolytics were combined. Indomethacin was associ-ated with a significant reduction in birth weight under2500 g in one study, and betamimetics were associatedwith a nonsignificant trend in that direction (Table 3).Betamimetics were also associated with a trend towardreduced RDS (Table 3). There were no other significantreductions in adverse perinatal or neonatal outcomesfor specific tocolytics.

Tocolytics increased risk of maternal palpitations (OR10.15, 95% CI 7.42, 13.87), nausea (OR 2.05, 95% CI 1.47,2.85), tremor (OR 8.30, 95% CI 5.79, 11.89), chorioam-nionitis (OR 2.88, 95% CI 1.13, 7.33), hyperglycemia (OR3.39, 95% CI 2.35, 4.90), hypokalemia (OR 6.43, 95% CI4.53, 9.14), and the need to discontinue treatment (OR

Table 2. Tocolytics Compared With Placebo or NoTreatment on Prolongation of Pregnancy andGestational Age at Delivery

Outcome bytocolytic

No. trialsincluded

No. womenwith outcome/

No. enrolled

OR 95% CITreatment Control

BetamimeticsDelivery within

24 h59,61,63,64,685 50/474 120/478 0.34 0.24, 0.48*

Delivery within48 h59,61,62,65

4 118/541 158/460 0.56 0.42, 0.74*

Delivery within72 h63

1 8/14 11/15 0.50 0.11, 2.26

Delivery within7 d59,61–64,68

6 211/493 265/497 0.65 0.50, 0.83*

Delivery before37 w†59,68

2 243/367 257/371 0.29 0.02, 4.15

Delivery before32 w59,61,64

3 162/445 184/448 0.81 0.61, 1.07

Delivery before30 w64

1 13/54 10/52 1.33 0.53, 3.33

MgSO4

Delivery within24 h69

1 22/76 22/80 1.07 0.54, 2.15

Delivery within48 h60,62

2 29/61 41/64 0.52 0.26, 1.05

Delivery within7 d62,69

2 50/92 45/99 1.54 0.85, 2.82

Delivery before36 w62,69

2 61/92 74/99 0.67 0.36, 1.26

IndomethacinDelivery within

48 h‡572 4/34 22/36 0.12 0.05, 0.32*

Delivery within7 d57

1 3/18 15/18 0.07 0.02, 0.27*

Delivery before37 w57

1 3/18 14/18 0.09 0.03, 0.34*

AtosibanDelivery within

24 h§1 67/246 107/255 0.52 0.36, 0.76*

Delivery within48 h§56

2 86/302 115/311 0.67 0.47, 0.95*

Delivery within7 d

1 93/246 130/255 0.59 0.41, 0.84*

EthanolDelivery within

72 h671 4/21 13/21 0.18 0.05, 0.60*

OR 5 odds ratio; CI 5 confidence interval; MgSO4 5 magnesiumsulfate.

* Statistically significant result.† Statistically significant heterogeneity among studies (random-ef-

fects model used).‡ Panter K, Hannah M, Farine D, Amankwah K, Jeffries A, Ohlsson

A. The effect of indomethacin tocolysis of preterm labor on perinataloutcome: A RCT [abstract]. Am J Obstet Gynecol 1997;176:S46.

§ Sibai BM, Romero R, Sanchez-Ramos L, Valenzuela G, Veille JC,Tabor B, et al. A double-blind, placebo-controlled trial of an oxytocin-receptor antagonist (antocin) in the treatment of preterm labor [ab-stract]. Am J Obstet Gynecol 1997;176:S2.


10.09, 95% CI 4.91, 20.74). Tocolytics were not associ-ated with a statistically significant increase in pulmo-nary edema (OR 7.47, 95% CI 0.15, 376.69), chest pain(OR 2.18, 95% CI 0.18, 26.95), cardiac arrythmias (OR

3.11, 95% CI 0.84, 11.58), dyspnea (OR 2.32, 95% CI 0.10,56.18), vomiting (OR 1.50, 95% CI 1.00, 2.26), headaches(OR 1.63, 95% CI 0.43, 6.13), endometritis (OR 2.26, 95%CI 0.92, 5.51), or hypotension (OR 1.97, 95% CI 0.38,10.12). Betamimetics were associated with increases inmost maternal side effects (Table 4). Magnesium sulfatewas associated with maternal side effects that requireddiscontinuation of treatment; indomethacin was associ-ated with increased risk of postpartum hemorrhage;and atosiban was associated with increased risk ofnausea (Table 4). There were no maternal deaths re-ported in any study.

Discussion

Tocolytics are widely used for women who presentwith signs and symptoms of preterm labor. Each type oftocolytic acts by a different mechanism to inhibit labor.The mechanisms that initiate labor are not well under-stood, and multiple routes appear to be involved. Thebetamimetics are a class of b-2 agonists that often areused for preterm labor. By activating the b-2 receptor,the cascade that ultimately leads to an increase in cyclicnucleotides and muscle contraction is inhibited. This isonly one mechanism of labor inhibition targeted bytocolytics. Because calcium is required for muscle con-traction, drugs that inhibit the release, entry, or bindingof calcium have become popular alternatives. Theseinclude the calcium channel blockers, PG synthetaseinhibitors, oxytocin receptor blockers, and magnesiumsulfate.

The rationale for using tocolytics is that prolongingpregnancy in certain instances will reduce neonatal andinfant morbidity and mortality, and benefits to infantswill be large enough to justify any associated increasedrisk of maternal morbidity or mortality. Previous sys-tematic reviews of RCTs of tocolytics found that somedrugs can prolong pregnancy for short periods oftime.71,72 There is no consensus on the merits of onetocolytic over another,73 so we believed it was reason-able to increase the statistical power of our review byincluding all trials of any tocolytic compared withplacebo or no treatment, realizing it might increaseheterogeneity among studies. To compensate for thatwe did the meta-analyses using a random-effects modelin situations of statistically significant heterogeneity,and did separate secondary meta-analyses for the dif-ferent types of tocolytics. We hypothesized that byincreasing the number of trials in the systematic review,we might be more likely to find an association betweentocolytics and improved perinatal outcomes, if oneexisted. Our finding of no reduction in any of thereported adverse perinatal outcomes, despite statisti-cally significant reductions in likelihood of deliverywithin 7 days, is of concern.

Table 3. Tocolytics Compared With Placebo or NoTreatment on Perinatal and Neonatal Outcomes

Perinatal/Neonataloutcome

by tocolytic

No.trials

included

No. infantswith outcomes/

No. enrolled


BetamimeticsPerinatal

death59,61–66,688 62/682 48/604 1.08 0.72, 1.62

RDS59,61–65 6 117/639 140/565 0.76 0.57, 1.01Intraventricular

hemorrhage59,61,62,644 28/494 40/505 0.70 0.43, 1.15

Necrotizingenterocolitis62,64

2 1/75 3/74 0.36 0.05, 2.59

Patent ductusarteriosus59,62

2 32/399 43/410 0.75 0.46, 1.20

Seizures59,62 2 7/399 6/410 1.20 0.39, 3.65Hypoglycemia59,62,64 3 42/455 33/465 1.33 0.83, 2.13Neonatal

sepsis*†59,61,623 46/438 42/450 1.60 0.29, 8.88

Birth weight, 2500 g59,62,64,65,68

5 332/601 332/525 0.79 0.61, 1.01

MgSO4

Perinataldeath60,62,69,70

4 11/169 7/182 1.83 0.70, 4.77

RDS60,62,69 3 22/139 22/153 1.19 0.61, 2.31Intraventricular

hemorrhage60,62,693 5/139 7/153 0.82 0.25, 2.63

Necrotizingenterocolitis60,62,69

3 4/139 4/153 1.15 0.28, 4.73

Patent ductusarteriosus62

1 2/16 0/19 9.52 0.57, 160.41

Seizures62 1 1/16 2/19 0.59 0.06, 6.12Hypoglycemia62 1 1/16 2/19 0.59 0.06, 6.12Neonatal sepsis62 1 2/16 0/19 9.52 0.57, 160.41Birth weight

, 2500 g62,692 61/94 69/108 1.06 0.58, 1.93

IndomethacinPerinatal death‡58 2 3/35 2/35 1.48 0.24, 9.20RDS57,58 2 4/34 6/33 0.61 0.16, 2.30Bronchopulmonary

dysplasia581 0/16 2/15 0.12 0.01, 1.98

Necrotizingenterocolitis58

1 3/16 2/15 1.47 0.22, 9.69

Neonatal sepsis58 1 0/16 1/15 0.13 0.00, 6.39Birth weight

, 2500 g571 3/18 15/18 0.07 0.02, 0.27†

AtosibanRDS56 1 3/57 0/57 7.66 0.78, 75.15Patent ductus

arteriosus561 2/57 0/57 7.52 0.46, 121.76

Hypoglycemia56 1 3/57 4/57 0.74 0.16, 3.39

OR 5 odds ratio; CI 5 confidence interval; RDS 5 respiratorydistress syndrome; MgSO4 5 magnesium sulfate.

* Statistically significant heterogeneity among studies (random-effects model used).

† Statistically significant result.‡ Panter K, Hannah M, Farine D, Amankwah K, Jeffries A, Ohlsson

A. The effect of indomethacin tocolysis of preterm labor on perinataloutcome: A RCT [abstract]. Am J Obstet Gynecol 1997;176:S46.


It was not possible to properly assess publication biasbecause there is no comprehensive database of unpub-lished studies. We were not able to rule out reportingbias because not all trials reported on all outcomes.Studies that show effective treatments are more likely tobe published, and outcomes are more likely to bereported on if studies show effect of treatment on theoutcome; therefore, meta-analyses probably overesti-mate any benefits to treatment. We reported on allstudy outcomes. We might have increased the proba-bility of a type 1 error by looking at many differentoutcomes. Despite that, we did not find any perinatalbenefit. This metaanalysis had over 80% power to finda reduction in risk of perinatal death from 6.6% (the ratein the control group) to 3.3%, and over 80% power tofind a reduction in incidence of RDS from 20.5% (therate in the control group) to 15%.

Reasons for the lack of beneficial perinatal outcomes

might be that the trials were too few or too small,tocolytics were not studied in populations most likely tobenefit (ie, gestational ages of borderline viability orwomen who needed transfer to tertiary care centers), ormaximum use was not made of the time gained in utero(antenatal corticosteroids). All RCTs evaluated effects oftocolytics in referral care settings; therefore, the effectsof tocolytics in primary care settings are not known. Inthe largest randomized tocolytic trial, done by theCanadian Preterm Labour Investigators’ Group,59 therewas a suggestion that ritodrine might benefit womenrandomized at 24–27 weeks’ gestation (a nonsignificanttrend toward reduction in perinatal mortality amongthose allocated to ritodrine), but that was not confirmedby appropriately sized randomized studies. The pro-portion of women who completed glucocorticoid treat-ment also was not high for either group (34.6% and36.0% in the ritodrine and placebo groups, respective-

Table 4. Tocolytics Compared With Placebo or No Treatment on Maternal Side Effects

Maternal side effects by tocolytic

No.trials

included

No. women withoutcome/No. enrolled


BetamimeticsPulmonary edema59,62,64 3 1/425 0/427 7.47 0.15, 376.69Chest pain59,64 2 39/406 3/408 6.17 3.31, 11.51*Cardiac arrhythmias59 1 7/352 2/356 3.11 0.84, 11.58Palpitations59,63,64 3 200/420 19/423 10.15 7.42, 13.87*Dyspnea59,64 2 55/406 4/408 6.57 3.87, 11.18*Tremor59 1 138/352 13/356 8.30 5.79, 11.89*Hypotension64,68 2 4/69 2/67 1.97 0.38, 10.12Nausea59 1 72/352 42/356 1.90 1.27, 2.83*Vomiting59,63 2 48/366 29/371 1.79 1.11, 2.87*Headache59,63 2 84/366 22/371 3.97 2.63, 5.99*Endometritis61,62 2 15/58 7/59 2.47 0.98, 6.22Chorioamnionitis61 1 14/39 7/40 2.54 0.94, 6.84Hyperglycemia59 1 106/352 37/356 3.39 2.35, 4.90*Hypokalemia59 1 138/352 23/356 6.43 4.53, 9.14*Need to discontinue treatment62,64,68 3 25/88 0/86 11.49 4.80, 27.54*

MgSO4

Pulmonary edema62 1 0/16 0/19 UnestimableEndometritis62 1 2/16 1/19 2.45 0.24, 25.50Need to discontinue treatment60,62,69 3 10/137 0/144 8.36 2.36, 29.61*

IndomethacinNausea57 1 2/18 0/18 7.84 0.47, 130.47Chorioamnionitis58 1 2/15 0/15 7.94 0.47, 133.27Postpartum hemorrhage† 1 7/16 2/18 5.09 1.13, 22.91*Need to discontinue treatment57 1 0/18 0/18 Unestimable

AtosibanChest pain‡56 2 3/306 13/307 0.28 0.10, 0.75*Dyspnea‡ 1 1/250 7/251 0.22 0.05, 0.89*Nausea‡56 2 33/306 15/307 2.28 1.26, 4.13*Vomiting‡56 2 10/306 13/307 0.77 0.33, 1.76Headache‡56 2 16/306 20/307 0.79 0.40, 1.56

OR 5 odds ratio; CI 5 confidence interval; MgSO4 5 magnesium sulfate.* Statistically significant result.† Panter K, Hannah M, Farine D, Amankwah K, Jeffries A, Ohlsson A. The effect of indomethacin tocolysis of preterm labor on perinatal outcome:

A RCT [abstract]. Am J Obstet Gynecol 1997;176:S46.‡ Silver H, Valenzuela G, Sanchez-Ramos L, Romero R, Sibai B, Goodwin T, et al. Maternal side effects and safety of the oxytocin receptor

antagonist antocin [abstract]. Am J Obstet Gynecol 1997;176:S45.


ly); thus time gained in utero, in that trial, might nothave been used effectively. The lack of reduction inadverse perinatal outcomes might also be becausemany fetuses whose mothers present with pretermlabor are compromised, and additional time in utero isharmful or not advantageous. Another possible expla-nation is that fetal side effects of the drugs offset anybenefit of prolonging pregnancy.

This was the first systematic review with meta-analyses of RCTs to examine the maternal side effects oftocolytic treatment. There were higher rates of maternalside effects with tocolytic use, particularly when treat-ment was with betamimetics. Thus, even if treatmentwith tocolytics is neither beneficial nor harmful toinfants, there is clear evidence that the treatment causedadverse effects for women. When weighing the risksand benefits of tocolytic treatment, one must not neglectthe adverse health effects imposed upon the mother.

Despite the lack of clear tocolytic effects, magnesiumsulfate is one of the most popular tocolytics in NorthAmerica.73 Reports from nonrandomized studies sug-gested that magnesium sulfate might reduce risk ofcerebral palsy.74,75 However, evidence from a recentRCT found it associated with a significant increase intotal pediatric mortality.70

Indomethacin was the only drug in this review toassociate with a decrease in risk of preterm birth andbirth weight under 2500 g. The three small trials ofindomethacin in this review showed no improvementin important perinatal outcomes (eg, decrease in RDS).A recent trial of indomethacin found a trend towardincreased risk of perinatal mortality or severe neonatalmorbidity (defined as necrotizing enterocolitis, bron-chopulmonary dysplasia, intraventricular hemorrhage,or periventricular leukomalacia), (Panter, 1997) andcompared with the betamimetic nylidrin hydrochloride,indomethacin was found in another study to increaserisk of bronchopulmonary dysplasia in infants bornpreterm.76 Therefore, risks and benefits of indometha-cin are uncertain, and its routine use should not beencouraged outside well-designed RCTs.

The trials of atosiban versus placebo in this reviewalso found that atosiban associated with significantprolongation of pregnancy, but in contrast to betami-metics, not with substantial maternal side effects. Im-provement in perinatal outcomes was not evident.

Prematurity was associated with very high costs tothe health care system.77 Despite advances in prematureinfant care, incidence of preterm birth has not decreasedin the last 2 decades.2,78,79 It is reasonable to assume thateven a small decrease would translate into reducedcosts, considering the frequency of its occurrence (7% to9% of all births).

Other new drugs are under investigation. A smallRCT of nitroglycerin suggested the drug might prolong

pregnancy (Smith GN, Walker MC, McGrath MJ. Ran-domized, double-blind, placebo controlled trial assess-ing nitroglycerin as a tocolytic. Am J Obstet Gynecol1998;178:S181), and other trials are under way. The aimof those investigations is to find tocolytic treatmentsthat are as or more effective at prolonging pregnancythan those currently available, but with fewer fetal andmaternal side effects. Although such investigations arestrongly encouraged, one cannot assume that signifi-cant prolongation of pregnancy will improve perinataloutcome. Thus, appropriately sized RCTs of newertocolytics for perinatal and maternal outcomes areneeded.

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Address reprint requests to:Mary E. Hannah, MDCMUniversity of Toronto Maternal Infant and Reproductive

Health Research UnitCentre for Research in Women’s Health790 Bay Street, Suite 714Toronto, Ontario M5G 1N8CanadaE-mail: [email protected]

Received October 30, 1998.Received in revised form February 22, 1999.Accepted March 4, 1999.

Copyright © 1999 by The American College of Obstetricians andGynecologists. Published by Elsevier Science Inc.


tocolytics for preterm labor: a systematic review

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