Participants

The participants in these studies were reasonably homogenous. In the placebo‐controlled studies, the minimum gestational age at inclusion was 20 weeks, and the maximum gestational age at inclusion was 37 weeks. In the studies comparing atosiban with betamimetic agents, the minimum gestational age at study entry ranged from 20 to 23 weeks and the maximum from 33 to 35 weeks. The presence of ruptured membranes was an exclusion criterion in all studies, except one (Nonnenmacher 2009). Exclusion of women with ruptured membranes reflects the clinical uncertainty about the role of tocolytic agents in this situation because infection is more likely to be present and delay in delivery may harm the mother and baby. In all studies, standard maternal and fetal contraindications to tocolysis were reported, e.g. pre‐eclampsia and gestational hypertension. Exclusion criteria also included the use of non‐steroidal anti‐inflammatory agents 12 hours prior to randomisation in five studies (European 2001; French/Australian 2001; Lin 2009; Moutquin 2000; Shim 2006), and prior tocolytic therapy within 72 hours in one study (Goodwin 1996) and within seven days in one study (Thornton 2009). High‐order multiple gestations (triplets or more) were reported as excluded in six studies (European 2001; French/Australian 2001; Lin 2009; Moutquin 2000; Richter 2005; Salim 2012) and all multiple pregnancies were excluded in three studies (Goodwin 1996; Shim 2006; Thornton 2009).

Tocolysis

Three studies compared atosiban with placebo (Goodwin 1994; Richter 2005; Romero 2000), one study compared barusiban with placebo (Thornton 2009), two studies compared atosiban with a CCB (nifedipine) (Kashanian 2005; Salim 2012) and eight studies compared atosiban with betamimetics (ritodrine, fenoterol, salbutamol, terbutaline) (Cabar 2008; European 2001; French/Australian 2001; Goodwin 1996; Lin 2009; Moutquin 2000; Nonnenmacher 2009; Shim 2006).

In the placebo‐controlled studies, two studies (Richter 2005; Romero 2000) administered atosiban as a initial bolus dose of 6.75 mg intravenously (i.v.) followed by an infusion of 300 µg/min for three hours, then 100 µg/minutes for 45 hours. In Romero 2000, maintenance therapy was thereafter administered via subcutaneous injections up to 36 weeks. One study (Goodwin 1994) administered atosiban as a initial bolus dose of 6.75 mg i.v. followed by an infusion of 300 µg/minutes for two hours. One study administered barusiban as a single bolus dose (1 mL of either 0.3 mg, 1 mg, 3 mg or 10 mg barusiban, i.v.). Two of the placebo‐controlled studies included rescue tocolysis as a part of the study protocol. In Goodwin 1994, the primary aim was to determine the effect of atosiban on uterine activity during an infusion limited to two hours. In the atosiban group, 19.6% of the participants required an additional rescue tocolytic agent versus 32% in the placebo group. In this study (Goodwin 1994), maintenance therapy after the two hour infusion was not instituted. In Goodwin 1994, of the 120 women enrolled, 29 (11 atosiban and 18 placebo) required additional tocolysis with magnesium sulphate (n = 23) or subcutaneous terbutaline (n = 6). There is, however, no description of the doses or duration of this additional tocolysis. In Romero 2000, rescue therapy was given in 42% of the atosiban group and in 51% of the placebo group. Participants received rescue tocolytic therapy with an alternate tocolytic of the investigator's choice after discontinuation of the study drug. Rescue tocolysis was considered in this study when preterm labour has progressed after at least one hour of observation and either of the following occurred: (1) cervical effacement of ≥ 75% (≤ 0.5 cm) with no decrease in the frequency or intensity of contractions and continued cervical change (at least a 1 cm change in dilatation or effacement); or (2) cervical dilatation of ≥ 4 cm with a 1 cm increase since the last cervical examination. Maintenance therapy was started with either atosiban or placebo in women who achieved uterine quiescence with a subcutaneous infusion of 0.004 mL (30 µg/minute for atosiban) and was ceased at the end of the 36^th week of gestation, at delivery, or if progression of labour necessitated an alternate tocolytic agent. In the third placebo‐controlled study (Richter 2005), rescue tocolysis was not performed. In cases of successful tocolysis but with persisted cervical dilatation, the woman was informed of the option of a cerclage and/or total occlusion of the cervix. One study (Thornton 2009) did not allow any tocolytics as rescue therapy.

In the studies comparing atosiban with nifedipine, one study (Salim 2012), administered atosiban as a initial bolus dose of 6.75 mg i.v. followed by an infusion of 300 µg/minute for three hours, then 100 µg/minute for 45 hours. The other study (Kashanian 2005) administered atosiban as an i.v. infusion of 300 µg/minute up to 12 hours, or six hours after contractions ceased. In one of the studies comparing atosiban with nifedipine (Kashanian 2005), rescue tocolysis was not performed. Nifedipine was given at an initial dose of 10 mg (one capsule) sublingually every 20 minutes for four doses. Maintenance dose with nifedipine was continued orally (20 mg) every six hours for the first 24 hours, and then every eight hours for the following 24 hours, and finally 10 mg every eight hours for the last 24 hours. In the other nifedipine‐controlled study (Salim 2012), rescue tocolysis was performed if progression of labour was determined after one hour but before 48 hours, or if adverse effects of the drug were noted, a cross‐over of the study drugs was performed and the alternative tocolytic drug (i.e. rescue treatment) was initiated. Nifedipine was given as a loading dose of 20 mg orally followed by another two doses of 20 mg, 20 to 30 minutes apart as needed. Maintenance was started after six hours with 20 to 40 mg four times daily for a total of 48 hours. If tocolysis failed from both drugs before 48 hours or admission at a gestational age below 28 weeks, indomethacin as a second rescue agent was started. Initial dose of indomethacin was two 100 mg per rectum tablets, one hour apart, followed by oral tablets of 25 mg four times daily up to a total of 48 hours.

In most of the studies comparing atosiban with betamimetics (Cabar 2008; European 2001; French/Australian 2001; Lin 2009; Moutquin 2000; Nonnenmacher 2009; Shim 2006), an initial bolus dose of 6.75 mg (i.v.) atosiban was given, followed by a continuous infusion of 300 µg/minute for three hours, then 100 µg/minute for a maximum of 15 to 48 hours. One study (Goodwin 1996) tested four atosiban regimens: 6.5 mg bolus dose followed by infusion 300 µg/mL, two mg bolus dose followed by infusion of 100 µg/mL, 0.6 mg bolus dose followed by infusion of 30 µg/minute. All treatments were continued up to 12 hours. In the studies comparing atosiban with betamimetics, betamimetic therapy was administered i.v. for a maximum of 48 hours. Rescue tocolytic therapy was reported as a part of the study protocol for all studies in this comparison. In the European study (European 2001), administration of an alternative tocolytic agent was dependent on both efficacy and tolerability of study medication and could be administered when there was recurrence or progression of preterm labour. In the French/Australian study (French/Australian 2001), if labour was progressing or women experienced intolerable adverse effects of study drug administration, an alternative tocolytic agent could be given. There were 58% (n = 69) in the atosiban group versus 63.1% (n = 77) in the salbutamol group who needed an alternate tocolytic agent. Goodwin 1996 included an alternate tocolytic agent to be used when: (1) the cervix dilated 1 cm or more during therapy; (2) uterine contraction persisted at a same or higher rate; or (3) labour was not controlled, according to the judgement of the investigator. In Shim 2006, rescue tocolysis could be given if the study drug failed either by progression of labour or intolerable adverse events judged by the investigator. Alternative drugs could be ritodrine or magnesium sulphate, but not atosiban as rescue tocolytic in case of failure for women in the ritodrine group. In Lin 2009, re‐treatment with the study drug was allowed when there was recurrence of preterm labour. In Moutquin 2000, an alternative tocolytic agent could be given after the study treatment was stopped if labour was progressing, or if any woman had an intolerable adverse event. Maintenance therapy was used in at least one study in this comparison (Goodwin 1996); however, the details of the regimen were not provided. One study reported that maintenance therapy was not a part of the study protocol (French/Australian 2001). Maintenance therapy was not used in the remaining six studies where atosiban therapy was administered i.v. for a maximum of 48 hours.

Please seeCharacteristics of included studies for further details.

Outcome measures

Most of the studies included reported on the important clinical outcome of respiratory distress syndrome (except Cabar 2008; Kashanian 2005; Nonnenmacher 2009; Richter 2005). Many studies also reported maternal adverse drug reaction (European 2001; Goodwin 1994; Kashanian 2005; Romero 2000; Salim 2012; Shim 2006; Thornton 2009). The outcome of birth within 48 hours of initiation of treatment was reported in 12 (Cabar 2008; European 2001; French/Australian 2001; Goodwin 1994; Goodwin 1996; Kashanian 2005; Lin 2009; Moutquin 2000; Nonnenmacher 2009; Richter 2005; Salim 2012; Shim 2006) of the 14 included studies and perinatal mortality in four studies (European 2001; French/Australian 2001; Moutquin 2000; Romero 2000). Other important outcomes were inconsistently reported including preterm birth, which was reported in four studies (European 2001; Romero 2000; Salim 2012; Thornton 2009), and major neonatal morbidity, which was largely not well reported across the studies.

Long‐term outcomes up to two years of age were reported as an abstract (Goodwin 1998a) for infants enrolled in one placebo‐controlled study (Romero 2000). Unfortunately, data were not reported in a format suitable for inclusion In this review. The authors have been contacted for further details before publication of the previous version of this review, but no further information has been forthcoming. The following outcomes were assessed: (1) illness, accidents, and physical abnormalities; (2) measurements of infant weight, length, and head circumference; (3) neurological examinations; (4) Bayley II assessment of mental and motor development; and (5) infant deaths. Although the report stated all infants were followed up and infant death up to 12 months was reported, only 55% of the infants who were originally included in the study were assessed for Bayley II Mental and Motor Development Index (Mean ± SD) and neurological examination at two years. One study comparing barusiban and placebo reported long‐term outcomes (Thornton 2009) for Bayley Scale evaluations of psychomotor developmental index (PDI) and mental developmental index (MDI) and physical growth. The long‐term outcomes were assessed at one year of age (Thornton 2009) and, as this time point was not prespecified, these data have not been included in this review.

In Romero 2000, data for the outcomes of birth less than 48 hours after trial entry and birth less than seven days after trial entry were reported only for women who did not receive alternative tocolytics and therefore these data were not included in the review.

Please seeCharacteristics of included studies for further details.

Assessment of studies that included multiple pregnancies

Seven studies included data from women with a multiple pregnancy (European 2001; French/Australian 2001; Goodwin 1994; Moutquin 2000; Nonnenmacher 2009; Romero 2000; Salim 2012). Two of these studies (Goodwin 1994; Romero 2000) compared ORA (atosiban) versus placebo, one study (Salim 2012) compared ORA versus CCB, and four studies compared ORA (atosiban) versus betamimetics (Nonnenmacher 2009; European 2001; French/Australian 2001; Moutquin 2000). As described previously (Methods), we have adjusted for clustering in the analyses of infant outcomes.

Primary outcomes

Birth less than 48 hours after trial entry (Analysis 1.1)

Comparing ORA (atosiban) with placebo, no difference was shown in birth less within 48 hours after trial entry (average risk ratio (RR) 1.05, 95% confidence interval (CI) 0.15 to 7.43; random‐effects, Tau² = 1.08, Chi² = 2.14, df = 1 (P = 0.14), I² = 53%) (two studies with 152 women) Analysis 1.1. A moderate degree of statistically heterogeneity was evident for this outcome measure. However, upon exploration of the possible reasons for the heterogeneity by examining clinical features of the studies, we considered an overall summary was meaningful using a random‐effects analysis.

No data were available for the subgroup of barusiban versus placebo.

Perinatal mortality, Stillbirth, Neonatal death and Infant death (Analysis 1.2) (Analysis 1.3) (Analysis 1.4) (Analysis 1.5)

Comparing ORA versus placebo no difference was shown in perinatal mortality (RR 2.25, 95% CI 0.79 to 6.38; two studies with 729 infants) (Analysis 1.2), stillbirth (average RR 0.40, 95% CI 0.04 to 4.47 random‐effects; four studies with 883 infants) (Analysis 1.3), or neonatal death (RR 4.09, 95% CI 0.88 to 19.07; two studies with 729 infants) (Analysis 1.4). These findings are driven by the subgroup of trials comparing atosiban versus placebo as no events were reported for the barusiban subgroup including a single trial (Thornton 2009).

A moderate degree of statistical heterogeneity was evident for the outcome measure of stillbirth (Heterogeneity: Tau² = 1.82; Chi² = 2.33, df = 1 (P = 0.13); I² = 57%). However, upon exploration of the possible reasons for the heterogeneity by examining clinical features of the studies, we considered an overall summary was meaningful using a random‐effects analysis.

Infant death (up to 12 months) was increased with the use of the ORA atosiban in one trial (Romero 2000; 566 infants) (RR 6.13, 95% CI 1.38 to 27.13; number needed to treat for harm (NNTH) 28, 95% CI 6 to 377) (Analysis 1.5).

As mentioned in Other potential sources of bias, it is likely that the adverse infant outcomes associated with atosiban in the Romero 2000 trial are due to an imbalance in randomisation which resulted in more women under 26 weeks' gestation and fewer over 32 weeks assigned to the atosiban group. It is of note that in the publication of the trial results, the authors used the denominator of women who were enrolled less than 28 weeks' gestation and reported a non‐statistically significant increase in birth less than 28 weeks' gestation.

Serious maternal outcome (Analysis 1.6)

One study Romero 2000 comparing ORA (atosiban only) with placebo (501 women) reported that no maternal deaths occurred during the trial period.

No data were available on other serious maternal outcomes or the other primary outcomes measure of very preterm birth before 34 weeks' gestation or long‐term outcomes for the child.

Secondary outcomes

Primary outcomes

Birth less than 48 hours after trial entry (Analysis 2.1)

No statistically significant differences were shown within or across subgroups.

• ORA versus betamimetics: RR 0.89, 95% CI 0.66 to 1.22 (eight studies with 1389 women).

• ORA versus CCB: average: RR 1.09, 95% CI 0.44 to 2.73 (two studies with 225 women).

Moderate heterogeneity was present for the ORA versus CCB comparison (Tau² = 0.22; Chi² = 2.04, df = 1 (P = 0.15); I² = 51%); however, upon exploration of the possible reasons for heterogeneity by examining clinical features of the studies, we considered an overall summary was meaningful using a random‐effects analysis.

Very preterm birth (before completion of 34 weeks of gestation) (Analysis 2.3)

• ORA versus betamimetics: no data were available.

• ORA versus CCB: no statistically significant difference was shown (RR 1.70, 95% CI 0.89 to 3.23; one study with 145 women).

Perinatal mortality (Analysis 2.2), Stillbirth (Analysis 2.4) and Neonatal death (Analysis 2.5).

No statistically significant differences were shown within or across subgroups

• ORA versus betamimetics: perinatal mortality (RR 0.55, 95% CI 0.21 to 1.48; three studies with 816 infants) (Analysis 2.2), stillbirth (RR 0.56, 95% CI 0.05 to 6.05; four studies with 861 infants) (Analysis 2.4) or neonatal death (RR 0.67, 95% CI 0.28 to 1.61; five studies with 1236 infants) (Analysis 2.5).

• ORA versus CCB: the single trial in this comparison (Salim 2012, 179 infants), reported that no neonatal deaths occurred during the trial period. No data were available on stillbirth or perinatal mortality.

Serious maternal outcome (Analysis 2.6)

• ORA versus betamimetics: one study with 45 women (Lin 2009) reported that no maternal deaths occurred during the trial period.

• ORA versus CCB: no data were available.

No other data were available on other serious maternal outcomes or long‐term outcomes for the child.

Secondary outcomes