Term pregnancy has been defined as pregnancy that has completed between 37 and 42 weeks of gestation, with preterm birth categorically defined as delivery of a viable pregnancy between 23 and 36 completed weeks of gestation 1,2. With the advances in perinatology, the lower end of this spectrum has been extended to include births at as early as 20 weeks of gestation. These delineators have been defined as the age at which a fetus has an acceptable chance of surviving postnatally, regardless of neonatal comorbidities 3.
The condition may result from a diverse array of causative factors, including maternal (e.g. infections and cervical incompetence), fetal (e.g. multiple gestation pregnancies), or idiopathic 4. In some cases, the early birth of the baby is possibly beneficial to the mother, child, or both (e.g. in cases of severe eclampsia, uncontrolled diabetes, or intrauterine growth restriction), whereas in the majority of cases the exact cause cannot be identified and the associated mortality and morbidity can be considerable 5,6.
Regardless of the causative factor, preterm infants are more prone to neurological impairment, short-term and long-term morbidity (e.g. respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, retrolental fibroplasias, and developmental problems), and neonatal mortality. Even those infants who are considered to be developmentally and physically normal at the time of discharge have revealed a high rate of developing long-term complications throughout their lives 7.
The incidence of preterm birth is high (ranging from 6.2% in Europe to 11.9% in Africa) and has been increasing worldwide; in the US, the current incidence of 12.7% has increased by 36% over the past 25 years 8,9. Interestingly, most of the increase is in ‘late preterm’ births, those at 34–36 weeks, constituting 60–70% all preterm births. The choice of a particular therapeutic approach for counteracting tocolysis does not seem to play a role in the observed trend 10.
Even with our increased understanding of the factors leading to uterine contractility and delivery, preterm labor is still a main contributor to fetal demise and morbidity. This is because, even though we have been able to prolong preterm labor, we have not been successful in stopping the process completely, and most pregnancies with a threat of preterm labor will not reach full gestation. Therefore, the purpose of tocolytic treatment has been to prolong pregnancy to allow for the administration of corticosteroids to the mother and transfer of expectant mothers to a tertiary care facility. Compared with placebo, tocolytics have been shown to decrease the likelihood of delivery within 24 and 48 h, and 7 days 11.
Tocolytics mainly work by either preventing oxytocin from interacting with receptors in the myometrium or by relaxing the smooth muscles of the uterus. Today, there are a multitude of agents that contain tocolytic properties, including betamimetics, magnesium sulfate, nonsteroidal anti-inflammatory drugs, calcium-channel blockers, and, more recently, oxytocin-receptor antagonists 12.
Betamimetics primarily stimulate β2-adrenergic receptors in the walls of smooth muscles, and to a lesser extent, β1-adrenergic receptors. The most commonly used betamimetics are ritodrine hydrochloride and terbutaline sulfate. Nifedipine, an orally and sublingually administered calcium antagonist, relaxes smooth muscles of the uterine wall, in addition to cardiac smooth muscle, by antagonizing smooth-muscle calcium channels required for contraction 13. Atosiban, the first specific oxytocin-receptor antagonist, binds with oxytocin receptors in the myometrium to prevent the formation of oxytocin-receptor complexes that lead to myometrial contractility 13. Because of their pleiotropic action on receptors outside of the reproductive system, the use of β-blockers and nifedipine is associated with numerous side effects, whereas action of atosiban is organ specific.
Despite its paramount clinical and economic importance, the amount of evidence available from randomized trials on interventions to prevent preterm labor is limited and often contradictory. It has been argued that no tocolytic trial has been designed to detect mortality or morbidity outcomes 10 and that even the largest studies were not sufficiently powered 14. Even meta-analyses involving many trials were underpowered and have not shown marked benefit. This has led recognized guidelines to deliver conflicting recommendations, with the American College of Obstetricians and Gynecologists stating that there are no drugs available as the ‘first line’ of treatment, whereas UK’s Royal College of Obstetricians and Gynecologists stating that, if the decision is made to use a tocolytic drug, nifedipine and atosiban appear to have comparable effectiveness in delaying delivery, with fewer maternal adverse effects and less risk of rare serious adverse events compared with alternative drugs 15,16. This further reflects the dearth of information on the comparative effectiveness of tocolytics.
Two Cochrane reviews comparing calcium-channel blockers 17 and oxytocin antagonists 18 with placebo or other tocolytics found that nifedipine was more effective than betamimetics; however, the same conclusion was not reached for oxytocin antagonists. This led the authors to recommend the use of nifedipine over betamimetics or oxytocin antagonists. Even so, the reviews are now considered outdated as they did not account for evidence from the new trials published over the past few years.
Therefore, the purpose of this systematic review was to determine the comparative clinical value of atosiban versus nifedipine in women in preterm labor by evaluating both, their comparative effectiveness and safety profiles.
To determine the efficacy of atosiban compared with nifedipine in preventing preterm labor, we designed a systematic review and meta-analysis of prospective, randomized controlled trials using both direct and indirect evidence. Direct evidence was obtained for outcomes of trials that compared atosiban with nifedipine directly. Indirect evidence was gathered from randomized trials that compared atosiban or nifedipine with betamimetics. This review was conducted and reported according to the guidelines of the Cochrane handbook for systematic reviews of interventions (version 5.0.1) 19 and according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines 20. A protocol for this review was prepared with guidance from the previously published reviews on tocolytics.
Criteria for considering studies for this review
Types of studies
All published, unpublished, and ongoing randomized trials that reported data comparing outcomes in women, fetuses, and infants in which atosiban was compared with nifedipine in pregnant women were sought. In addition, trials comparing atosiban or nifedipine with betamimetics were sought to allow for indirect comparison. Indirect comparison with a placebo was not included in the protocol, as no placebo-controlled studies of nifedipine were found in the exploratory searches. Moreover, a previously published meta-analysis was based on the indirect comparison with betamimetics, as no studies on nifedipine versus placebo were identified in the systematic review 59. Study design was limited to randomized trials because of the methodological concerns with other classes of comparative study designs.
Types of participants
Pregnant women assessed as being in spontaneous preterm labor (between 20 and 36 weeks), with or without a history of preterm labor, and considered suitable for tocolytic therapy were included. Preterm labor was generally defined as the presence of regular uterine contractions, with intact or ruptured membranes, with or without cervical dilatation; investigator-identified definitions were also accepted.
Types of interventions
Trials comparing pregnant women presenting with preterm labor and randomized to therapeutic doses of oxytocin (intravenous) versus nifedipine (oral), oxytocin versus betamimetics (intravenous or oral), or nifedipine versus betamimetics were eligible for inclusion.
Types of outcome measures
The clinical outcome measures were related to the prolongation of pregnancy, prevention of preterm labor, or cessation of contractions (as appropriate), as well as to maternal and fetal side effects and infant morbidity and mortality (Table 1).
Search methods for identification of studies
Using a modified version of the Cochrane highly sensitive search strategy, we searched the following electronic databases using DataStar and Ovid: MEDLINE (1985 to present), EMBASE (1985 to present), CENTRAL (Cochrane library), and ISI Web of Knowledge (1985 to present), with no language barriers (Appendix 1). The last search was performed in August 2011. Further, we hand-searched conference abstracts of major proceedings over the past 5 years, reference lists of expert-identified major review articles relevant to this review, and the reference lists of included trials. Finally, we searched prospective trial registers (e.g. WHO, ClinicalTrials.gov, ISRCTN etc.) for citations of ongoing and unpublished trials.
Data collection and analysis
Data were collected using a standardized data extraction form, which was developed and piloted for consistency and completeness. Data from trials considered for inclusion were extracted by one review author (A.M.A.S.) and checked for accuracy and completeness by a second reviewer (J.W.) according to the inclusion criteria, with conflicts being resolved by consensus. Data management and analysis were carried out using Microsoft Excel Microsoft Corporation (Redmond, Washington, USA) and Review Manager (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen Denmark).
Individual outcome data were included in the analysis if they met the prestated criteria. Where possible, data were extracted to allow an intention-to-treat analysis. If data from the trial reports were insufficient or missing, the authors attempted to contact the investigators of individual trials through e-mail to obtain additional information or to clarify methodological issues.
Quantitative data synthesis and statistical analysis
For the meta-analysis, two comparative methods were used for evaluation: the direct (head-to-head) comparison and the adjusted indirect comparison methods. For direct comparisons, comparison of the result of intervention B with the result of intervention C within a randomized controlled trial gave an estimate of the efficacy of intervention B versus C 21. The direct meta-analysis of dichotomous data and continuous data was carried out using random-effects model, and the odds ratio (OR) and mean difference were evaluated, along with their 95% confidence intervals (CI).
For indirect comparisons, the results of the comparison between interventions B and C were adjusted using the results of their direct comparisons with a common intervention A 21. For example, given two estimated effects Θ AB and Θ AC for comparisons between group A and group B (AvB) and between group A and group C (AvC), respectively, the effect for the comparison between groups B and C (BvC) is estimated as follows: Θ BC=Θ AB–Θ AC, and its variance is var(Θ BC)=var(Θ AB)+var(Θ AC). A 95% CI for Θ BC is obtained as Θ BC±1.96 √[var(Θ BC)]. The estimates of effect, denoted by Θ, relate to the scale on which the data would be analyzed, in this case the scale being the log OR, mean difference, or standardized mean difference.
The results of the direct and indirect meta-analyses were combined using the generic inverse method. Similar to the other meta-analyses, the data were analyzed on the same scale in which the data were originally meta-analyzed (e.g. log OR).
Assessment of heterogeneity
Homogeneity of the data from the included trials was assessed by visual inspection of the outcome tables and using the χ 2-test for heterogeneity with a 10% level of statistical significance. For χ 2, a P-value of 0.1 was selected as a cutoff point for rejection of the null hypothesis of study homogeneity to limit type II errors 22. In addition, heterogeneity was quantified using the I 2-test. The I 2-test describes the percentage of variability in effect estimates that is due to heterogeneity rather than due to sampling error (chance) 23. If heterogeneity was considered high (I 2>80%), results of the pooling were not presented.
Assessment of publication bias
Funnel plot analysis of the outcomes, carried out in addition to the Trim and Fill method, was planned to detect the possibility of publication bias when there were at least 10 included trials.
To assess the validity of studies with regard to the risk of bias in their results (e.g. risk of overestimation or underestimation of the true intervention effect), we performed a domain-based risk-of-bias assessment according the principles of the Cochrane Collaboration’s Risk of Bias tool 19. The main domains were: (i) sequence generation (e.g. was the allocation sequence adequately generated?); (ii) allocation concealment (e.g. was allocation adequately concealed?); (iii) blinding of participants, personnel, outcome, and assessors (e.g. was knowledge of the allocated intervention adequately prevented during the study?); (iv) incomplete outcome data (e.g. were incomplete outcome data adequately addressed?); (v) selective outcome reporting (e.g. are reports of the study free of suggestions of selective outcome reporting?); (vi) other sources of bias (e.g. was the study apparently free of other problems that could put it at a high risk of bias?).
Electronic and hand searches identified 3128 potentially relevant citations, of which 293 were considered to be duplicate citations. Of the remaining 2835 citations, 388 were considered eligible for further evaluation on the basis of title/abstract screening. Following screening of the full-text manuscripts, 35 trials were identified to have met the inclusion criteria: atosiban versus nifedipine (n=4) 24–27, atosiban versus betamimetics (n=9) 28–36, and nifedipine versus betamimetics (n=22) 37–58 (Fig. 1). Of these trials, one (atosiban vs. nifedipine) was excluded because it was still ongoing and no data were available for quantitative meta-analysis 27. Characteristics of the included trials and their risk of bias are presented in Tables 2 and 3. Initially, nifedipine was most commonly administered sublingually 24–26,37–46, but subsequent studies 47–57 have reported oral administration from the start. None of the trials reported using nifedipine intravenously, and one trial did not report the details of administration 58.
Publication bias for trials comparing atosiban with nifedipine was not assessed because of the insufficient number of available trials. Even so, potential publication bias for the primary outcomes in trials comparing atosiban or nifedipine with betamimetics was investigated and shown to be improbable.
Atosiban versus nifedipine (direct evidence)
Data for the majority of the primary and secondary outcome measures were unavailable for review (Appendix 2). Direct meta-analysis of data from the three included randomized trials revealed that there was no clear difference between atosiban and nifedipine with regard to the significant effects exerted by them on pregnancy prolongation and fetal outcome measures (Table 4; Figs 2 and 3). The safety profile of atosiban was superior, with the following outcomes in its favor: incidence of maternal adverse drug reactions (atosiban: 7/40 vs. nifedipine: 16/40; OR=0.32, 95% CI=0.11–0.89), flushing (atosiban: 2/31 vs. nifedipine: 16/32; OR=0.07, 95% CI=0.01–0.34), gastrointestinal tract upset (atosiban: 1/31 vs. nifedipine: 11/32; OR=0.06, 95% CI=0.01–0.53), hypotension (atosiban: 1/71 vs. nifedipine: 25/72; OR=0.04, 95% CI=0.01–0.21), palpitation (atosiban: 2/71 vs. nifedipine: 16/72; OR=0.11, 95% CI=0.03–0.44), and tachycardia (atosiban: 1/71 vs. nifedipine: 9/72; OR=0.14, 95% CI=0.02–0.82). However, nausea occurred more frequently in participants receiving atosiban (atosiban: 23/31 vs. nifedipine 3/32; OR=27.79, 95% CI=6.62–116.75; Table 4).
Atosiban versus nifedipine (direct+indirect evidence)
Combining direct data from trials comparing atosiban with nifedipine with indirect data obtained from nine trials that compared atosiban with betamimetics and 22 trials that compared nifedipine with betamimetics led to a reanalysis of 16 outcomes (Table 4). The results demonstrated that there was no clear difference between atosiban and nifedipine with regard to the significant effects exerted by them on the majority of outcome measures, with the exception of the incidence of treatment failure within 7 days of initiation of treatment (birth or alternative tocolytic therapy) as well as the incidence of headache and tachycardia, all in favor of atosiban. Nausea was more frequently reported with the use of atosiban.
The results of this meticulous systematic review and meta-analysis using direct and indirect evidence demonstrate a comparable effectiveness of atosiban and nifedipine in pregnancy prolongation and fetal mortality and morbidity. In addition, they demonstrate a superior safety profile for atosiban with less probability of maternal side effects compared with nifedipine. The results of this review are in contrast with those of a previous systematic review using only indirect evidence to compare atosiban with nifedipine 18,59, and also with the recommendations of a Cochrane review 18.
There is no general consensus on the merits of one tocolytic over another, or whether tocolytics in general should be recommended 15,16. This has been fueled by the lack of adequately powered, high-quality randomized trials comparing different tocolytics in direct, head-to-head comparisons. To compensate for this fact, during this systematic review, both direct and a combination of direct/indirect evidence was used to determine the comparative effectiveness and safety of atosiban and nifedipine.
It is well accepted that well-designed prospective randomized controlled trials provide the most valid evidence of relative efficacy of competing interventions, and this evidence is utilized first and foremost in evaluations. Many competing interventions, however, have not been compared directly (head-to-head) in randomized trials, nor have they been compared in a small body of literature. In cases of paucity of direct evidence, indirect comparisons have been recommended and used for evaluating the efficacy of treatment alternatives 60. Adjusted indirect comparisons offer a unique opportunity to compare competing interventions. The results of these comparisons usually, but not always, agree with the results of head-to-head randomized trials. When direct evidence from randomized trials is not available, or is insufficient, the adjusted indirect comparison may provide valuable information on the relative efficacy of the competing interventions 21. The validity of the adjusted indirect comparison depends on the internal validity and similarity of the included trials. As all the controlled trials in this review were randomized and conducted in similar settings and in women with a threat of preterm labor, we believed that the results from the indirect evidence investigated would be similar to the results of the direct evidence. In addition, the homogenous results of the combination of direct and indirect evidence were clearly another confirmation of the appropriateness of using indirect analyses in this review.
Some factors can increase the risk of bias of trials. They include improper randomization, allocation concealment and blinding procedures, patient attrition during the course of the trial, early termination for benefit, and improper influence of sponsors. The majority of the trials were affected by these limitations (Table 3).
In a previous meta-analysis using only indirect evidence of nifedipine versus atosiban 59, there was a nonsignificant difference in the proportion of women who had not given birth at 48 h (OR=1.20, 95% CI=0.73–1.95). Even so, nifedipine was found to be associated with a significant reduction in respiratory distress syndrome compared with atosiban. This outcome was built completely on indirect evidence, making any firm conclusions preemptive. We believe that our updated indirect comparison along with a direct comparison of atosiban with nifedipine invalidates those conclusions. A recent review of the efficacy and safety of nifedipine compared with other tocolytics 17 included only one study versus atosiban 25; hence, conclusions from that meta-analysis could not be generalized. In addition, the authors included 16 studies comparing nifedipine with betamimetics, out of 22 included in this meta-analysis. Although the results for most outcomes of nifedipine versus betamimetics are comparable to our results, it is notable that, in our meta-analysis, treatment failure within 48 h was significantly lower with nifedipine than with betamimetics, whereas Conde-Agudelo and colleagues found no statistical significance. This shows that our results are more conservative than those of Conde-Agudelo and colleagues with regard to implications for the indirect comparison of nifedipine with atosiban: the greater the advantage of nifedipine over betamimetics, the greater the indirect advantage of atosiban over nifedipine. However, the difference in methodologies in the two meta-analyses would have no bearing on the statistical significance of the indirect comparison.
The majority of the investigated outcomes were not reported by the researchers, leading to the possibility of reporting bias when nonsignificant results are omitted from the final report. Even so, the results of the meta-analyses demonstrated that the likelihood of pregnancy prolongation with atosiban and nifedipine was similar, with no clear evidence of a difference in significant effects between the two tocolytics. In addition, the effect on perinatal outcomes was deemed to be similar. Nonetheless, the safety profile of atosiban was shown to be better than that of nifedipine with a higher incidence of adverse drug reactions, flushing, gastrointestinal tract upset, headache, hypotension, palpitation, and tachycardia in participants randomized to nifedipine. The only adverse event that was noted to be more frequently associated with atosiban was nausea.
The reason for the lack of difference in the beneficial perinatal outcomes between the two tocolytics might be the fact that the included trials were too few or underpowered to identify small differences. Another explanation could be the possibility that the fetal side effects of the drugs may have offset any benefit of prolonging pregnancy; however, this cannot be confirmed without adequately powered placebo-controlled trials, which are lacking in the literature 17,18.
This meta-analysis was unable to distinguish between the efficacy of atosiban and nifedipine but pointed to a more favorable safety profile for atosiban. Importantly, more studies comparing nifedipine with other tocolytics and with placebo should be conducted to provide direct evidence of the safety of nifedipine, which remains unlicensed for tocolysis. Even so, it should be noted that there was a dearth of information on serious adverse events and long-term outcomes in randomized trials. It can be hypothesized that an analysis including observational studies would uncover more adverse events associated with tocolytics. Although the evidence base for our analyses was restricted to randomized controlled trials, large prospective cohort studies can also provide insights for clinical decision making. In one such multicentric study of 1920 consecutive women in the Netherlands and Belgium, the relative risk of an adverse drug reaction for single treatment with a calcium antagonist compared with atosiban was 12 (95% CI=1.9–69) 61. It was shown recently that case series reported more adverse events of nifedipine compared with randomized trials 62, although, in any conclusion, the risk of bias in observational studies must always be considered. As has been found previously from the comparison of atosiban with betamimetics, safety has not only clinical but also economic implications 63. Accordingly, although the unit cost of nifedipine may be less than that of atosiban, the full economic implications should also be considered in decision making. Until there is more evidence on efficacy, cost-effectiveness, and safety, consideration should be given to the viewpoints of the local clinical governance and risk management.
Ahmed Abou-Setta led all stages of the review process including, but not limited to, study design, preparation and implementation of the search strategy, screening the retrieved citations, data extraction and analysis, and manuscript preparation. Jaro Wex conceived the review question and collaborated on all stages of the review process, including, but not limited to, study design, preparation and implementation of the search strategy, screening the retrieved citations, data extraction and analysis, and manuscript preparation. Hesham Al-Inany provided guidance during the review process and reviewed the final manuscript.
The authors thank all the researchers who were contacted and who provided additional information regarding their trials.
Conflicts of interest
Dr Ahmed Abou-Setta received funding from PharmArchitecture Limited. Dr Hesham Al-Inany declared no conflict of interest. Dr Jaro Wex is the director of PharmArchitecture Limited, an independent consultancy, who received an unrestricted grant from Ferring Pharmaceuticals to study the efficacy and safety of tocolytics. The funding agency did not have any influence on the conduct of the study.
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51. Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labour. BJOG. 1993;100:1090–1094
52. Laohapojanart N, Soorapan S, Wacharaprechanont T, Ratanajamit C. Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor. J Med Assoc Thai. 2007;90:2461–2469
53. Mawaldi L, Duminy P, Tamim H. Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor. Int J Gynaecol Obstet. 2008;100:65–68
54. Meyer WR, Randall HW, Graves WL. Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med Obstet Gynecol. 1990;35:649–653
55. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. BJOG. 1986;93:933–937
56. Roy UK, Pan S. Use of calcium antagonist (nifedipine) in premature labour. J Indian Med Assoc. 1993;91:8–10
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Appendix 1: DataStar search syntax
- RANDOMISED ADJ CONTROLLED ADJ TRIAL$1.DE.
- CONTROLLED ADJ CLINICAL ADJ TRIALS ADJ RANDOMISED.DE.
- Trials adj Randomised adj Clinical.de.
- Clinical adj Trials adj Randomised.de.
- RANDOM ADJ ALLOCATION$1.DE.
- DOUBLE ADJ BLIND ADJ METHOD$1.DE.
- SINGLE ADJ BLIND ADJ METHOD$1.DE.
- CLINICAL ADJ TRIAL$1.DE.
- CONTROLLED ADJ CLINICAL ADJ TRIAL$1.DE.
- COMPAR$5.ti,ab. ADJ (TRIAL$1.ti,ab. OR STUD$.ti,ab.) or (Comparative adj Study.de.)
- (CROSS-OVER.DE. OR (CROSS ADJ OVER.DE.) OR CROSSOVER.DE.) ADJ (STUD$3.DE. OR TRIAL$1.DE. OR PROCEDURE.DE.)
- CLINIC$ NEAR TRIAL$1.TI,AB.
- ((SINGL$.TI,AB. OR DOUBL$.TI,AB. OR TREB$.TI,AB. OR TRIPL$.TI,AB.) ADJ (BLIND$3.TI,AB. OR MASK$3.TI,AB.))
- RANDOMLY ADJ ALLOCATED.TI,AB.
- ALLOCATED ADJ RANDOM.TI,AB.
- CROSSOVER.TI,AB. OR CROSS-OVER.TI,AB. OR (CROSS ADJ OVER.TI,AB.)
- Double adj Blind adj Method.de.
- (FOLLOW ADJ UP ADJ STUDIES.DE.) or (FOLLOW ADJ UP ADJ STUD$.DE.) or (FOLLOWUP ADJ STUD$.DE.) or (FOLLOWUP ADJ STUDIES.DE.)
- Pilot adj Project$1.de.
- Prospective adj Stud$3.de.
- Random adj Allocation.de.
- Single adj Blind adj Method.de.
- Multicentre.de. adj (Stud$3.de. or trial$1.de.)
- 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27
- CASE ADJ REPORT$1.TI.
- LETTER$1.DE,PT. OR COMMENT$3.DE,PT. or Correspondence-as-Topic.de.
- HISTORIC$2 ADJ ARTICLE$1.DE,PT.
- (REVIEW ADJ MULTICASE.DE.) OR (REVIEW-MULTICASE.DE.) or (Review-Literature-as-Topic.de.)
- 29 OR 30 OR 31 OR 32 OR 33 or 34
- 28 NOT 35
- animal$1.de. not (human$1.de. and animal$1.de.)
- 36 not 37
- ANTOCIN$.TI,AB. OR ANTOCIL$2.TI,AB. OR (‘CAP’ ADJ ‘476’.TI,AB.) OR (‘D’ ADJ ‘TVT’.TI,AB.) OR (‘DE’ ADJ ‘TVT’.TI,AB.) OR DETVT.TI,AB. OR DETO-OXY.TI,AB. OR (‘DETO’ ADJ ‘OXY’.TI,AB.)
- ATOSIBAN$.TI,AB. OR ATOSIBAANI.TI,AB.
- HORMONE ADJ ANTAGONIST$1.DE.
- ‘ORF’ ADJ ‘22164’.TI,AB.
- OXYTOCIN ADJ ANTAGONIST$1.TI,AB.
- OXYTOCIN AND ANTAGONIST$1.TI,AB.
- ‘RWJ’ ADJ ‘22164’.TI,AB.
- VASOTOCIN$.DE. OR 2480–41–3.RN.
- 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49
- (CALCIUM ADJ CHANNEL ADJ BLOCK$4.DE.) or (calcium-channel-blockers)
- CALCIUM ADJ BLOCK$3.TI,AB.
- (CALCIUM ADJ ANTAGONIST$2.TI,AB.) OR VERAPAMIL$.TI,AB. OR IFENPRODIL$.TI,AB. OR (CALCIUM ADJ CHANNEL ADJ BLOCKADE.TI,AB.)
- 51 or 52 or 53 or 54 or 55
- ADALAT$1.TI,AB. OR ADALEX$1.TI,AB. OR ADAPINE$1.TI,AB. OR ADAPRESS$1.TI,AB. OR ADCOR$1.TI,AB. OR ADDOS$1.TI,AB. OR ADIFEN$1.TI,AB. OR ADIPINE$1.TI,AB. OR AFEDITAB$1.TI,AB.
- ALDAR$1.TI,AB. OR ALDIPIN$1.TI,AB. OR ANGINOR$1.TI,AB. OR ANGIOPINE$1.TI,AB. OR ANGIPINA$1.TI,AB. OR ANIFED$1.TI,AB. OR ANPINE$1.TI,AB. OR ANTAMEX$1.TI,AB.
- ANTIBLUT$1.TI,AB. OR ANTROLIN$1.TI,AB. OR APO-FEDIPISAL$1.TI,AB. OR (APO ADJ FEDIPISAL$1.TI,AB.) OR APO-NIFED$1.TI,AB. OR (APO ADJ NIFED$1.TI,AB. ) OR APRICAL$1.TI,AB.
- (ATEL ADJ ‘N’$1.TI,AB.) OR (ATENIF ADJ BETA$1.TI,AB.) OR ATE-NIFE$1.TI,AB. OR (ATE ADJ NIFE$1.TI,AB.) OR ATENSES$1.TI,AB. OR BELNIF$1.TI,AB.
- (BETA-ADALAT$1.TI,AB.) OR (BETA ADJ ADALAT$1.TI,AB. ) OR (BETA ADJ NICARDIA$1.TI,AB.) OR (BETA-NICARDIA$1.TI,AB.) OR BIOCORD$1.TI,AB. OR BIONIF$1.TI,AB. OR BRESBEN$1.TI,AB.
- BUCONIF$1.TI,AB. OR CALANIF$1.TI,AB. OR CALCHAN$1.TI,AB. OR CALCHECK$1.TI,AB. OR CALCIANTA$1.TI,AB. OR CALCIBLOC$1.TI,AB. OR CALCIGARD$1.TI,AB.
- CALCILAT$1.TI,AB. OR CALNIF$1.TI,AB. OR CARBLOC$1.TI,AB. OR CARDALIN$1.TI,AB. OR CARDICAP$1.TI,AB. OR CARDICON$1.TI,AB. OR CARDIFEN$1.TI,AB. OR CARDILAT$1.TI,AB.
- CARDILATE ADJ ‘MR’$1.TI,AB. OR CARDIOPINA$1.TI,AB. OR CARDIOPINE$1.TI,AB. OR CARDIPIN$1.TI,AB. OR CARDULES$1.TI,AB. OR CARVAS$1.TI,AB. OR CHRONADALATE$1.TI,AB.
- CIPALAT$1.TI,AB. OR CISDAY$1.TI,AB. OR CITILAT$1.TI,AB. OR CLINOLAT$1.TI,AB. OR CONDUCIL$1.TI,AB. OR CORACTEN$1.TI,AB. OR CORAL$1.TI,AB. OR CORDAFEN$1.TI,AB.
- CORDAFLEX$1.TI,AB. OR CORDALAT$1.TI,AB. OR CORDICANT$1.TI,AB. OR CORDILAN$1.TI,AB. OR CORDIPIN$1.TI,AB. OR CORINFAR$1.TI,AB. OR CORODAY$1.TI,AB. OR COROGAL$1.TI,AB.
- CORONIPIN$1.TI,AB. OR CORONOVO$1.TI,AB. OR COROTREND$1.TI,AB. OR DARAT$1.TI,AB. OR DARI$1.TI,AB. OR DEPICOR$1.TI,AB. OR DEPIN$1.TI,AB. OR DEPIN$1.TI,AB. OR DEPTEN$1.TI,AB.
- DIGNOKONSTANT$1.TI,AB. OR DILAFLUX$1.TI,AB. OR DILCOR$1.TI,AB. OR DIPINAL$1.TI,AB. OR DURANIFIN$1.TI,AB. OR ECODIPINE$1.TI,AB. OR EDIP$1.TI,AB. OR INALAT$1.TI,AB. OR ELOCOR$1.TI,AB.
- EUXAT$1.TI,AB. OR FARMALAT$1.TI,AB. OR FEDILEX$1.TI,AB. OR FEDIP$1.TI,AB. OR FENAMON$1.TI,AB. OR FENIDINA$1.TI,AB. OR FENIKEN$1.TI,AB. OR FICOR$1.TI,AB. OR FLECOR-N$1.TI,AB. OR (FLECOR ADJ ‘N’$1.TI,AB.)
- FORTIPINE$1.TI,AB. OR FUSEPINA$1.TI,AB. OR GELPRIM$1.TI,AB. OR GEWADILAT$1.TI,AB. OR GLOPIR$1.TI,AB. OR HEBLOPIN$1.TI,AB. OR HEXADILAT$1.TI,AB. OR HYPAN$1.TI,AB. OR (HYPOLAR ADJ RETARD$1.TI,AB.)
- JEDIPIN$1.TI,AB. OR JUTADILAT$1.TI,AB. OR KARDILAT$1.TI,AB. OR LONCORD$1.TI,AB. OR MACOREL$1.TI,AB. OR MAJOLAT$1.TI,AB. OR MEBORILAN$1.TI,AB. OR MEDIPINA$1.TI,AB. OR MEGALAT$1.TI,AB.
- MYOGARD$1.TI,AB. OR NADIPINIA$1.TI,AB. OR NEFELID$1.TI,AB. OR NELAPINE$1.TI,AB. OR (NEO ADJ FEDIPINA$1.TI,AB.) OR NICARDIA$1.TI,AB. OR NIDICARD$1.TI,AB. OR NIDILAT$1.TI,AB.
- NIFADIL$1.TI,AB. OR NIFANGIN$1.TI,AB. OR NIF-ATENIL$1.TI,AB. OR NIFATENOL$1.TI,AB. OR (NIF ADJ ATENIL$1.TI,AB.) OR NIFDEMIN$1.TI,AB. OR NIFE$1.TI,AB. OR NIFE-BASAN$1.TI,AB. OR (NIFE ADJ BASAN$1.TI,AB.)
- NIFEBENE$1.TI,AB. OR NIFECARD$1.TI,AB. OR NIFECIP$1.TI,AB. OR NIFECLAIR$1.TI,AB. OR NIFECODAN$1.TI,AB. OR NIFECOR$1.TI,AB. OR NIFED$1.TI,AB. OR NIFEDALAT$1.TI,AB. OR NIFEDATE$1.TI,AB.
- NIFEDAX$1.TI,AB. OR NIFEDEL$1.TI,AB. OR NIFEDIAC$1.TI,AB. OR NIFEDICAL$1.TI,AB. OR NIFEDICARD$1.TI,AB. OR NIFEDICOR$1.TI,AB. OR NIFEDICRON$1.TI,AB. OR NIFEDI-DENK$1.TI,AB.
- NIFEDIGEL$1.TI,AB. OR NIFEDIN$1.TI,AB. OR NIFEDIPAT$1.TI,AB. OR NIFEDIPRESS$1.TI,AB. OR NIFEDOTARD$1.TI,AB. OR NIFEHEXAL$1.TI,AB. OR NIFELAT$1.TI,AB. OR NIFELEASE$1.TI,AB.
- NIFENSAR$1.TI,AB. OR NIFESTAD$1.TI,AB. OR NIFETEX$1.TI,AB. OR NIFETOLOL$1.TI,AB. OR NIFEZZARD$1.TI,AB. OR NIFICAL$1.TI,AB. OR NIFICARD$1.TI,AB. OR NIFIDINE$1.TI,AB.
- NIFIRAN$1.TI,AB. OR NIFOPRESS$1.TI,AB. OR NIFREAL$1.TI,AB. OR NIFSER$1.TI,AB. OR NIF-TEN$1.TI,AB. OR NIMODREL$1.TI,AB. OR (NIF ADJ TEN$1.TI,AB.) OR NIOXIL$1.TI,AB.
- NIPIN$1.TI,AB. OR NIPRESS$1.TI,AB. OR NIVATEN$1.TI,AB. OR NORMOPRES$1.TI,AB. OR NOVIKEN$1.TI,AB. OR NOVO-NIFEDIN$1.TI,AB. OR (NOVO ADJ NIFEDIN$1.TI,AB.)
- NU-NIFED$1.TI,AB. OR (NU ADJ NIFED$1.TI,AB.) OR NYCOPIN$1.TI,AB. OR NYEFAX$1.TI,AB. OR NYPINE$1.TI,AB. OR ODIPIN$1.TI,AB. OR OSMO-ADALAT$1.TI,AB. OR (OSMO ADJ ADALAT$1.TI,AB.)
- OSPOCARD$1.TI,AB. OR OXCORD$1.TI,AB. OR PABALAT$1.TI,AB. OR PERTENSAL$1.TI,AB. OR PIDILAT$1.TI,AB. OR PINIFED$1.TI,AB. OR PLENACOR$1.TI,AB. OR PONTUC$1.TI,AB.
- PRESOLAR$1.TI,AB. OR PRESSOLAT$1.TI,AB. OR PROCARDIA$1.TI,AB. OR PRODOPINA$1.TI,AB. OR PRUDENCIAL$1.TI,AB. OR SALI-ADALAT$1.TI,AB. OR (SALI ADJ ADALAT$1.TI,AB.)
- SERVIDIPINE$1.TI,AB. OR SLOFEDIPINE$1.TI,AB. OR SPONIF$1.TI,AB. OR SULOTIL$1.TI,AB. OR SUPRACORDIN$1.TI,AB. OR SYSTEPIN$1.TI,AB. OR TENIF$1.TI,AB.
- TENOFED$1.TI,AB. OR TENORDATE$1.TI,AB. OR TENSIBLOC$1.TI,AB. OR TENSIPINE$1.TI,AB. OR TENSOMAX$1.TI,AB. OR TENSOPIN$1.TI,AB. OR TREDALAT$1.TI,AB.
- UNIDIPIN$1.TI,AB. OR VASAD$1.TI,AB. OR VASCARD$1.TI,AB. OR VASDALAT$1.TI,AB. OR VASOFED$1.TI,AB. OR VIDALAT$1.TI,AB. OR VISCARD$1.TI,AB. OR WARIDIPIN$1.TI,AB. OR XEPALAT$1.TI,AB. OR ZENUSIN$1.TI,AB.
- 57 OR 58 OR 59 OR 60 OR 61 OR 62 OR 63 OR 64 OR 65 OR 66 OR 67 OR 68 OR 69 OR 70 OR 71 OR 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82 or 83 or 84 or 85
- 56 or 86
- 50 or 87
- (ADRENERGIC ADJ BETA-AGONIST$1.DE.) OR (ADRENERGIC ADJ BETA ADJ AGONIST$1.DE.)
- 89 or 90 or 91 or 92 or 93 or 94 or 95 or 96 or 97 or 98 or 99 or 100 or 101
- 88 or 102
- 38 and 103
- (abortion adj threatened.de.) or (threatened adj abortion.de.)
- threatened adj abortion.ti,ab.
- uter$ and contractions.ti,ab.
- (infant adj premature.de.) or (premature adj infant$.de.)
- (obstetric adj labor adj premature.de.) or (premature adj obstetric adj labor.de.)
- (tocolytic adj agents.de.) or (tocolytic adj agent$1.de.)
- uterin$ and contraction$1.ti,ab.
- 105 or 106 or 107 or 108 or 109 or 110 or 111 or 112 or 113 or 114 or 115 or 116
- 117 and 104
Appendix 2: outcome measures without any data available for evaluation Atosiban versus betamimetics
[Mortality] perinatal death; perinatal mortality excluding congenital abnormality; infant death; infant death excluding congenital abnormality. [Birth weight] birth weight less than the 10th centile for gestational age. [Health service use] duration of maternal hospital stay (days); duration of neonatal hospital stay (days). [Maternal adverse events] satisfaction with treatment; quality of life at 12–24 months after giving birth (measured using validated instruments); maternal sepsis. [Infant adverse events] bronchopulmonary dysplasia; intraventricular hemorrhage (grade 3 or 4); severe or profound vision impairment; sensorineural deafness requiring hearing aids; moderate or severe cerebral palsy or developmental delay/intellectual impairment; duration of mechanical ventilation.
Nifedipine versus betamimetics
[Mortality] infant death; infant death excluding congenital abnormality; maternal death. [Gestational age at birth] preterm neonate delivered with full course of antenatal steroids completed at least 12 h before birth. [Birth weight] birth weight less than the 10th centile for gestational age. [Health service use] maternal admission to intensive care unit (ICU). [Maternal adverse events] maternal cardiac arrest; maternal respiratory arrest; antepartum hemorrhage; postpartum hemorrhage; satisfaction with treatment; quality of life at 12–24 months after giving birth (measured by validated instruments); maternal sepsis. [Infant adverse events] severe or profound vision impairment; sensorineural deafness requiring hearing aids; hypoglycemia; patent ductus arteriosus; duration of mechanical ventilation; persistent pulmonary hypertension of the neonate; oligohydraminos.
Atosiban versus nifedipine (direct)
[Mortality] fetal, perinatal, neonatal, or infant death excluding congenital abnormality; fetal death; fetal death excluding congenital abnormality; perinatal death; perinatal mortality excluding congenital abnormality; neonatal death excluding congenital abnormality; infant death; infant death excluding congenital abnormality; maternal death. [Gestational age at birth] preterm birth less than 37 weeks’ gestation (37+0 days; 259 days); birth earlier than 34 weeks of gestation (34+0 days; 238 days); birth earlier than 28 weeks of gestation (28+0 days; 196 days); preterm neonate delivered with the full course of antenatal steroids completed at least 12 h before birth. [Birth weight] birth weight (grams); birth weight less than 1500 g; birth weight less than 2500 g; birth weight less than the 10th centile for gestational age. [Apgar score] Apgar score less than 7 at 5 min. [Health service use] duration of maternal hospital stay (days); maternal admission to ICU; duration of neonatal hospital stay (days); admission to neonatal ICU. [Maternal adverse events] maternal drug reaction requiring cessation of treatment; maternal cardiac arrest; maternal respiratory arrest; cesarean section birth; antepartum hemorrhage; postpartum hemorrhage; satisfaction with treatment; quality of life at 12–24 months after giving birth (measured using validated instruments); maternal sepsis. [Infant adverse events] respiratory distress syndrome; bronchopulmonary dysplasia; intraventricular hemorrhage (any grade); intraventricular hemorrhage (grade 3 or 4); severe or profound vision impairment; sensorineural deafness requiring hearing aids; moderate or severe cerebral palsy or developmental delay/intellectual impairment; necrotizing enterocolitis; neonatal sepsis; hypoglycemia; patent ductus arteriosus; neonatal jaundice; retinopathy of prematurity; use of mechanical ventilation; duration of mechanical ventilation; persistent pulmonary hypertension of the neonate; oligohydraminos.