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Progesterone in women with arrested premature labor, a report of a randomised clinical trial and updated… Wood, Stephen; Rabi, Yacov; Tang, Selphee; Brant, Rollin; Ross, Susan Aug 2, 2017

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RESEARCH ARTICLEProgesterone in women wmannrenlyyswsiban [4] have not been clearly effective in maintenancetocolysis. Based on the success of progesterone treatment inwith tocolytics or those with contractions that spontan-eously resolved but had a positive vaginal fetal fibronectinof membranesindication toallocated by aial statisticiand in randomified into twoWood et al. BMC Pregnancy and Childbirth  (2017) 17:258 DOI 10.1186/s12884-017-1400-y(ii) no tocolytic use. The primary investigators and studyT2N 2T9, CanadaFull list of author information is available at the end of the articlestrata to ensure balance in these important risk factors forpreterm birth between the two groups: (i) tocolytic use;* Correspondence: Stephen.wood@albertahealthservices.ca1Department of Obstetrics and Gynaecology, University of Calgary, 4th Floor,North Tower, Foothills Medical Centre 1441 - 29th Street NW, Calgary, ABwe initiated a clinical trial of progesterone in women witharrested premature labor. We report the results of our trialof treatment with 200 mg vaginal progesterone in womenwith arrested premature labor along with a meta-analysis ofall types of progesterone for maintenance tocolysis.placenta previa, preterm premature rupture(PPROM) at presentation and any contraprogesterone use. Consenting subjects wererandomization schedule developed by the tr(R.B) using a random number generator anblocks of 2 or 4. Randomization was stratpreventing prematurity in some high risk populations [5, 6], (>50 ng/ml). Exclusion criteria were multiple pregnancy,the mean latency to delivery: 44.5 days versus 46.6 days, p = .841. In the updated meta-analysis, progesteronetreatment did reduce delivery <37 weeks gestation and increase latency to delivery, but this treatment effectwas not evident in the high quality trials: (OR 1.23, 95% CI 0.91, 1.67) and (−0.95 days, 95% CI −5.54, 3.64)respectively.Conclusion: Progesterone is not effective for preventing preterm birth following arrested preterm labor.Keywords: Premature labor, Maintenance tocolysis, Progesterone, Clinical trial, Meta-analysisBackgroundA significant number of women who eventually deliverprematurely present with threatened preterm labor. Despitethe success of initial tocolysis [1], many will develop recur-rent labor and go on to deliver prematurely. These patientsrepresent an opportunity for the secondary prevention ofprematurity. Unfortunately, drugs such as calcium channelblockers [2], non-steroidal anti-inflammatories [3] and anto-MethodsRandomized Clinical TrialWomen presenting in premature labor to our center, theFoothills Medical Center in Calgary, Alberta, Canada,were approached by the primary investigator or studynurse for enrollment in the study. Inclusion criteria werewomen with gestational age 230–326 weeks with symp-tomatic contractions successfully arrested for at least 12 hdid not change the median gestational age at delivery: 36+2 weeks versus 36+4 weeks, p = .865 nor increasepremature labor, a reportclinical trial and updatedStephen Wood1* , Yacov Rabi2, Selphee Tang1, Rollin BrAbstractBackground: Progesterone may be effective in preventioWomen with arrested premature labor are at risk of recurtocolytics has not been successful.Methods: Randomized double blinded clinical trial of daiwith arrested premature labor and an updated meta-analResults: The clinical trial was terminated early after 41© The Author(s). 2017 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zeOpen Accessith arrestedof a randomisedeta-analysist3 and Susan Ross4of premature birth in some high risk populations.t labor and maintenance therapy with standardtreatment with 200 mg vaginal progesterone in womenis.omen were enrolled. Vaginal progesterone treatmentle is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.personnel involved in recruitment were not aware of theallocation sequence. Treatment packs containing 200 mgtablets of either micronized progesterone (Utrogestan,Besins-Healthcare) or an identical placebo were dispensedby a central research pharmacy. The treatment durationwas from the time of randomization until 356 weeks gesta-tion or until delivery of the fetus, if sooner. The primaryoutcomes of the trial were gestational age at delivery andlatency to delivery. Outcome assessors were blind to treat-ment status. The expected date of delivery recorded in thechart, at the time of randomization, was used subse-quently to determine gestational age at delivery. Second-ary outcomes included delivery <37 and <35 weeksgestation, recurrent premature labor and neonatal out-comes including death, broncho-pulmonary dysplasia,intraventricular hemorrhage, necrotizing enterocolitis,respiratory distress syndrome, hyperbilirubinemia, sepsisand need for ventilation. Our planned sample size was 60per group, based on a 90% power to detect a 2 week differ-ence in gestational age at delivery [7] at a significance levelof (0.05). The outcomes were analyzed by intention totreat with the subjects remaining in the group they wererandomized to, regardless of compliance with treatment.significance assessed by Fisher’s exact test. The othersecondary outcomes were analyzed similarly. The trial wasregistered at ClinicalTrials.gov (NCT01286246). The trialwas reported following CONSORT guidelines.Meta-analysisThe primary research question of the meta-analysis was:Does maintenance tocolysis with progesterone prevent pre-maturity, (<37 and <34 weeks gestation) or extend latencyto delivery? The secondary question was: Does treatmentreduce perinatal mortality. A literature search up to April2015 was performed using the following databases andMeSH terms: Medline (Tocolytic Agents, or Tocolysis, orObstetric labor, premature and Progesterone and Clinicaltrial), Embase (Premature labor or Tocolysis and Progester-one and Clinical trial), PubMed (premature labor andProgesterone and Clinical trial) and the Cochrane CentralRegister of Controlled Trials (Obstetric labor, premature orTocolysis and Progesterone). These searches were subse-quently updated in October 2015 and again in April 2016and February 2017. The identified abstracts and appropriatemanuscripts were reviewed by two of the authors (SW, SR).Studies were included if they were clinical trials ofWood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 2 of 12The gestational age at delivery were compared betweenthe two groups using the Mann-Whitney U test, as thedata was skewed. Mean latency to delivery was assessedusing the student’s t-test. For preterm delivery <37 weeksand <35 weeks, a relative risk was calculated and statisticalFig. 1 Flow diagram of studies included in the meta-analysisprogesterone in women with premature labor followingtocolysis. Risk of bias and quality of the manuscripts wasjudged independently by the reviewers using standard cri-teria [8]. All studies were graded as high or low qualitybased on four key quality indicators: adequaterandomization and allocation concealment, blinding, limitedlosses to follow up (<20%) and intention to treat analysis.Studies that were deficient in any of these areas were gradedas low quality. Studies were not included in the quantitativesummary analysis unless intent to treat analysis waspresented or could be calculated from the available data.Authors were contacted to obtain missing data. The primaryoutcomes of the meta-analysis were premature delivery <37and <34 weeks gestation and latency to delivery. Quantita-tive analysis with a fixed and random effects models wereperformed with RevMan 5.1. Statistical assessment forheterogeneity was performed and considered statisticallysignificant if p < .05. Random effects models were used foranalyses with significant heterogeneity. A subgroup analysisby type of progesterone (oral, vaginal or intra-muscular) andby trial quality was planned a priori. This analysis was donewith a fixed effects model even if there was significant het-erogeneity between high and low quality studies then pooledanalysis of all studies would not be meaningful. The meta-analysis results were reported as per PRISMA guidelines.ResultsRandomized Clinical TrialBetween February 2011 and February 2014 41 womenwere enrolled in the trial. Unfortunately, this did notmeet our recruitment goals. Furthermore, the study drugwe had been provided reached an expiry in August 2014and the provider had changed its progesterone product.To continue the trial a new application would have beennecessary to Health Canada. Given all these factors adecision was made to terminate the trial.The patient characteristics are provided in the AppendixTable 3 and were adequately balanced between the twogroups. The flow diagram for the trial is provided in Appen-dix Figure 8. There were no losses to follow up nor postrandomization exclusions. Treatment with progesterone,compared to placebo, did not result in an increase in mediangestational age at delivery: 36+2 weeks versus 36+4 weeks,mean difference − .02 (−3+1 to 2+3) nor in mean latency todelivery: 44.5 days versus 46.6 days, mean difference − 2.1(−22.8, 16.8). No significant differences were detected in anyTable 1 Study characteristics of randomized controlled trials of progesterone for maintenance tocolysisStudy Year Country Number ofSubjectsStudy Population Treatment/controlsAreia [22] 2013 Portugal 52 24–34 weeks gestation cervical length≤ 25 mm after tocolysis with antosiban.Progesterone 200 mg vaginally/Notreatment.Borna [21] 2008 Iran 70 24–34 weeks gestation after tocolysiswith MgSO4, cervical dilation ≤2 cm.Progesterone 400 mg vaginally/Notreatment.Choudhary [13] 2014 India 90 24–34 weeks gestation after tocolysiswith nifedipine, cervical dilation >1 cm.Progesterone 200 mg orally/PlaceboFacchinetti [15] 2007 Italy 60 25–34 weeks gestation after tocolysiswith antosiban.17-hydroxyprogesterone caporate341 mg IM q 4 days/ No treatmenteste.geeestritgeermgemgegentokergeipigegeWood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 3 of 12Kamat [20] 2014 India 110 <37 weeks gwith nifedipinLotfalizadeh [24] 2013 Iran 110 26–36 weekswith nifedipinNoblot [12] 1991 France 44 <37 weeks gtocolysis withPalacio [19] 2013 Spain 265 24–34 weeks≤ 25 mm.Arrested pretnot specifiedRozenberg [14] 2012 France 188 24–31 weekslength < 25 mSharami [18] 2010 Iran 173 28–36 weeksde Tejada 2015 Switzerland andArgentina384 24–33 weeksβ-mimetics, achannel blocBriery [16] 2014 USA 45 20–30 weeksNSAIDS, nifedGargari [23] 2012 Iran 110 24–33 weekswith MgSO4Wood 2017 Canada 41 23–33 weekswith NSAIDS orand positive vagation, after tocolysis Progesterone 400 mg vaginally/nifedipine 20 mg q8h.station, after tocolysisor MgSO4Progesterone 400 mg vaginally, or17-hydroxyprogesterone caporate250 mg IM/No treatment.ation, regular contractions,odrineProgesterone 400 mg orally, startedbefore cessation of contractions/Placebo.station, cervical lengthlabour, tocolyticProgesterone 200 mg vaginally/Placebo.station and cervicalafter tocolysis17-hydroxyprogesterone caporate500 mg biweekly/No treatment.station, tocolysis with MgS04 Progesterone 200 mg vaginally/Placebo.station, tocolysis withsiban, or calciums.Progesterone 200 mg vaginally/Placebo.station, tocolysis withne or MgSO417-hydroxyprogesterone caporate250 mg IM weekly/ Placebostation, tocolysis Progesterone 400 mg vaginally/Notreatmentstation, after tocolysis Progesterone 200 mg vaginally/Placebo.nifedipine or no tocolysisinal fetal fibronectinof the secondary outcomes, Appendix Table 4. There wereno perinatal deaths. Only 50% of subjects returned theirtreatment diaries and unused capsules so reliable estimates ofcompliance could not be made.Meta-analysisThe initial literature search initially identified 96 (Medline),167 (Embase), 163 (PubMed) and 18 (Cochrane) abstracts.The updated literature search identified a further 60abstracts. The details of the review process are presented inFig. 1. Ultimately, 18 trials (including ours) were identifiedand 15 were included in the meta-analysis. The reasons forexclusion were: two trials were single dose progesteronetreatment for acute tocolysis only not maintenance tocoly-sis [9, 10] and one was a trial of prophylactic 17-hydroxyprogesterone caporate in women with previouspremature delivery [11]. The details of the included trialsare presented in Table 1. Two trials employed oralprogesterone [12, 13], three used intra-muscular 17-hydroxyprogesterone caporate [14–16], our trial and sevenothers used vaginal progesterone [17–23] and one trialcompared intramuscular 17-hydroxyprogesterone caporateor vaginal progesterone to no treatment [24]. Eight authorswere contacted by email requesting additional informationregarding outcomes not reported in their manuscripts andresponses were received from three. All the trials werereviewed for quality by two reviewers (SW, JR). Five werejudged to be high quality and nine low quality (Table 2).Overall, treatment with progesterone reduced preterm birthless than 37 weeks gestation (OR 0.77, 95% CI 0.62, 0.96).However, this was not statistically significant for the vaginalprogesterone nor intra-muscular 17-hydroxyprogesteronecaporate subgroups (Fig. 2). The proportion of births before34 weeks gestation was also reduced with treatment (ORTable 2 Quality assessment of randomized controlled trials of progesterone for maintenance tocolysisStudy Randomization/Allocationconcealment methodBlinding Compliance with treatment Post RandomizationExclusionsIntention toTreat analysisQuality Included inmeta-analysisAreia “no allocation concealment” No None discontinuedtreatmentNo Yes Low YesBorna Random number list, noallocation concealmentNo Unclear No Yes Low YesChoudhary Computer generated list,“randomly allocated bythird party”Yes Unclear Yes, 2 in progesteronegroup, 3 in placebo groupYes Low YesFacchinetti Computer generated list,“managed by the seniormidwife”No “Patients werecompliant”No Yes Low YesKamat Computer generatedrandom number table.Unclear allocationconcealmentNo Unclear Yes, 4 in progesteronegroup 6 in control.Yes Low Yesndtop58Wood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 4 of 12Lotfalizadeh No information provided. No UnclearNoblot Randomized scheduleprepared by pharmacyYes UnclearPalacio Centralized computerrandomizationYes UnclearRozenberg Centralized computerrandomization.NoSharami “randomized into twogroups using the randomblock allocation method”Yes Unclearde Tejada Centralized computerrandomization.Yes 4 in progesterone ain placebo groups smedication. OverallcomplianceBriery Sequentially numberedsealed opaque envelopesYes UnclearGargari Unclear No UnclearWood Pharmacy randomization Yes Unclearwith schedule concealedfrom clinicians.? ? Low YesNone Yes High YesYes 6 in progesteronegroup.Yes High YesYes, 1 in progesteronegroup and 4 in control.Yes Low YesYes, 6 in progesteronegroup, 4 in placeboYes Low Yes5ped%Yes 4 in progesteronegroup, 2 in placebo.Yes High YesNone Yes High YesYes, 38 subjects ? Low YesNone Yes High Yes0.80, 95% CI 0.60, 1.08) but this difference was notstatistically significant (Fig. 3). Additionally, a statisti-cally significant increase in latency to delivery wasapparent for all three progesterone treatments (Fig. 4).Planned subgroup analysis by quality revealed that theresults varied significantly between high and low qualitytrials (Figs. 5, 6 and 7). The pooled results of the lowquality trials suggested a reduction in the risk of deliveryless than 37 weeks (OR 0.47, 95% CI 0.34, 0.64), less than34 weeks (OR 0.55, 95% CI 0.35, 0.86) and increasedlatency to delivery (15.97 days, 95% CI 14.09, 17.84).However, the summary of high quality trials did not revealany benefit for any of the outcomes: delivery less than37 weeks (OR 1.23, 95% CI 0.91, 1.67), delivery less than34 weeks (OR 1.12, 95% CI 0.74, 1.69) nor latency todelivery (−0.95 days, 95% CI −5.54, 3.64). Only five trialsreported any perinatal deaths, 31 in the low quality trialsand 9 in the high quality trials. Progesterone treatmentwas associated with a reduction in risk of perinataldeath in the low quality trials: (OR 0.39, 95% CI 0.17,0.87) but not the high quality trials: (OR 0.52, 95% CI0.14, 1.95).DiscussionNeither our trial result nor the meta-analysis suggestprogesterone is effective for maintenance tocolysis. Al-though the overall pooled analysis in the meta-analysisfavors a treatment effect, the high quality studies donot. One previously published meta-analysis of vaginalprogesterone for maintenance tocolysis concluded thattreatment was associated with a reduced risk of prema-turity and prolongation of pregnancy [25]. However, nosubgroup analysis by study quality was reported. Over-all, we feel that the results of the high quality studies arethe most reliable indicator of a null treatment effect. Ifanything, it could be argued that these studies suggest apotential for harm with as the point estimates suggestedan increase in prematurity and shorter latency withtreatment. The substantial effect of trial quality that weobserved has been reported previously. Several groupshave found that poor allocation concealment andblinding influence results, usually, by increasing posi-tive treatment effects [26–28]. Although some readersmay prefer the results of the pooled analysis of allthe trials, we would caution against this. The historyWood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 5 of 12Fig. 2 Forest plot for the outcome: Delivery less than 37 weeks comparing treatment with progesterone to controlsFig. 3 Forest plot for the outcome: Delivery less than 34 weeks comparing treatment with progesterone to controlsFig. 4 Forest plot for the outcome latency to delivery (days) comparing treatment with progesterone to controlsWood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 6 of 12Wood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 7 of 12of clinical trials has taught trialists the importanceof protecting their research from their own biases byusing good study design. Therefore, results fromstudies with good design and execution are morelikely to produces reliable estimates of effect. In thisinstance, such studies do not suggest progesterone,by any route, is an effective therapy for prolongingpregnancy in women who have arrested prematurelabor.Still, alternative explanations should be consideredfor the negative results of both our trial and themeta-analysis. One typical issue, low power, is notone we feel is likely. Although latency to delivery isnot necessarily, by itself, a clinically important end-point, it should be a sensitive indicator of biologic ef-fect. That we observe no discernible effect on latencyin our trial and the summary of the high quality trialssupport a conclusion that progesterone is ineffective.It does remain a possibility that an effective proges-terone dose has yet to be determined and future trialsof increased doses may show positive results. Unfor-tunately, although our review found a fair number ofstudies that used higher doses of both vaginal andFig. 5 Forest plot for the outcome: Delivery less than 37 weeks comparingintra-muscular progesterone, none of these was highquality trial. A search of ClinicalTrials.gov only iden-tified one additional, terminated, and unreported trialthat used 400 mg vaginal progesterone which re-cruited 7 subjects (NCT00946088). Poor patient com-pliance is also a potential explanation for our results.Regrettably, in our study, we were unable to reliablycomment on compliance, as too few subjects returnedtheir pill diaries or unused medications. This did notseem to be unique to our trial as very few of thestudies reported any measures of patient compliance.While in the case of treatment with intra-muscular17-hydroxyprogesterone caporate, poor compliancemay be evident to the investigators, the same cannotbe said of vaginal or oral routes.ConclusionsIn summary, our results do not support the routine useof progesterone, in any form, for maintenance tocolysis.However, further clinical trials with good measurementof patient compliance and higher doses of progesteronecould be justified.treatment with progesterone to controls stratified by trial qualityFig. 6 Forest plot for the outcome: Delivery less than 34 weeks comparing treatment with progesterone to controls, stratified by trial qualityFig. 7 Forest plot for the outcome latency to delivery (days) comparing treatment with progesterone to controls, stratified by trial qualityWood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 8 of 12AppendixTable 3 Patient CharacteristicsCharacteristic Progesteronen = 19Placebon = 22Mean Maternal age (years) 26.5 (SD 3.9)Range 20–3429.1 (SD 5.9)Range 19 to 39Mean Gestational age at randomization (weeks and days) 29+0 (SD 2+2)Range 24+2 to 32+528+4 (SD 2+5)Range 23+1 to 32+3Gravidity1 4 (21.1%) 7 (31.8%)2 9 (47.4%) 7 (31.8%)3 or more 6 (31.6%) 8 (36.4%)Parity0 6 (31.6%) 10 (45.5%)1 8 (42.1%) 7 (31.8%)2 or more 5 (26.3%) 5 (22.7%)Number of previous PTB <37 weeks0 10 (58.8%) 16 (72.7%)1 5 (29.4%) 3 (13.6%)2 2 (11.8%) 3 (13.6%)Unknown 2 0Conception (this pregnancy)Spontaneous 14 (93.3%) 17 (81.0%)Ovulation induction alone 1 (6.7%) 3 (14.3%)IVF 0 (0.0%) 1 (4.8%)Unknown 4 1Multiple reduction (before randomization)No 16 (100%) 22 (100%)Unknown 3 0Pregnancy complications (this pregnancy, before or at time of randomization)None 3 (17.6%) 10 (47.6%)Diabetes 1 (5.9%) 0 (0.0%)Uterine abnormality 0 (0.0%) 1 (4.8%)Previous AP bleed 5 (29.4%) 3 (14.3%)Recreational drugs 0 (0.0%) 1 (4.8%)Smoker 6 (35.3%) 4 (19.0%)Othera 7 (41.2%) 5 (23.8%)Unknown 2 1a Other in Group A includes cardiac disease; crohns/ileostomy/mult bowel resections; epilepsy/fam hx von willebrands; hypothyroidism/hx post partumdepression; and limb girdle muscular dystrophy/ marginal placenta previa/prev thyroidectomy. Other in Group B includes depression/prev ruptured spleen; hxgenital herpes; migraines/small septate uterus; depression/maternal grade 2 cardiac murmer; asthmatic; small subchorionic bleed noted on 8w US; and twoprev csWood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 9 of 12Fig. 8 Consort DiagramTable 4 Outcomes to 28 days after deliveryProgesteronen = 19Placebon = 22p-value* Median/Mean/Risk Difference(95% Confidence Interval)*Primary outcomeMedian Gestational age at delivery (weeks and days) 36+2 (IQR 7+4)Range 26+6 to 41+236+4 (IQR 8+0)Range 24+3 to 41+20.865 −0+2(−3+1 to 2+3)Mean Latency from randomization to delivery (days) 44.5 (SD 35.6)Range 0 to 11346.6 (SD 29.9)Range 2 to 1160.841 −2.1(−22.8 to 18.6)Secondary outcomesMaternal outcomesGestational age at delivery <37 weeks 11 (57.9%) 11 (50.0%) 0.758 7.9%(−23.1% to 38.0%)Gestational age at delivery <35 weeks 8 (42.1%) 9 (40.9%) >0.999 1.2%(−29.5% to 31.4%)Gestational age at delivery <34 weeks 7 (36.8%) 8 (36.4%) >0.999 0.5%(−30.0% to 30.4%)Tocolytics at any time during this pregnancyYes 14 (77.8%) 16 (84.2%) 0.693 −6.4%(−36.3% to 26.3%)No 4 (22.2%) 3 (15.8%)Unknown 1 3PPROMYes 3 (16.7%) 4 (18.2%) >0.999 −1.5%(−32.0% to 28.8%)No 15 (83.3%) 18 (81.8%)Unknown 1 0Betamethasone treatmentYes 15 (93.8%) 18 (94.7%) >0.999 −1.0%(−33.1% to 31.6%)No 1 (6.3%) 1 (5.3%)Unknown 3 3Mode of deliveryVaginal 9 (47.4%) 16 (72.7%) 0.493 14.1%Wood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 10 of 12Hypertension 0 (0.0%)Wood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 11 of 12AP bleed 0 (0.0%)Othera 3 (16.7%)Table 4 Outcomes to 28 days after delivery (Continued)Operative vaginal 3 (15.8%)Cesarean Section 7 (36.8%)Delivery complicationsNone 15 (83.3%)AbbreviationsCI: Confidence interval; OR: Odds ration; PPROM: Preterm premature ruptureof membranesFundingThe trial was funded by the Calgary Perinatal Funding Competitions which isfunded by Ross Products a division of Abbott. Besins Healthcare (UK)provided the study medication and placebos. The authors are members ofthe Partnership for Research and Education in Mothers and Infants whichhas been funded by Ross Products a division of Abbott.Availability of data and materialsData is available on request from the corresponding author.Unknown 1Infant outcomesMedian Birth weight (grams) 2625 (IQR 1340)Range 750 to 37(missing = 1)Adverse outcomesOne or more 10 (66.7%)None 5 (33.3%)Unknown 4Description of outcomes (could be more than one)Stillbirth/neonatal death 0BPD 0IVH 0NEC 0RDS 4Apnea/bradycardia 1Jaundice/hyperbilirubinemia 4Suspected sepsis 2Transient tachypnea 1Otherb 8On ventilator 0Median Baby length of stay (days) 6 (IQR 29)Range 0 to 86(missing = 3)a Other includes: 3rd degree tear, maternal pancreatitis, and assisted breech extractb Other in Group A includes: ventriculomegaly, admission to nicu (reason unknownbilateral echogenic kidneys, PDA, positive enterobacter CONS tracheal aspirate, edenephrocalcinosis, HMD, bilateral inguinal hernia, SGA, RT hydro ureter. Other in Grohypotension, minor hypospadius, oral aversion, SGA* Fisher’s exact test for categorical variables, Mann-Whitney U test or t-test for contvariables, Hodges-Lehmann estimation of location shift (median of differences) or d(−16.5% to 43.2%)1 (4.6%)5 (22.7%)18 (90.0%) 0.653 6.7%(−24.7% to 38.1%)1 (5.0%)1 (5.0%)0 (0.0%)Authors’ contributionsAll authors contributed to the design of the study. SW, SR, JR, and RBdesigned the trial. SW and SR designed the review. SW and JR reviewed andscored all the abstracts. SW, RB and ST performed the statistical analysis andall the authors contributed to the interpretation of the results. SW draftedthe manuscript which was reviewed by all of the authors. All authors readand approved the final manuscript.Ethics approval and consent to participateThe study was approved by the local ethics review board REB15-1435 and ano objection letter was also obtained from Health Canada. Signed informedconsent was obtained from all subjects.Consent for publicationNA2662660 (IQR 1555)Range 670 to 39550.734 −105(−739 to 506)0.732 9.5%(−23.9% to 41.1%)12 (57.1%)9 (42.9%)10301726222043 (IQR 38)Range 1 to 127(missing = 4)0.903 0(−15 to 10)ion), hypoglycemia, ROP, pulmonary insufficiency, GERD, esophageal atrenia,ma, hyperkalemia, anemia, metabolic acidosis, acute renal insufficiency,up B includes: hypoglycemia, small cleft palate, hypovolemia, query infection,inuous variables; Risk difference and exact 95% confidence limits for categoricalifference in means and 95% confidence limits for continuous variables2014;34(4):322–5.21. Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy afterthreatened preterm labour: a randomised controlled trial. Aust N Z J Obst Gynaecol.2008;48(1):58–63.22. Areia A, Fonseca E, Moura P. Progesterone use after successful treatment ofthreatened pre-term delivery. J Obstet Gynaecol. 2013;33:678–81.23. Gargari SS, Habibolahi M, Zonobi ZKZ, Sarfjoo FS, Robati AK, Etemad R, et al.Outcome of Vaginal Progesterone as a Tocolytic Agent: Randomized Clinical Trial.ISRN Obstet Gynecol. 2012;2012:607906.24. Lotfalizadeh M, Ghomian N, Reihani A. The effects of progesterone therapyon the gestation length and reduction of neonatal complications inpatients who had received tocolytic therapy for acute phase of pretermlabor. Iran Red Crescent Med J. 2013;15(10):e7947.25. Suhag A, Saccone G, Berghella V. Vaginal progesterone for maintenancetocolysis: a systematic review and metaanalysis of randomized trials.Am J Obstet Gynecol. 2015;213:479–87.26. Odgaard-Jensen J, Vist GE, Timmer A, Kunz R, Akl EA, Schunemann H, et al.Wood et al. BMC Pregnancy and Childbirth  (2017) 17:258 Page 12 of 12Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Obstetrics and Gynaecology, University of Calgary, 4th Floor,North Tower, Foothills Medical Centre 1441 - 29th Street NW, Calgary, ABT2N 2T9, Canada. 2Alberta Children’s Hospital Research Institute, FoothillsMedical Centre, Room, rm C211 1403 - 29th Street NW, Calgary, AB T2N 2T9,Canada. 3Department of Statistics, University of British Columbia, ESB rm3146, 2207 Main Mall F512-4480 Oak Street, Vancouver, BC, Canada.4Obstetrics & Gynecology, University of Alberta, 5S141 Lois Hole Hosp/Robbins Pav/RAH, Edmonton, AB T5H 3V9, Canada.Received: 22 April 2016 Accepted: 2 July 2017References1. 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