Advertisement

Is oxytocin receptor antagonist administration around embryo transfer associated with IVF treatment success? A systematic review and meta-analysis

Published:August 27, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.08.020

      Abstract

      A systematic literature review and meta-analysis was conducted to evaluate whether the administration of an oxytocin receptor antagonist (OTR-a) around embryo transfer is associated with live birth and pregnancy achievement in IVF treatment. Multiple databases were searched for randomized controlled trials (RCT) comparing the outcome of IVF treatment with administration of an OTR-a before, during or after embryo transfer versus administration of placebo/nil. The literature search identified 11 eligible RCT. The active compound was intravenous atosiban (n = 7), subcutaneous barusiban (n = 1) and oral nolasiban (n = 3). Clinical pregnancy rate was significantly higher in women receiving an OTR-a around embryo transfer (relative risk [RR] 1.31, 95% confidence interval [CI] 1.13–1.51, P = 0.0002, I2 = 61%, n = 11 studies, n = 3611); however, live birth rate was not statistically significantly affected (RR 1.09, 95% CI 0.98–1.20, P = 0.11, I2 = 25%, n = 5 studies, n = 2765). A sensitivity analysis on low risk of bias studies likewise indicates a higher clinical pregnancy chance (RR 1.11, 95% CI 1.01–1.22, P = 0.03, I2 = 5%, n = 5 RCT, n = 2765). OTR-a administration in IVF treatment has the potential to increase IVF efficacy, although the treatment effects observed so far are small and have not been sufficiently corroborated.

      Keywords

      Introduction

      Despite significant improvements and standardization of IVF treatment regimens in recent decades, the success rate has remained stable, with a likelihood of live birth per IVF treatment cycle of approximately 25–30% (
      Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology
      2014 Assisted Reproductive Technology National Summary Report.
      ;
      • Luke B.
      • Brown M.B.
      • Wantman E.
      • Lederman A.
      • Gibbons W.
      • Schattman G.L.
      • Lobo R.A.
      • Leach R.E.
      • Stern J.E.
      Cumulative birth rates with linked assisted reproductive technology cycles.
      ;
      • Toftager M.
      • Bogstad J.
      • Løssl K.
      • Prætorius L.
      • Zedeler A.
      • Bryndorf T.
      • Nilas L.
      • Pinborg A.
      Cumulative live-birth rates after one ART cycle including all subsequent frozen-thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols.
      ). New technologies are therefore constantly proposed to improve IVF treatment outcomes (
      • Harper J.
      • Jackson E.
      • Sermon K.
      • Aitken R.J.
      • Harbottle S.
      • Mocanu E.
      • Hardarson T.
      • Mathur R.
      • Viville S.
      • Vail A.
      • Lundin K.
      Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions?.
      ). The list of currently offered, presumably beneficial, adjuncts is long and includes pharmacological add-ons (e.g. dehydroepiandrostenedione, growth hormones, testosterone, coenzyme Q10, heparin, low-dose aspirin, vasodilators, myo-inositol), laboratory technology (e.g. sperm DNA fragmentation testing, sperm selection procedures, time-lapse embryo monitoring, preimplantation genetic testing, assisted hatching, endometrial injury or embryo adherence compounds), and others such as lifestyle interventions or acupuncture. Because failure of embryonic implantation is the most frequent cause of IVF failure, maternal mechanisms around embryo attachment and invasion have attracted great interest.
      Uterine contractions have been described to be negatively correlated with the likelihood of embryonic implantation (
      • Fanchin R.
      • Righini C.
      • Olivennes F.
      • Taylor S.
      • de Ziegler D.
      • Frydman R.
      Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization.
      ;
      • Zhu L.
      • Che H.S.
      • Xiao L.
      • Li Y.P.
      Uterine peristalsis before embryo transfer affects the chance of clinical pregnancy in fresh and frozen-thawed embryo transfer cycles.
      ). In addition, endometrial blood flow was postulated to be a positive predictor for endometrial receptivity. In the myometrium, endometrium and in blood vessels of the uterus, oxytocin receptors have been shown to be expressed around the time of implantation (
      • Kim A.
      • Jung H.
      • Choi W.J.
      • Hong S.N.
      • Kim H.Y.
      Detection of endometrial and subendometrial vasculature on the day of embryo transfer and prediction of pregnancy during fresh in vitro fertilization cycles.
      ). Blocking of oxytocin receptors was found to decrease uterine contractility and increase endometrial perfusion (
      • Kalmantis K.
      • Loutradis D.
      • Lymperopoulos E.
      • Beretsos P.
      • Bletsa R.
      • Antsaklis A.
      Three dimensional power Doppler evaluation of human endometrium after administration of oxytocine receptor antagonist (OTRa) in an IVF program.
      ;
      • Pierzynski P.
      • Reinheimer T.M.
      • Kuczynski W.
      Oxytocin antagonists may improve infertility treatment.
      ;
      • Pierzynski P.
      Oxytocin and vasopressin V(1A) receptors as new therapeutic targets in assisted reproduction.
      ). Additionally, evidence for increased endometrial receptivity and decidualization after oxytocin receptor antagonist (OTR-a) administration was previously reported (
      • Sztachelska M.
      • Ponikwicka-Tyszko D.
      • Sokolowska G.
      • Anisimowicz S.
      • Czerniecki J.
      • Lebiedzinska W.
      • Zbucka-Kretowska M.
      • Zygmunt M.
      • Wolczynski S.
      • Pierzynski P.
      Oxytocin antagonism reverses the effects of high oestrogen levels and oxytocin on decidualization and cyclooxygenase activity in endometrial tissues.
      ). A recent investigation reported an altered gene expression profile favourable for embryo implantation following administration of an OTR-a (
      • Pierzyński P.
      • Pohl O.
      • Marchand L.
      • Mackens S.
      • Lorch U.
      • Gotteland J.P.
      • Blockeel C.
      Oxytocin antagonist mechanism of action in ART – a prospective, randomized study of nolasiban effects on uterine contraction, perfusion and gene expression in healthy female volunteers.
      ). A previous clinical study showing an increased likelihood of embryo implantation for patients having an OTR-a administered irrespective of the frequency of uterine contractions, points towards a potential clinical significance of these effects (
      • Lan V.T.
      • Khang V.N.
      • Nhu G.H.
      • Tuong H.M.
      Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure.
      ).
      As a result, it has been postulated that antagonism of oxytocin receptors around embryo transfer may have the potential to increase the likelihood of implantation of an embryo.
      The drug atosiban is a peptide functioning as a mixed OTR-a and vasopressin receptor antagonist. It is approved for use in pregnancy to delay imminent preterm birth. However, atosiban administration is rather challenging in an IVF treatment due to its short half-life (t½) of 13 minutes, necessitating intravenous administration. The use of atosiban around embryo transfer was reported in the literature for the first time in a case report on an implantation failure patient (
      • Pierzynski P.
      • Reinheimer T.M.
      • Kuczynski W.
      Oxytocin antagonists may improve infertility treatment.
      ), and was later investigated by a number of clinical studies. A systematic review and meta-analysis including four randomized controlled trials (RCT) and two observational studies suggested an association of atosiban administration with improved IVF outcomes (
      • Schwarze J.E.
      • Crosby J.
      • Mackenna A.
      Atosiban improves the outcome of embryo transfer. A systematic review and meta-analysis of randomized and non-randomized trials.
      ). As an alternative to atosiban, the OTR-a barusiban has been developed for subcutaneous administration (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ). Barusiban is a peptide with a longer half-life of 8 h and higher selectivity for oxytocin receptors. While found to be ineffective for the indication of preterm birth delay (
      • Reinheimer T.M.
      • Bee W.H.
      • Resendez J.C.
      • Meyer J.K.
      • Haluska G.J.
      • Chellman G.J.
      Barusiban, a new highly potent and long-acting oxytocin antagonist: pharmacokinetic and pharmacodynamic comparison with atosiban in a cynomolgus monkey model of preterm labor.
      ), some preliminary data on barusiban administration in IVF treatment have been released recently (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ). A further OTR-a is the orally active compound nolasiban (
      • Kim S.H.
      • Pohl O.
      • Chollet A.
      • Gotteland J.P.
      • Fairhurst A.D.
      • Bennett P.R.
      • Terzidou V.
      Differential effects of oxytocin receptor antagonists, atosiban and nolasiban, on oxytocin receptor-mediated signaling in human amnion and myometrium.
      ), a non-peptide showing a higher specificity for oxytocin receptors and with a longer t½ of up to 2 days compared with atosiban. Recently the use of nolasiban has been investigated in a large Phase 2/3 trial programme (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ). The present systematic literature review and meta-analysis collates the existing evidence from RCT on the use of all drugs functioning as OTR-a in the context of improving IVF treatment outcomes.

      Materials and methods

      This systematic review was prospectively registered at PROSPERO (ID CRD42021227919). An electronic search was performed in the databases PubMed, EMBASE, Web of Science, Google Scholar, Cochrane Library and ClinicalTrials.gov. No restrictions were applied on language or timeframe. The literature search and study selection were conducted according to PRISMA guidelines (
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • Shamseer L.
      • Tetzlaff J.M.
      • Akl E.A.
      • Brennan S.E.
      • Chou R.
      • Glanville J.
      • Grimshaw J.M.
      • Hróbjartsson A.
      • Lalu M.M.
      • Li T.
      • Loder E.Q.
      • Mayo-Wilson E.
      • McDonald S.
      • McGuinness L.A.
      • Stewart L.A.
      • Thomas J.
      • Tricco A.C.
      • Welch V.A.
      • Whiting P.
      • Moher D.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ).
      The literature search aimed to identify RCT, from which comparative data were retrieved on clinical outcomes after application of an OTR-a versus placebo or nil in IVF patients. The computerized literature search was performed using various combinations of involved terminology and keywords and was completed on 12 February 2021 (Supplementary Information).

      Selection criteria

      RCT (i.e. trials having a control group and a random allocation to either group) in IVF patients using an OTR-a around embryo transfer were considered for inclusion in this systematic review. There were no exclusion criteria regarding specific drugs, patient number, route of drug administration, patient population or stage/quality of transferred embryos. Two review authors (KN, GG) independently scanned titles and abstracts identified from the searches. Potentially relevant trials were selected and independently assessed for inclusion in this review.

      Criteria for considering studies for this review

      Types of included studies

      RCT were included in the review; non-randomized studies were excluded. Studies in which one subject could contribute more than one treatment cycle (e.g. crossover study designs) were considered for exclusion.

      Types of participants and treatment cycles

      Subfertile women undergoing IVF or intracytoplasmic sperm injection (ICSI) for treatment of infertility who were randomly assigned to receive an OTR-a or placebo/nil shortly before, during or after embryo transfer.
      Women who were not undergoing IVF or ICSI (i.e. those undergoing intrauterine insemination) were not included.

      Types of interventions

      OTR-a in comparison with placebo or nil administered around embryo transfer with or without luteal phase support, in autologous or donor cycles, in fresh or frozen embryo transfer cycles.

      Types of outcome measures

      Primary outcomes: live birth rate and clinical pregnancy rate per intention-to-treat (ITT) analysis (
      • Duffy J.M.N.
      • Bhattacharya S.
      • Bhattacharya S.
      • Bofill M.
      • Collura B.
      • Curtis C.
      • Evers J.L.H.
      • Giudice L.C.
      • Farquharson R.G.
      • Franik S.
      • Hickey M.
      • Hull M.L.
      • Jordan V.
      • Khalaf Y.
      • Legro R.S.
      • Lensen S.
      • Mavrelos D.
      • Mol B.W.
      • Niederberger C.
      • Ng E.H.Y.
      • Puscasiu L.
      • Repping S.
      • Sarris I.
      • Showell M.
      • Strandell A.
      • Vail A.
      • van Wely M.
      • Vercoe M.
      • Vuong N.L.
      • Wang A.Y.
      • Wang R.
      • Wilkinson J.
      • Youssef M.A.
      • Farquhar C.M.
      Core Outcome Measure for Infertility Trials (COMMIT) Initiative. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study.
      ).
      Secondary outcomes: ongoing pregnancy rate per ITT analysis; miscarriage rate per ITT analysis; multiple pregnancy per ITT analysis; ectopic pregnancy per ITT analysis. Implantation rate is not an outcome of the present meta-analysis because methodological issues are associated with its use (
      • Griesinger G.
      Beware of the ‘implantation rate’! Why the outcome parameter ‘implantation rate’ should be abandoned from infertility research.
      ;
      • Harbin Consensus Conference Workshop Group
      • Conference Chairs
      • Legro R.S.
      • Wu X.
      • Scientific Committee
      • Barnhart K.T.
      • Farquhar C.
      • Fauser B.C.
      • Mol B.
      Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement.
      ).

      Subgroup and sensitivity analyses

      Subgroup: by compound

      A subgroup analysis was planned for type of investigated compound.

      Sensitivity: by randomization

      A sensitivity analysis was planned by excluding trials with a high risk (e.g. pseudo-randomized and unclear if truly randomized or unclear allocation concealment) of bias in any of the domains of the grading table. Grading of the evidence was performed in Review Manager (RevMan) Version 5.4.1 according to Cochrane recommendations (The Cochrane Collaboration, 2020).

      Data extraction and analysis

      Features of studies and results were assembled in tabular form and a formal meta-analysis was conducted. For each study the dichotomous data results were expressed as a relative risk (RR) with a 95% confidence interval (CI). For meta-analysis, these results were combined with RevMan 5.4.1 using the Mantel–Haenszel method. Study-to-study variation was assessed using Cochrane's Q test. For heterogeneity (I2 ≥ 40%) a random-effect model was used and for I2 < 40% a fixed-effect model was chosen based on considerations in the Cochrane Handbook (https://training.cochrane.org/handbook/current/chapter-10).

      Results

      Study selection

      Figure 1 depicts a flow chart of identified and included studies according to PRISMA guidelines (
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • Shamseer L.
      • Tetzlaff J.M.
      • Akl E.A.
      • Brennan S.E.
      • Chou R.
      • Glanville J.
      • Grimshaw J.M.
      • Hróbjartsson A.
      • Lalu M.M.
      • Li T.
      • Loder E.Q.
      • Mayo-Wilson E.
      • McDonald S.
      • McGuinness L.A.
      • Stewart L.A.
      • Thomas J.
      • Tricco A.C.
      • Welch V.A.
      • Whiting P.
      • Moher D.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ). Of the 165 records identified, 41 full-text articles were assessed for eligibility. Thirty of these were excluded for the following reasons: 16 were duplicates, three studies had no control group, two studies had no randomization and one study was still ongoing. Furthermore, six registrations of RCT were found by the electronic literature search of the databases ClinicalTrials.gov and the World Health Organization (WHO) trials registry platform. Five of these studies described an investigation of the compound atosiban; one study description did not specify the type of investigated OTR-a. Investigators involved in these studies were contacted for further information on the status of these RCT, but no responses were received.
      Figure 1
      Figure 1PRISMA flow chart of study selection.
      One RCT (
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ) had to be partially translated into English. The studies by
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      and
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      were only published as an abstract and a poster at a conference, respectively; no full-text publication was available. Eleven studies fulfilled the inclusion criteria (
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ;
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ;
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      ;
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ;
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ;
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ). Characteristics of all included RCT are shown in Table 1.
      Table 1Included randomized controlled studies investigating the use of oxytocin receptor antagonists
      Study (year of publication)Primary / secondary endpointsPatients randomized (n)Hypothesis / sample size calculationPatient populationDrugDose and administrationControl group interventionEmbryo quality / day of ET
      Partially translated into English.
      Primary: clinical pregnancy rate; implantation rate

      Secondary: miscarriage rate, ectopic pregnancy rate
      40No sample size calculation or primary hypothesis providedTwo or more previously failed IVF/ICSI cycles; exclusion of patients with low ovarian reserve; no previous hormonal treatment for three months before inclusionAtosibanBolus dose i.v. of 6.25 mg 1 h before ET and continuous infusion rate of 18 mg/h; post-transfer infusion was reduced to 6 mg/h for 2 hInformation not providedNo specific stipulations
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      , BASIC study
      No full text available
      Primary: ongoing implantation (= viable fetuses 10–11 weeks after transfer divided by the number of embryos/blastocysts transferred)

      Secondary: pregnancy rate, live birth rate
      255Sample size calculation unclear, superiority designPatients with IVF/ICSI; 18-37 years with ‘history of repeated implantation failure’; normal karyotype; no uterine pathology or hydrosalpinx; single or double ET in a fresh cycleBarusiban40 mg 45 min before transfer and 10 mg 15 min post-transfer s.c.PlaceboSingle or double transfer of good-quality embryos on D3 or D5
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ; IMPLANT 1
      Primary: clinical pregnancy rate

      Secondary: ongoing pregnancy rate, live birth rate, miscarriage rate, multiple pregnancy rate, ectopic pregnancy rate, uterine contractions prior to ET
      125 (900 mg)125 subjects calculated to provide 80% power (α = 0.05) to detect a trend in clinical pregnancy chances assuming 20% in the placebo group and up to 40% in the nolasiban 900 mg groupPatients with IVF/ICSI and fresh ET 18–36 years, no more than one previous failed stimulation cycle, evidence of at least 1.5 uterine contractions/minute on transvaginal ultrasound on baseline or on day of ET, main exclusion of patients with endometriosis ASRM ≥III (for full list see reference)NolasibanSingle 100, 300 or 900 mg dose orally 4 h before ETPlaceboSingle or double transfer of D3 embryo of at least good quality
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ; IMPLANT 2
      Primary: ongoing pregnancy rate

      Secondary: live birth rate, clinical pregnancy rate, miscarriage rate, multiple pregnancy rate, ectopic pregnancy rate
      779760 subjects calculated to detect with ∼90% (α = 0.05) an odds ratio ≥1.63 for increase in ongoing pregnancy ratePatients with IVF/ICSI and fresh ET 18–36 years, no more than one previous failed stimulation cycle, main exclusion criteria were serum progesterone concentrations >1.5 ng/ml or >20 cumulus–oocyte complexes, endometriosis ASRM ≥III (for full list see reference)NolasibanSingle 900 mg dose orally 4 h before embryo transferPlaceboSingle D3 or D5 embryo with at least good quality
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ; IMPLANT 4
      Primary: Ongoing pregnancy rate

      Secondary: live birth rate, clinical pregnancy rate, miscarriage rate, multiple pregnancy rate, ectopic pregnancy rate
      1264820 subjects, calculated based on the IMPLANT 2 D5 results, to provide ∼90% power (α = 0.05) to detect an odds ratio ≥1.59 for the ongoing pregnancy ratePatients with IVF/ICSI and fresh ET 18–37 years, no more than one previous failed stimulation cycle, main exclusion criteria were serum progesterone concentrations >1.5 ng/ml or >20 cumulus–oocyte complexes, endometriosis ASRM ≥III (for full list see reference)NolasibanSingle 900 mg dose orally 4 h before ETPlaceboSingle D5 embryo with at least good quality
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      Primary: clinical pregnancy rate, implantation rate

      Secondary: frequency of uterine contractions, serum concentrations of oxytocin and prostaglandin F2a, miscarriage rate, twin pregnancy rate, triplet pregnancy rate
      12058 patients per group based on a minimum absolute difference of 25% between groups; α = 0.05 and β = 0.20 (unclear whether this applies to implantation rate or clinical pregnancy rate)Patients 20–45 years having frozen ET and baseline FSH <10 IU/l, endometriosis, confirmed by laparoscopy, <3 previously failed treatment cycles, exclusion of patients with uterine anomaly; fibroids or hydrosalpinges, fresh ET cycle, patients received GnRH agonist or antagonist treatment before frozen–thawed ET, endometrial thickness <8 mm and endocrine disordersAtosibanBolus dose i.v. of 6.75 mg approximately 30 min before ETNilAt least one D5 good-quality embryo
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      Primary: Clinical pregnancy rate, implantation rate182UnclearPatients 25–35 years, BMI <35 kg/m2, tubal or male factor infertility, ICSI with fresh semen.

      Exclusion criteria: polycystic ovary, endometriosis, anti-Müllerian hormone <1.5 ng/ml, pre-ovulatory endometrium (≤6 mm) on previous cycle
      AtosibanSlow i.v. infusion of 7.5 mg atosiban 20 min before ETPlaceboD5 embryo transfer
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      Primary: clinical pregnancy rate, implantation rate

      Secondary: multiple pregnancy rate
      180180 patients (90 per group) to detect a 20% difference in the clinical pregnancy rate between groups; α = 0.05 and β = 0.20Basal FSH hormone <10 IU/l, age 20–39 years, first fresh IVF/ICSI cycle, long protocol with GnRH agonist, exclusion of patients with severe male factor, endometriosis, endocrine disorders, or uterine anomaly or uterine fibroids and hydrosalpinges, patients with difficult transferAtosiban30 min before ET bolus of 6.75 mg and continuation with a rate of 18 mg/h, post-ET procedure, the dose was reduced to 6 mg/h and the infusion was continued for 2 h (total administered dose: 37.5 mg)PlaceboTwo top-quality embryos on D2
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      Primary: live birth rate

      Secondary: positive pregnancy test, clinical pregnancy rate, ongoing pregnancy rate, miscarriage rate, multiple pregnancy and ectopic pregnancy rates
      800Superiority trial designed to detect an increase of 10% live birth rate from 35% control group live birth rate; α = 0.05 and β = 0.20Age <43 years, normal uterine cavity shown on ultrasound, exclusion of patients with three or more previous IVF cycles, use of donor oocytes, natural IVF cycles; endometrial thickness 8 mm, hydrosalpinxAtosiban30 min before ET bolus of 6.75 mg and continuation with a rate of 18 mg/h, post-ET the dose was reduced to 6 mg/h (total administered dose: 37.5 mg)PlaceboNo blastocyst transfers included
      No full text available
      Primary: clinical pregnancy rate, implantation rate, miscarriage rate120No sample size calculation or primary hypothesis availableWomen undergoing thawed ET at the Reproductive Medical Center, General Hospital of Tianjin Medical University, China between July and December 2012Atosiban30 minutes before ET with a total administered dose of 37.5 mgNilTransfer of embryos at 7–8 cell stage
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      Primary: clinical pregnancy rate, implantation rate

      Secondary: biochemical pregnancy rate, miscarriage rate, multiple pregnancy rate, ectopic pregnancy rate
      204No sample size calculation or primary hypothesis providedAge <43 years, frozen–thawed ET, normal uterine cavity, clear information about previous IVF ET cycles, history of previous difficult transfer, exclusion of patients with uterine anomaly, hydrosalpinx endometrial thickness <7.5 mm, blastocyst transferAtosiban30 min before ET bolus of 6.75 mg and continuation with a rate of 18 mg/h, post-ET the dose was reduced to 6 mg/h (total administered dose: 37.5 mg)PlaceboOne or more good-quality embryos on the day of transfer, no blastocysts
      ASRM = American Society for Reproductive Medicine; D2/3/5 = Day 2, Day 3, Day 5; ET = embryo transfer; GnRH = gonadotrophin-releasing hormone; ICSI = intracytoplasmic sperm injection.
      a Partially translated into English.
      b No full text available
      Only five studies had the objective of testing for a difference in the likelihood of a live birth (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ); the necessary sample size was determined a priori by
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      . All included studies reported on the clinical pregnancy rate. The OTR-a atosiban was administered in seven RCT, nolasiban in three and barusiban was administered in one RCT. Administration of the respective drug was performed before (nolasiban,
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4], atosiban (
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ;
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      ;
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      )); before and after (barusiban,
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ); or before, during and after the embryo transfer procedure (atosiban,
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ;
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ;
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ). In the control group, a placebo was administered in eight trials (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      ;
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ;
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ) and in two trials nil (
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ;
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      ) was administered. The study by
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      did not provide information on an intervention in the control group. In all trials randomization was conducted in a 1:1 ratio. The trials were conducted between 2007 (
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ) and 2019 (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4]).

      Grading of studies and publication bias

      Only four out of the eleven included studies reported the chance of a live birth which was defined a priori. Authors of the seven studies not reporting number of live births were contacted; however, further data could only be retrieved for the study by
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      . All included studies investigated the likelihood of a clinical pregnancy per embryo transfer/ITT analysis. Adverse outcomes such as risk of a miscarriage, an ectopic pregnancy or the chance of a multiple pregnancy were reported by eight, five and seven RCT, respectively. Authors of two studies were contacted for clarification of outcomes (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ); no response was received from
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      , which is why the data on miscarriages from that study could not be included in the meta-analysis.
      The risk of bias assessment is presented in Table 2 and Figure 2. Double-blinding was described by six studies (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ) whereas two studies reported blinding of either staff (
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ) or patients (
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ), and three studies did not provide information on blinding (
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ;
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      ;
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      ). A bias stemming from absence of allocation concealment was avoided in two studies by using sealed envelopes (
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ;
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ) and by five studies by a web response system/electronic case report form (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ). Four studies (
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ;
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      ;
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ;
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      ) did not report the presence of allocation concealment. A valid randomization was performed by using computer-generated sequences (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ;
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ) or a quasi-randomization was performed according to weekday of patient entry (
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ); no information on the generation of a random allocation of patients was provided for
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ,
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      and
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      . A visual inspection of the funnel plot for the outcome clinical pregnancy rate does not indicate selective publication (Figure 3).
      Table 2Risk of bias assessment of included studies
      Study (year of publication)Adequate sequence generation?Authors’ judgementAllocation concealment?Authors’ judgementBlinding?All outcomesAuthors’ judgementIncomplete outcome data addressed for all outcomesAuthors’ judgementFree of selective reporting?Authors’ judgement
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      UnclearHigh riskUnclearHigh riskBlinding unclearHigh riskLive birth rate data not reported, clinical pregnancy and implantation data completeHigh riskNo evidence for selective reportingLow risk
      No full text available.
      Central randomization through electronic case report formLow riskConcealment via central randomization through electronic case report formLow riskDouble-blindLow riskLive birth and clinical pregnancy data received on personal request to authorsLow riskNo evidence for selective reportingLow risk
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ; IMPLANT 1
      Randomization list generated by a statistician a prioriLow riskInteractive web response system for concealmentLow riskDouble-blindLow riskIncomplete data for testing of low doses; adequate reporting on outcome data for 900 mgLow riskNo evidence for selective reportingLow risk
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ; IMPLANT 2
      Randomization list generated by a statistician a prioriLow riskInteractive web response system for concealmentLow riskDouble-blindLow riskAdequate report on outcome dataLow riskNo evidence for selective reportingLow risk
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      IMPLANT 4
      Randomization list generated by a statistician a prioriLow riskInteractive web response system for concealmentLow riskDouble-blindLow riskAdequate report on outcome dataLow riskNo evidence for selective reportingLow risk
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      Computer-generated systemLow riskSealed envelopes for concealmentLow riskBlinding of laboratory staff and embryo transfer operator onlyHigh riskLive birth rate data not reported, clinical pregnancy and implantation data completeHigh riskNo evidence for selective reportingLow risk
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      UnclearHigh riskUnclearHigh riskUnclearHigh riskIncomplete data reported for all outcomesHigh riskNo evidence for selective reportingLow risk
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      Randomization based on weekdays of patient entryHigh riskConcealment to staff unclearHigh riskBlinding of patients onlyHigh riskLive birth rate data not reported, incomplete miscarriage data, clinical pregnancy and implantation data completeHigh riskNo evidence for selective reportingLow risk
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      Computer-generated randomization list with blocks of 10Low riskSealed envelopes handled by a research nurse not involved in the studyLow riskDouble-blindLow riskAdequate report on outcome dataLow riskNo evidence for selective reportingLow risk
      No full text available.
      UnclearHigh riskUnclearHigh riskNo blindingHigh riskLive birth rate data not reported, clinical pregnancy and implantation data completeHigh riskNo evidence for selective reportingLow risk
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      Computer-generated randomization list by a research staff not involved in the studyLow riskComputer-generated randomization list by a research staff not involved in the studyLow riskDouble-blindLow riskLive birth rate data not reported, complete clinical pregnancy, implantation, miscarriage, multiples and ectopic pregnancy outcomesHigh riskNo evidence for selective reportingLow risk
      a No full text available.
      Figure 2
      Figure 2Risk of bias assessment. (A) Random sequence generation (selection bias). (B) Allocation concealment (selection bias). (C) Blinding of participants and personnel (performance bias). (D) Blinding of outcome assessment (detection bias). (E) Incomplete outcome data (attrition bias). (F) Selective reporting (reporting bias). (G) Other bias.
      Figure 3
      Figure 3Funnel plot of the clinical pregnancy rate (effect on x-axis versus precision on the y-axis).

      Demography and treatment

      No trial reported a difference in baseline characteristics such as age, body weight, body mass index or overall gonadotrophin consumption.
      The embryo transfer took place in nine studies in the setting of a fresh IVF cycle, whereas two trials investigated OTR-a in a frozen embryo transfer cycle (
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ). The availability of a good- or top-quality embryo was an inclusion criterion in seven studies (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ;
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ) and the transfer of a Day 5 embryo in two RCT (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 4];
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ). With respect to patient population, one trial (
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ) focused exclusively on endometriosis patients whereas five RCT excluded patients with (severe) endometriosis (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      ;
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ). The age of included patients varied from 25 to 35 (
      • Hebisha S.A.
      • Hisham A.M.
      Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
      ), 18 to 36 (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2]), 18 to 37 (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 4]), 20 to 45 (
      • He Y.
      • Wu H.
      • He X.
      • Xing Q.
      • Zhou P.
      • Cao Y.
      • Wei Z.
      Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
      ) or <43 years (
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ) and 20 to 39 years (
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ). No information on age ranges was available for the trials by
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      and
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      . Features of all included studies are shown in Table 1.

      Clinical and ongoing pregnancy and live birth rates

      Administration of an OTR-a around embryo transfer is associated with an increased clinical pregnancy rate (RR 1.31, 95% CI 1.13–1.51, P = 0.0002, I2 = 61%, n = 11 RCT, n = 3611; Figure 4a) as well as ongoing pregnancy rate (RR 1.14, 95% CI 1.03–1.26, P = 0.01, I2 = 18%, n = 4 RCT, n = 2510; Figure 4b). However, there is no statistically significant association with the likelihood of a live birth, as statistical significance defined as P < 0.05 is missed (RR 1.09, 95% CI 0.98–1.20, P = 0.11, I2 = 25%, n = 5 studies, n = 2765, Figure 4c). A sensitivity analysis on studies with low risk of bias only (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ) confirmed a significant increase in the clinical pregnancy chance for patients having an OTR-a administered (RR 1.11, 95% CI 1.01–1.22, P = 0.03, I2 = 5%, n = 5 RCT, n = 2765). Exclusion of the studies without full publication available (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ;
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      ) and with translation to English (
      • Ahn J.W.
      • Kim C.H.
      • Kim S.R.
      • Jeon G.H.
      • Kim S.H.
      • Chae H.D.
      • Kang B.M.
      Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
      ) does not alter the findings of the present meta-analysis (clinical pregnancy rate: RR 1.33, 95% CI 1.13–1.57, P = 0.0007, I2 = 68%, n = 8 RCT, n = 3196).
      Figure 4
      Figure 4Forest plots of (a) clinical pregnancy rate, (b) ongoing pregnancy rate and (c) live birth rate.

      Subanalysis for compound and day of embryo transfer

      A stratification for each investigated compound shows a significant increase in the clinical pregnancy rate for the studies on nolasiban (RR 1.16, 95% CI 1.02–1.31, P = 0.02, I2 = 36%, n = 3 RCT, n = 1710) and atosiban (RR 1.50, 95% CI 1.18–1.89, P = 0.0008; I2 = 69%, n = 7 RCT, n = 1646), whereas the study on barusiban does not report a difference in favour of the OTR-a (RR 0.98, 95% CI 0.72–1.34, P = 0.91, I2 = not applicable, n = 1 RCT, n = 255). Stratification of studies for day of embryo transfer shows a significant effect in favour of an OTR-a on the clinical pregnancy rate for Day 2/3 transfers (RR 1.52, 95% CI 1.10–2.09, P = 0.01, I2 = 78%, n = 5 RCT) (
      • Moraloglu O.
      • Tonguc E.
      • Var T.
      • Zeyrek T.
      • Batioglu S.
      Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
      ;
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1];
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ;
      • Song X.R.
      • Zhao X.H.
      • Bai X.H.
      • Lü Y.H.
      • Zhang H.J.
      • Wang Y.X.
      • Lü R.
      [Application of oxytocin antagonists in thaw embryo transfer].
      ;
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      ) (n = 1429) which, however, was not significant for Day 5 embryo transfers (RR 1.22, 95% CI 0.98–1.53, P = 0.08, I2 = 55%, n = 3 RCT, n = 1109).

      Miscarriage, ectopic pregnancy and multiple pregnancy

      The risk of miscarriage had no statistically significant association to OTR-a administration (RR 0.90, 95% CI 0.72–1.12, P = 0.35, I2 = 0%, n = 7 RCT, n = 2954; Figure 5a). The risk of a multiple pregnancy (RR 1.05, 95% CI 0.81–1.36, P = 0.73, I2 = 5%, n = 7 RCT, n = 3014; Figure 5b) is not significantly different between groups, nor is the ectopic pregnancy rate (RR 0.88, 95% CI 0.43–1.8, P = 0.73, I2 = 0%, n = 5 RCT, n = 2714; Figure 5c).
      Figure 5
      Figure 5Forest plots of (a) miscarriage rate, (b) multiple pregnancy rate and (c) ectopic pregnancy rate.

      Discussion

      The present meta-analysis collates data from eleven RCT comprising 3611 patients, which were performed to test for an increase in the likelihood of live birth and/or clinical pregnancy in patients having an OTR-a administered around embryo transfer. The clinical pregnancy rate was found to be significantly increased in patients having an OTR-a administered. Although a higher chance of a live birth would be the expected consequence, a statistically significant difference was not found (P = 0.11), which could be due to only five RCT reporting live birth incidences. The present systematic review also highlights a number of important limitations and shortcomings of the existing evidence. While the funnel plot does not formally indicate publication bias, the smaller studies on atosiban utilization show strong positive effect sizes, which is not the case for the large study by
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      , which is the methodologically most robust of the atosiban trials. Accordingly, a potential overestimation of the underlying effect has to be considered. However, a sensitivity analysis including low risk of bias studies only confirms a positive effect of OTR-a on the clinical pregnancy rate but shows a smaller effect size (RR 1.11, 95% CI 1.01–1.22) versus all studies (RR 1.31, 95% CI 1.13–1.51).
      Another issue of concern is that within a robust and large clinical trial programme (IMPLANT 1, 2 and 4 studies), the OTR-a effect is not consistent across trials (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ) and the single trial on barusiban was negative for clinical pregnancy rate increase per randomized woman and only suggested a benefit in a stratum of women and on a surrogate outcome, implantation rate (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ). The use of a surrogate outcome for live birth is another deficit of a number of the identified trials, with six of the included studies using clinical pregnancy and/or implantation rate. Only five studies examined live births, which is the recommended outcome for clinical studies in IVF (
      • Harbin Consensus Conference Workshop Group
      • Conference Chairs
      • Legro R.S.
      • Wu X.
      • Scientific Committee
      • Barnhart K.T.
      • Farquhar C.
      • Fauser B.C.
      • Mol B.
      Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement.
      ).
      Heterogeneity in drug and administration regimen between studies is a potential source of significant confounding. Additionally, studies in the present meta-analysis differ in type of treatment with assisted reproductive technologies, patient populations and quality and stage of embryos transferred, which could also impact the findings. Adequate information on randomization is provided by seven studies; double-blinding, the gold standard for RCT, was conducted by only six RCT, which underlines the need for high-quality RCT for evaluation of interventions.
      Looking at the different OTR-a compounds in more detail, conflicting results from the registration studies of nolasiban become evident. The IMPLANT 4 trial could not replicate the significant increase in the likelihood of live birth that was observed in the IMPLANT 1 and 2 studies (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      ). Based on pharmacokinetic investigations, it was speculated whether adjustment of nolasiban posology may provide a higher efficacy, suspecting an underexposure of some patients as a possible explanation for the ambiguous results from the IMPLANT trials. For barusiban, only one study investigated its association with clinical outcomes. An increased chance of pregnancy exclusively for transfer of Day 5 embryos was observed by that study. Thus, it was discussed whether an administration closer to the timeframe of embryo implantation may impact the efficacy of barusiban (
      • Bosch E.
      • Aasted H.
      • Klein N.J.
      • Arce J.C.
      A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
      ).
      For atosiban, a previous systematic review and meta-analysis reported an increased likelihood of a clinical pregnancy with moderate between-study heterogeneity, but with the inclusion of observational studies (
      • Schwarze J.E.
      • Crosby J.
      • Mackenna A.
      Atosiban improves the outcome of embryo transfer. A systematic review and meta-analysis of randomized and non-randomized trials.
      ). The present meta-analysis focuses on RCT only and adds (with respect to atosiban) the study by
      • Yuan C.
      • Song H.
      • Fan L.
      • Su S.
      • Dong B.
      The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
      . Of note, the majority of available studies on atosiban are generally limited by insufficient information on randomization, blinding and reporting on outcomes, as outlined in Table 2 and Figure 2.
      The strength of the present meta-analysis is the inclusion of all RCT using drugs functioning as OTR-a, thereby summing up a sufficient sample size to test for clinically relevant differences.
      Adverse events were systematically reported by only four of the included studies for OTR-a administration (
      • Griesinger G.
      • Blockeel C.
      • Pierzynski P.
      • Tournaye H.
      • Višňová H.
      • Humberstone A.
      • Terrill P.
      • Pohl O.
      • Garner E.
      • Donnez J.
      • Loumaye E.
      Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
      [IMPLANT 1, 2 and 4];
      • Ng E.H.
      • Li R.H.
      • Chen L.
      • Lan V.T.
      • Tuong H.M.
      • Quan S.
      A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
      ). The same is true for detailed obstetric and neonatal outcomes.
      From a cost-effectiveness perspective, a significant increase in the chance of a live birth per embryo transfer via administration of an OTR-a would appear attractive as an additional drug administration around embryo transfer is a rather simple add-on versus other more complex and costly procedures (e.g. PGT-A). To date, no cost-effectiveness models or studies on the use of OTR-a have been published. The present meta-analysis may, however, serve as a starting point for such an exercise.
      In summary, administration of an OTR-a around embryo transfer is associated with a significant increase in the likelihood of a clinical pregnancy, whereas the likelihood of a live birth is not statistically significantly increased. High-quality studies investigating further adjustments of posology, timeframe of administration and reporting on the likelihood of a live birth are warranted.
      Declaration: The authors report no financial or commercial conflicts of interest. KN has received honoraria and/or non-financial support from Ferring, Merck and MSD; GG has received honoraria and/or non-financial support from Abbott, Ferring, Gedeon Richter, Guerbet, Merck, MSD, ObsEva, PregLem, ReprodWissen GmbH and Vifor. GG was an investigator in the IMPLANT trial programme.

      Acknowledgements

      We would like to thank Maurizio Grilli, Librarian at the University of Heidelberg, Germany, for assistance with the literature search.

      Appendix. Supplementary materials

      References

        • Ahn J.W.
        • Kim C.H.
        • Kim S.R.
        • Jeon G.H.
        • Kim S.H.
        • Chae H.D.
        • Kang B.M.
        Effects of administration of oxytocin antagonist on implantation and pregnancy rates in patients with repeated failure of IVF/ICSI treatment.
        Clin. Exp. Reprod. Med. 2009; 36: 275-281
        • Bosch E.
        • Aasted H.
        • Klein N.J.
        • Arce J.C.
        A randomized, double-blind, placebo-controlled, multi-center, phase 2 trial to investigate the effect of barusiban on implantation in IVF/ICSI patients. P-182 ASRM.
        2019 (Philadelphia, PA, USA)
        • Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology
        2014 Assisted Reproductive Technology National Summary Report.
        US Dept of Health and Human Services, Atlanta, GA2016
        • Duffy J.M.N.
        • Bhattacharya S.
        • Bhattacharya S.
        • Bofill M.
        • Collura B.
        • Curtis C.
        • Evers J.L.H.
        • Giudice L.C.
        • Farquharson R.G.
        • Franik S.
        • Hickey M.
        • Hull M.L.
        • Jordan V.
        • Khalaf Y.
        • Legro R.S.
        • Lensen S.
        • Mavrelos D.
        • Mol B.W.
        • Niederberger C.
        • Ng E.H.Y.
        • Puscasiu L.
        • Repping S.
        • Sarris I.
        • Showell M.
        • Strandell A.
        • Vail A.
        • van Wely M.
        • Vercoe M.
        • Vuong N.L.
        • Wang A.Y.
        • Wang R.
        • Wilkinson J.
        • Youssef M.A.
        • Farquhar C.M.
        Core Outcome Measure for Infertility Trials (COMMIT) Initiative. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study.
        Fertil. Steril. 2021; 115 (Jan): 201-212
        • Fanchin R.
        • Righini C.
        • Olivennes F.
        • Taylor S.
        • de Ziegler D.
        • Frydman R.
        Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization.
        Hum. Reprod. 1998; 13: 1968-1974
        • Griesinger G.
        • Blockeel C.
        • Pierzynski P.
        • Tournaye H.
        • Višňová H.
        • Humberstone A.
        • Terrill P.
        • Pohl O.
        • Garner E.
        • Donnez J.
        • Loumaye E.
        Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
        Hum. Reprod. 2021; 36 (Mar 18): 1007-1020
        • Griesinger G.
        Beware of the ‘implantation rate’! Why the outcome parameter ‘implantation rate’ should be abandoned from infertility research.
        Hum. Reprod. 2016; 31 (Feb): 249-251
        • Harbin Consensus Conference Workshop Group
        • Conference Chairs
        • Legro R.S.
        • Wu X.
        • Scientific Committee
        • Barnhart K.T.
        • Farquhar C.
        • Fauser B.C.
        • Mol B.
        Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement.
        Hum. Reprod. 2014; 29 (Oct 10): 2075-2082
        • Harper J.
        • Jackson E.
        • Sermon K.
        • Aitken R.J.
        • Harbottle S.
        • Mocanu E.
        • Hardarson T.
        • Mathur R.
        • Viville S.
        • Vail A.
        • Lundin K.
        Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions?.
        Hum. Reprod. 2017; 32 (Mar 1): 485-491
        • He Y.
        • Wu H.
        • He X.
        • Xing Q.
        • Zhou P.
        • Cao Y.
        • Wei Z.
        Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.
        Fertil. Steril. 2016; 106 (Aug): 416-422
        • Hebisha S.A.
        • Hisham A.M.
        Impact of the oxytocin receptor antagonist atosiban administered shortly before embryo transfer on pregnancy rates after ICSI.
        Clin. Exp. Obstet. Gynecol. 2018; 45: 513-516
        • Kalmantis K.
        • Loutradis D.
        • Lymperopoulos E.
        • Beretsos P.
        • Bletsa R.
        • Antsaklis A.
        Three dimensional power Doppler evaluation of human endometrium after administration of oxytocine receptor antagonist (OTRa) in an IVF program.
        Arch. Gynecol. Obstet. 2012; 285: 265-270
        • Kim A.
        • Jung H.
        • Choi W.J.
        • Hong S.N.
        • Kim H.Y.
        Detection of endometrial and subendometrial vasculature on the day of embryo transfer and prediction of pregnancy during fresh in vitro fertilization cycles.
        Taiwan J. Obstet. Gynecol. 2014; 53: 360-365
        • Kim S.H.
        • Pohl O.
        • Chollet A.
        • Gotteland J.P.
        • Fairhurst A.D.
        • Bennett P.R.
        • Terzidou V.
        Differential effects of oxytocin receptor antagonists, atosiban and nolasiban, on oxytocin receptor-mediated signaling in human amnion and myometrium.
        Mol. Pharmacol. 2017; 91: 403-415
        • Lan V.T.
        • Khang V.N.
        • Nhu G.H.
        • Tuong H.M.
        Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure.
        Reprod. Biomed. Online. 2012; 25: 254-260
        • Luke B.
        • Brown M.B.
        • Wantman E.
        • Lederman A.
        • Gibbons W.
        • Schattman G.L.
        • Lobo R.A.
        • Leach R.E.
        • Stern J.E.
        Cumulative birth rates with linked assisted reproductive technology cycles.
        N. Engl. J. Med. 2012; 366: 2483-2491
        • Moraloglu O.
        • Tonguc E.
        • Var T.
        • Zeyrek T.
        • Batioglu S.
        Treatment with oxytocin antagonists before embryo transfer may increase implantation rates after IVF.
        Reprod. Biomed. Online. 2010; 21 (Sep): 338-343
        • Ng E.H.
        • Li R.H.
        • Chen L.
        • Lan V.T.
        • Tuong H.M.
        • Quan S.
        A randomized double blind comparison of atosiban in patients undergoing IVF treatment.
        Hum. Reprod. 2014; 29 (Dec): 2687-2694
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • Shamseer L.
        • Tetzlaff J.M.
        • Akl E.A.
        • Brennan S.E.
        • Chou R.
        • Glanville J.
        • Grimshaw J.M.
        • Hróbjartsson A.
        • Lalu M.M.
        • Li T.
        • Loder E.Q.
        • Mayo-Wilson E.
        • McDonald S.
        • McGuinness L.A.
        • Stewart L.A.
        • Thomas J.
        • Tricco A.C.
        • Welch V.A.
        • Whiting P.
        • Moher D.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n71
        • Pierzynski P.
        Oxytocin and vasopressin V(1A) receptors as new therapeutic targets in assisted reproduction.
        Reprod. Biomed. Online. 2011; 22: 9-16
        • Pierzynski P.
        • Reinheimer T.M.
        • Kuczynski W.
        Oxytocin antagonists may improve infertility treatment.
        Fertil. Steril. 2007; 88: 213-222
        • Pierzyński P.
        • Pohl O.
        • Marchand L.
        • Mackens S.
        • Lorch U.
        • Gotteland J.P.
        • Blockeel C.
        Oxytocin antagonist mechanism of action in ART – a prospective, randomized study of nolasiban effects on uterine contraction, perfusion and gene expression in healthy female volunteers.
        Reprod. BioMed. Online. 2021; 43: 184-192
        • Reinheimer T.M.
        • Bee W.H.
        • Resendez J.C.
        • Meyer J.K.
        • Haluska G.J.
        • Chellman G.J.
        Barusiban, a new highly potent and long-acting oxytocin antagonist: pharmacokinetic and pharmacodynamic comparison with atosiban in a cynomolgus monkey model of preterm labor.
        J. Clin. Endocrinol. Metab. 2005; 90 (Apr): 2275-2281
        • Schwarze J.E.
        • Crosby J.
        • Mackenna A.
        Atosiban improves the outcome of embryo transfer. A systematic review and meta-analysis of randomized and non-randomized trials.
        JBRA Assist. Reprod. 2020; 24: 421-427
        • Song X.R.
        • Zhao X.H.
        • Bai X.H.
        • Lü Y.H.
        • Zhang H.J.
        • Wang Y.X.
        • Lü R.
        [Application of oxytocin antagonists in thaw embryo transfer].
        Zhonghua Fu Chan Ke Za Zhi. 2013; 48 (Sep): 667-670
        • Sztachelska M.
        • Ponikwicka-Tyszko D.
        • Sokolowska G.
        • Anisimowicz S.
        • Czerniecki J.
        • Lebiedzinska W.
        • Zbucka-Kretowska M.
        • Zygmunt M.
        • Wolczynski S.
        • Pierzynski P.
        Oxytocin antagonism reverses the effects of high oestrogen levels and oxytocin on decidualization and cyclooxygenase activity in endometrial tissues.
        Reprod. Biomed. Online. 2019; 39: 737-744
        • Toftager M.
        • Bogstad J.
        • Løssl K.
        • Prætorius L.
        • Zedeler A.
        • Bryndorf T.
        • Nilas L.
        • Pinborg A.
        Cumulative live-birth rates after one ART cycle including all subsequent frozen-thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols.
        Hum. Reprod. 2017; 32: 556-567
        • Yuan C.
        • Song H.
        • Fan L.
        • Su S.
        • Dong B.
        The effect of atosiban on patients with difficult embryo transfers undergoing in vitro fertilization-embryo transfer.
        Reprod. Sci. 2019; 26 (Dec): 1613-1617
        • Zhu L.
        • Che H.S.
        • Xiao L.
        • Li Y.P.
        Uterine peristalsis before embryo transfer affects the chance of clinical pregnancy in fresh and frozen-thawed embryo transfer cycles.
        Hum. Reprod. 2014; 29: 1238-1243

      Biography

      Kay Neumann is a physician and was undergoing subspeciality training in reproductive medicine at the Department of Gynaecological Endocrinology and Reproductive Medicine of the University of Luebeck, Germany. In 2020 he completed his PhD thesis at the University of Luebeck. In February 2021 he started work at the Kinderwunsch Praxisklinik Fleetinsel in Hamburg, Germany.
      Key message
      Oxytocin receptor antagonists may increase clinical pregnancy rate when administered around the time of embryo transfer to women undergoing IVF. However, more data are needed to corroborate this finding and to assess the effect on live birth rate. Further research is needed into the optimal compound, dosage and administration regimen.