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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.
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.
US Dept of Health and Human Services,
Atlanta, GA2016
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.
). 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 (
). 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 (
Detection of endometrial and subendometrial vasculature on the day of embryo transfer and prediction of pregnancy during fresh in vitro fertilization cycles.
). Additionally, evidence for increased endometrial receptivity and decidualization after oxytocin receptor antagonist (OTR-a) administration was previously reported (
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 (
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 (
), 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 (
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 (
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
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 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 (
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 (
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 (
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 (
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 (
). 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.
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 (
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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
No sample size calculation or primary hypothesis provided
Two or more previously failed IVF/ICSI cycles; exclusion of patients with low ovarian reserve; no previous hormonal treatment for three months before inclusion
Atosiban
Bolus 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 h
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.
Primary: ongoing implantation (= viable fetuses 10–11 weeks after transfer divided by the number of embryos/blastocysts transferred) Secondary: pregnancy rate, live birth rate
Patients 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 cycle
Barusiban
40 mg 45 min before transfer and 10 mg 15 min post-transfer s.c.
Placebo
Single or double transfer of good-quality embryos on D3 or D5
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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 group
Patients 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)
Nolasiban
Single 100, 300 or 900 mg dose orally 4 h before ET
Placebo
Single or double transfer of D3 embryo of at least good quality
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
760 subjects calculated to detect with ∼90% (α = 0.05) an odds ratio ≥1.63 for increase in ongoing pregnancy rate
Patients 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)
Nolasiban
Single 900 mg dose orally 4 h before embryo transfer
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
820 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 rate
Patients 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)
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
120
58 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 disorders
Atosiban
Bolus dose i.v. of 6.75 mg approximately 30 min before ET
180 patients (90 per group) to detect a 20% difference in the clinical pregnancy rate between groups; α = 0.05 and β = 0.20
Basal 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 transfer
Atosiban
30 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)
Superiority trial designed to detect an increase of 10% live birth rate from 35% control group live birth rate; α = 0.05 and β = 0.20
Age <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, hydrosalpinx
Atosiban
30 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)
No sample size calculation or primary hypothesis provided
Age <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 transfer
Atosiban
30 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)
Placebo
One 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 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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
. 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,
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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 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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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 (
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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
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 (
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 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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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 (
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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
. 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 (
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.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
) 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 (
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.
) 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 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) (
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
) (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 5Forest plots of (a) miscarriage rate, (b) multiple pregnancy rate and (c) ectopic pregnancy rate.
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
, 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 (
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 (
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 (
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 (
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 (
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 (
. 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 (
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
). 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.
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.
Core Outcome Measure for Infertility Trials (COMMIT) Initiative. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study.
Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.
Detection of endometrial and subendometrial vasculature on the day of embryo transfer and prediction of pregnancy during fresh in vitro fertilization cycles.
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.
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
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.
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.
Article info
Publication history
Published online: August 27, 2021
Accepted:
August 19,
2021
Received in revised form:
August 17,
2021
Received:
June 25,
2021
Declarlation: The authors report no financial or commercial conflicts of interest.
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