A randomized double blind comparison of atosiban in patients with recurrent implantation failure undergoing IVF treatment

Study population

This prospective, double-blind study was conducted in Shanghai First Maternity and Infant Hospital between July 2017 and December 2019. Consecutive women attending the center for IVF were screened and recruited if they fulfilled the selection criteria. The inclusion criteria included: (i) less than 40 years of age; (ii) failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles; (iii) use of gonadotropin-releasing hormone (GnRH) agonist or antagonist protocol for ovulation induction; (iv) endometrial thickness ≥ 8 mm on day of hCG; (v) normal uterine cavity shown on hysterosalpingogram or hysteroscopy. (vi) one or more D3 good-quality embryos on the day of embryo transfer. Women were excluded if they had: (i) use of donor eggs/sperm; (ii) hydrosalpinges shown on scanning and not treated; (iii) moderate or severe endometriosis; (iv) an abnormal chromosome in either or both partners; (v) a congenital uterine anomaly; (vi) blastocyst transfer; (vii) unclear information of previous transfer cycles.

All women were fully counselled and informed written consents were obtained prior to participation. All participants are voluntarily joined this study which means no monetary benefit was paid during the recruiting. The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722.

Ovarian stimulation and IVF

Women started ovarian stimulation using either the long agonist or antagonist protocol. For the long protocol, 1.25 mg GnRH agonist (Triptorelin acetate, Diphereline, Ipsen Pharma Biotech, France) was given for pituitary desensitization from the mid-luteal phase in the previous cycle. Transvaginal ultrasound examination and serum estradiol measurement were then performed on Day 2–3 of the menstrual cycle. And urine-derived hMG (Lebaode, Lizhu, China) or recombinant FSH (Puregon, Organon, Dublin, Ireland or Gonal F, Merck Serono S.p.A, Modugno, Italy) was given at 150–225 IU per day based on the antral follicle count, age of women and previous ovarian response, according to the standard operation procedures of the center. Ovarian response was monitored by serial transvaginal scanning with or without hormonal monitoring. Further dosage adjustments were based on the ovarian response at the discretion of the clinicians in charge. For the antagonist protocol, patients were evaluated on Day 2–3 of the menstrual cycle and gonadotropins were administered afterwards. Antagonist 0.25 mg daily (Orgalutran, Organon, Dublin, Ireland) was given from the 6th day of ovarian stimulation until the day of ovulation trigger.

When three leading follicles reached ≥ 18 mm in diameter, hCG 10 000 IU (Lizhu, China) or Ovitrelle 250 µg (Merck Serono S.p.A., Modugno, Italy) was given to trigger final maturation of oocytes. Oocyte retrieval was performed around 36 h later.

Fertilization and embryo evaluation and transfer

Semen samples were prepared by the swim-up procedure. About 2 h after oocyte retrieval, each oocyte was inseminated with approximately 20,000–30,000 motile spermatozoa. If the total number of motile sperm was < 105 after washing or normal morphology was < 1%, intracytoplasmic sperm injection (ICSI) was performed. Oocytes were decoronated and checked for the presence of two pronuclei to confirm fertilization 24 h later. Embryos were graded on day 3 after retrieval as grade one to grade six according to the evenness of each blastomere and the percentage of fragmentation [11]. Embryos of 6–8 cells and of grade one or two were regarded as top-quality embryos. Some non-top-quality embryos were placed in extended culture until they reached the blastocyst stage.

A maximum of two embryos were transferred 3 days after the retrieval. Embryo transfer was performed by experienced clinicians. Excess good quality embryos were frozen for subsequent transfer.

Randomization, intervention and blinding

On the day of embryo transfer, women were randomized into the atosiban (Tractocile, Ferring Pharmaceuticals, Kiel, Germany) or placebo groups in a 1 to 1 ratio according to a computer-generated randomization list. The number was placed in sealed envelopes, and opened by a nurse who was not involved in the study. Women in the atosiban group received intravenous administration of atosiban about 30 min before the transfer with a bolus dose of 6.75 mg over one minute (IRB of the hospital recommended to use smaller dose concerning the possible side effect of the atosiban). Those in the placebo group received only normal saline infusion for the same duration. In both the atosiban and placebo groups, women were medicated by syringes which looked identical and were prepared by a dedicated nurse in the center not involved in the study. Subjects, clinicians and laboratory staff were blinded to the group assignment. According to the standard operation procedures, all patients received oral and vaginal progesterone as the luteal phase support for 2 weeks. The codes for the treatment groups were revealed to the investigators only after the whole study and statistical analysis was completed.

Pregnancy outcomes measures

The primary outcome measure was the live birth rate and the secondary outcome measures include positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy and ectopic pregnancy rates. A baby born alive after 20 weeks gestation was classified as a live birth. Clinical pregnancy was defined as the presence of at least one gestational sac on ultrasound at 6 weeks. Ongoing pregnancy was defined as the presence of at least one fetus with heart pulsation on ultrasound beyond 8 weeks. Miscarriage rate was defined as the number of miscarriages before 20 weeks divided by the number of women with positive pregnancy test. Multiple pregnancy was defined as a pregnancy with more than one gestational sac detected on ultrasound at 6 weeks. Implantation rate was calculated as the number of gestational sacs seen on scanning divided by the number of embryos replaced. All pregnant women were followed up for the pregnancy outcome after delivery or miscarriage.

Sample size calculation

The average live birth rate in the women with RIF of our center in 2016 was 20% per transfer. Assuming 20% increase in the clinical pregnancy rate to 40% after the use of atosiban, about 82 women in each arm were required at a power of 80% and a significance level of 5%. A total of 194 patients were recruited in this study to account for 15% drop-outs.

Statistical analysis

Analysis was performed based on the intention-to-treat principle. Statistical comparisons were carried out using Mann–Whitney U-test, Chi-square test, Fisher’s exact test and Student t-test where appropriate with the Statistical Program for Social Sciences (SPSS, Version 20.0, Chicago, Illinois). Pearson correlation was used to analyze the association between serum estradiol (E2) level on the day of hCG with frequency of endometrial peristalsis on embryo transfer day. Logistic regression analysis was used to analyze factors predicting the live birth. A two-sided P < 0.05 was taken as statistically significant.

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