GnRHantagonist protocol 具較低OHSS機率 (compared to long protocol)

二者懷孕率類似

Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles 

STUDY QUESTION

Is the risk of severe ovarian hyperstimulation syndrome (OHSS) similar in a short GnRH antagonist and long GnRH agonist protocol in first cycle IVF/ICSI patients less than 40 years of age?.

SUMMARY ANSWER

There is an increased risk of severe OHSS in the long GnRH agonist group compared with the short GnRH antagonist protocol.

WHAT IS KNOWN ALREADY?

In the most recent Cochrane review, the GnRH antagonist protocol was associated with a similar live birth rate (LBR), a similar on-going pregnancy rate (OPR), and a lower incidence of OHSS (odds ratio (OR) = 0.43 95% confidence interval (CI): 0.33–0.57) compared with the traditional GnRH agonist protocol. Previous trials comparing the two protocols mainly included selected patient populations, a limited number of patients and the applied OHSS criteria differed, making direct comparisons difficult. In two recent large meta-analyses, no significant differences in LBR (OR = 0.86; 95% CI: 0.72–1.02) or in the incidence of severe OHSS were reported, while others found a lower LBR (OR = 0.82; 95% CI: 0.68–0.97) and a reduced risk of severe OHSS using the GnRH antagonist protocol (OR = 0.60; 95% CI: 0.40–0.88).

STUDY DESIGN, SIZE, DURATION

Phase IV, dual-centre, open-label, RCT including 1050 women allocated to either short GnRH antagonist or long GnRH agonist protocol in a 1:1 ratio and enrolled over a 5-year period using a web-based concealed randomization code. This is a superiority study designed to detect a difference in severe OHSS, the primary outcome, between the two groups with a power of 80% and stratified for age, assisted reproductive technology (ART) clinic and planned fertilization procedure (IVF/ICSI). The secondary aims were to compare rates of mild and moderate OHSS, positive plasma (p)-hCG, on-going pregnancy and live birth between the two arms. None of the women had undergone previous ART treatment.

PARTICIPANTS/MATERIALS, SETTING, METHODS

All infertile women referred for their first IVF/ICSI at two public fertility clinics, less than 40 years of age and with no uterine malformations were asked to participate. A total of 1099 subjects were randomized, including women with poor ovarian reserve, polycystic ovary syndrome and irregular cycles. A total of 49 women withdrew their consent, thus 1050 subjects were allocated to the GnRH antagonist (n = 534) and agonist protocol (n = 516), respectively. In total 1023 women started recombinant human follitropin-β (rFSH) stimulation, 528 in the GnRH antagonist group and 495 in the GnRH agonist group. All subjects were given a fixed rFSH dose of 150 IU or 225 IU according to age ≤36 years or >36 years, with the option to adjust dose at stimulation day 6. Clinical OHSS parameters were collected at oocyte retrieval, and Days 3 and 14 post-transfer. On-going pregnancy was determined by transvaginal ultrasonography at gestational weeks 7–9. In the intention-to-treat (ITT) analysis for reproductive outcomes, 1050 subjects were included. For the ITT analyses on OHSS 1023 subjects who started gonadotrophin stimulation were included.

MAIN RESULTS AND THE ROLE OF CHANCE

The incidence of severe OHSS [5.1% (27/528) versus 8.9% (44/495) (difference in proportion percentage point (Δpp) = −3.8pp; 95% CI: −7.1 to −0.4; P = 0.02)] and moderate OHSS [10.2% (54/528) versus 15.6% (77/495) (Δpp = −5.3pp; 95% CI: −9.6 to −1.0; P = 0.01) ] was significantly lower in the GnRH antagonist group compared with the agonist group, respectively. In the GnRH antagonist and agonist group, respectively, 4.7% (25/528) versus 8.5% (42/495) women were seen by a physician due to OHSS (P = 0.01), and 1.7% (9/528) versus 3.6% (18/495) were admitted to hospital due to OHSS (P = 0.06). No women had ascites-puncture in the GnRH antagonist group versus 2.0% (10/495) in the GnRH agonist group (P < 0.01). LBRs were 22.8% (122/534) versus 23.8% (123/516) (Δpp = −1.0pp; 95% CI: −6.3 to 4.3; P = 0.70) and OPRs were 24.9% (133/528) versus 26.2% (135/516) (Δpp = −1.3pp; 95% CI: −6.7 to 4.2; P = 0.64) per randomized subject in the GnRH antagonist versus agonist group, with a mean number of 1.1 versus 1.2 embryos transferred in the two groups. Pregnancy rates (PR) per randomized subject, per started gonadotrophin stimulation and per embryo transfer were all similar in the two groups.

 GnRH antagonist, depot GnRHa and long GnRHa protocols.  三種protocol臨床懷孕率類似

The depot GnRH agonist protocol improves the live birth rate per fresh embryo transfer cycle, but not the cumulative live birth rate in normal responders: a randomized controlled trial and molecular mechanism study 

Do cumulative live birth rates (CLBRs) after one complete ART cycle differ between the three commonly used controlled ovarian stimulation (COS) protocols (GnRH antagonist, depot GnRHa (GnRH agonist) and long GnRHa) in normal responders undergoing IVF/ICSI?

SUMMARY ANSWER

There were similar CLBRs between the GnRH antagonist, depot GnRHa and long GnRHa protocols.

WHAT IS KNOWN ALREADY

There is no consensus on which COS protocol is the most optimal in women with normal ovarian response. The CLBR provides the final success rate after one complete ART cycle, including the fresh and all subsequent frozen–thawed embryo transfer (ET) cycles. We suggest that the CLBR measure would allow for better comparisons between the different treatment protocols.

STUDY DESIGN, SIZE, DURATION

A prospective controlled, randomized, open label trial was performed between May 2016 and May 2017. A total of 819 patients were allocated to the GnRH antagonist, depot GnRHa or long GnRHa protocol in a 1:1:1 ratio. The minimum follow-up time from the first IVF cycle was 2 years. To further investigate the potential effect of COS with the GnRH antagonist, depot GnRHa or long GnRHa protocol on endometrial receptivity, the expression of homeobox A10 (HOXA10), myeloid ecotropic viral integration site 1 (MEIS1) and leukemia inhibitory factor (LIF) endometrial receptivity markers was evaluated in endometrial tissue from patients treated with the different COS protocols.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Infertile women with normal ovarian response (n = 819) undergoing IVF/ICSI treatment were randomized to the GnRH antagonist, depot GnRHa or long GnRHa protocol. Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen partner ejaculates or frozen donor ejaculates. The primary outcome was the live birth rate (LBR) per fresh ET cycle, and the CLBR after one complete ART cycle, until the birth of a first child (after 28 weeks) or until all frozen embryos were used, whichever occurred first. Pipelle endometrial biopsies from 34 female patients were obtained on Days 7–8 after oocyte retrieval or spontaneous ovulation in natural cycles, respectively, and HOXA10, MEIS1 and LIF mRNA and protein expression levels in the human endometrium was determined by quantitative real-time PCR and western blot, respectively.

MAIN RESULTS AND THE ROLE OF CHANCE

There were no significant differences in CLBRs between the GnRH antagonist, depot GnRHa or long GnRHa protocol (71.4 versus 75.5 versus 72.2%, respectively). However, there was a significantly higher LBR per fresh ET cycle in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (62.6 versus 52.1% versus 45.6%, P < 0.05). Furthermore, HOXA10, MEIS1 and LIF mRNA and protein expression in endometrium all showed significantly higher in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (P < 0.05).