Follicular flushing leads to higher oocyte yield in monofollicular IVF: a randomized controlled trial

Abstract

STUDY QUESTION Does follicular flushing increase the number of mature oocytes in monofollicular IVF? SUMMARY ANSWER Follicular flushing increases the number of mature oocytes in monofollicular IVF. WHAT IS KNOWN ALREADY Flushing increases neither the oocyte yield nor the pregnancy rate in polyfollicular IVF or in poor responder patients. In monofollicular IVF, the effect of flushing has so far been addressed by two studies: (i) a prospective study with minimal stimulation IVF demonstrated an increased oocyte yield, and (ii) a retrospective study with natural cycle (NC)-IVF showed an increased oocyte yield and an increased transfer rate. STUDY DESIGN, SIZE, DURATION Randomized controlled trial including 164 women who were randomized for either aspiration with or without flushing from 2016 to 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS Infertile women 18–42 years of age with an indication for IVF treatment at a university-based infertility unit. Women undergoing monofollicular IVF were randomized to either follicular aspiration only or follicular aspiration directly followed by five follicular flushes at a 1:1 ratio. The intervention was done without anaesthesia, using a gauge 19 single-lumen needle. Flushing volume was calculated (sphere formula) based on the size of the follicle. MAIN RESULTS AND THE ROLE OF CHANCE A total of 164 women were included; 81 were allocated to ‘aspiration only’ and 83 to additional ‘flushing’. Primary analysis was based on the intention-to-treat: oocyte yield, defined as the collected mature oocyte rate, was higher (n = 64/83, 77.1%) in the flushing group compared to the aspiration only group (n = 48/81, 59.3%, adjusted risk difference (RD): 18.2% (95% CI 3.9–31.7%), P-value = 0.02). In the flushing group, most oocytes were retrieved within the first three flushes (63/83, 75.8%). Fertilization rate was higher in the flushing group (n = 53/83, 63.9% vs n = 38/81, 46.9%; adjusted RD: 16.8% (96% CI 1.5–31.4%), P = 0.045). Transfer rate was also higher in the flushing group (n = 52/83, 62.7% vs n = 38/81, 46.9%; RD: 15.71 (95% CI 0.3–30.3%)), but the difference was not significant (P = 0.06). The clinical pregnancy rate n = 9/83 versus n = 9/81 (RD: −0.3% (95% CI −9.9% to 9.5%)) and live birth rate n = 7/83 versus n = 8/81 (RD: −1.5% (95% CI −10.4% to 7.1%)) were not significantly different between the flushing and the aspiration group. The median duration of the intervention was significantly longer with flushing (2.38 min; quartiles 2.0, 2.7) versus aspiration only (0.43 min; quartiles 0.3, 0.5) (P < 0.01). There was no significant difference in the mean (±SD) visual analogue scales pain score between the follicular flushing (3.4 ± 1.8) and the aspiration group (3.1 ± 1.89). LIMITATIONS, REASONS FOR CAUTION Blinding of the procedure was not possible. WIDER IMPLICATIONS OF THE FINDINGS Our study proved that flushing of single follicles in NC-IVF increases the oocyte yield. In contrast to polyfollicular IVF flushing seems to be beneficial in a monofollicular setting if the technique used in our study (single-lumen needle, 5 flushings with flushing volume adaptation) is applied. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the financial sources of the division and in part by a research grant provided by NMS Biomedical SA, Switzerland. The company did not have any roles in design or conduct of the study or in the preparation of the manuscript. The authors have no other conflicts of interest. TRIAL REGISTRATION NUMBER Clinicaltrials.gov NCT 02641808. TRIAL REGISTRATION DATE 29 December 2015 DATE OF FIRST PATIENT’S ENROLMENT 22 August 2016

What is the optimum number of follicular flushes in mono-follicular in-vitro fertilization cycles in a poor responder population?

“…During flushing the increase in intra-follicular pressure, longer procedure time, and change in paracrine milieu due to dilution may cause damage to the oocyte, either fracturing the zona or stripping the cumulus mass ( 4 , 14 ). In contrast, Kohl Schwartz et al ( 10 ) showed no association between the number of flushes and quality of embryos [odds ratio (OR): 1.39; 95% CI: 0.93-2.11]. We observed that the last flushing episode that yielded an M-II oocyte was the fourth and for an oocyte with fertilization capacity this was the third.…”

“…Similarly, Mendez Lozano et al ( 8 ) showed an increase in the oocyte yield from 46.8% to 84.6% in minimally stimulated cycles and von Wolff et al ( 9 ) reported an increase from 44.5% to 80.5% in mono-follicular cycles. A recent randomized trial showed significant increase in the mature oocyte retrieval rate by flushing (77.1% versus 59.3%) ( 10 ). Compared to previous reports, the rate of mature oocyte retrieval was lower in our study (65%, 160/246).…”

“…Xiao et al ( 13 ) was able to collect an oocyte from the ninth flushing episode but suggested that a reasonable maximum number of flushes was four. Kohl Schwartz et al ( 10 ) reported that the majority of mature oocytes were retrieved in three flushing episodes.…”

Optimal Timing of Ovulation Triggering to Achieve Highest Success Rates in Natural Cycles—An Analysis Based on Follicle Size and Oestradiol Concentration in Natural Cycle IVF

“…When the follicle diameter reached 14–22 mm or when the E2 concentration was expected to be ≥700–800 pmol/l, 5,000 IU of hCG (Choriomon ® , IBSA Institut Biochimique SA, Lugano, Switzerland) was administrated without LH suppression or ovarian stimulation and patients were scheduled 36 h later for oocyte retrieval (average number of days between the last consultation and HCG administration: 2.4 days (SD 0.6)). Oocyte retrieval was performed without anaesthesia and without analgesia using 19-G single lumen needles, and follicles were flushed five times ( 19 ). Embryos were transferred 2 or 3 days after aspiration.…”

Clomiphene citrate stimulated cycles – additional gonadotrophin stimulation increases endometrium thickness without increasing implantation rate

“…The oocyte pick-up was performed using 19G single lumen needles. Follicles were flushed five times (Kohl Schwartz et al, 2020).…”