Puncture of ovarian follicles and ovarian endometrial in an in vitro fertilization program

Piotr Marianowski MD, PhD; Iwona Szymusik MD, PhD

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In the past, the method used to obtain the follicular contents was puncture implemented during laparos-copy, effectively used in the 80-ies and 90-ies of the pre-vious century. The introduction of transvaginal probe in gynaecologic ultrasonography has revolutionized the method of puncture of ovarian follicles. During the past 20 years collecting the egg cell under transvaginal ultra-sound control (USG-TV) has become the standard method. This made it possible to increase the safety and efficacy in comparison with previously used laparo-scopic methods [1, 2].

Popularisation of this method has led to continuous im-provement of shape of the needle for aspiration, poten-tially maximizing the probability of egg cell retrieval [3, 4]. As a result, the double lumen needle was introduced to minimize the possibility of leaving the oocyte within the follicle.

One channel is used for oocyte aspiration, and the other for injection of fluid into the bladder and its flushing. The theoretical benefit of the double lumen needle is that the additional flushing of fluid into the follicle maximizes the probability of obtaining an oocyte [f5]. This concept has initially been supported by several non-randomized studies, which showed encouraging data with applica-tion of follicle flushing [6-8]. However, subsequent rand-omized studies did not confirm these results [9, 10].

Despite the limited data to support the routine use of flushing the follicle [12], it is still frequently practiced procedure in many IVF clinics. However, there remain concerns about the potential benefits of flushing, per-formance techniques and therapeutic effects of thera-peutic cycle [13-15]. The purpose of this systematic review of the literature and the meta-analysis is a sum-mary of available published, randomized controlled trials on the effects of follicle rising, obtaining an egg cell and other parameters of therapeutic cycle under IVF program.

Flushing the follicle – simple aspiration

Levy et al, in a large meta-analysis published in the „Human Reproduction” did not show the prevalence of follicle flushing technique over simple follicle aspira-

tion. [15] Both techniques provided similar number of oocytes retrieved and the performance of the proce-dures. These results were consistent in all six rand-omized clinical studies, which were subject to analysis.

Flushing the follicles involves longer duration of treat-ment, which in theory could lead to a slight increase in costs and risks of the procedure, although there are no data for a more detailed description of the problem [16]. The most extensive group was analysed by Haydard-edeoglu et al (2011) - 518 cycles of IVF, while earlier work included 164 cycles (17). The materials developed did not show any difference in the effectiveness of IVF treatment between the group with follicle flushing and the group without follicle flushing.

These results differ from several non-randomized stud-ies, which suggested that flushing the follicle increases the efficiency of procedures for egg cell obtaining [5]. However, they have in their design potential methodo-logical errors, which may have influenced the results. In all three studies, each of these patients has been sub-jected to flushing the follicle and the control group was not created. Each of the follicles was punctured once and then the aspiration and flushing was made.

It was considered that oocytes obtained at the begin-ning are the result of direct aspiration, and oocytes ob-tained later on – of flushing. It is possible that oocytes classified to flushing phase were contained in the nee-dle after aspiration and originated in fact from the first phase of procedure, even though they were assigned to follicle flushing phase. Some of studies carried out in the past, tried to address this issue by classifying the residue of oocytes obtained in the first flushing to cells derived from simple aspiration. Randomization of pa-tients to flushing vs no flushing is the best method of comparing these techniques and solving the issue of improper assignment of oocytes to each of them.

In theory, increasing the efficiency of oocyte retrieval should lead to an increase in the number of embryos available for transfer, potentially increasing the likeli-hood of live birth. In the analysis of more than 400 000 IVF cycles Sunka-ra et al [15] showed that the probabil-ity of live births after applying IVF techniques signifi-

In an in vitro fertilization (IVF) program the culminating

moment of ovulating stimulation is the follicular fluid aspiration

from the ovaries.

cantly increases in the event in which the total number of oocytes obtained increases from 1 to 10. Similar in-crease is no longer observed at higher number of oo-cytes, and in case of obtaining 15-30 oocytes the probability of live births remained at similar level.

Based on these data it can be concluded that in cor-rectly responding patients we can expect no great ad-vantage of follicle flushing because obtaining one or two additional oocytes does not improve the results significantly. However, women in whom the number of available oocytes is limited, can be a group in which the follicle flushing shall be potentially beneficial. The women belonging to this group are, among others, women poorly responding to therapy, women in the IVF program in natural cycles and those that received the minimum stimulation [12-14].

In one randomized controlled trial that evaluated the pa-tients poorly responding to therapy, Levens et al ob-served no significant differences between the groups, and demonstrated classified insignificantly better quality of oocytes and their higher number in the group col-lected during flushing the follicles. However, this study was limited by the small number of attempts, i.e. 30 pa-tients. A systematic review did not show any control data with randomization estimating the follicle flushing in IVF program in natural cycle or with minimal stimulation (11).

Endometrial cysts in patients with infertility

Another issue emerging in terms of follicular puncture is the presence of endometrial cysts in patients with in-fertility problems. Including to the program the stimu-lation with exogenous gonadotropins in program of IVF patients with endometriosis is associated with the possibility of obtaining a smaller number of oocytes, a need to use higher doses of drugs and lower the con-centrations of estradiol on the day of human chorionic gonadotropin (hCG) administration. However, data on the quality of the embryos obtained in patients with en-dometriosis in the literature are inconclusive. Recent studies on large groups of patients showed no signifi-cant difference between the quality of obtained em-bryos and the percentage of pregnancies after assisted reproduction treatment techniques in the groups of patients with endometriosis and ovarian factor related infertility. Thus, postulated in most publications less ef-fective infertility treatment may be caused by improper selection of treatment group, in which there is a worse response to stimulation, resulting in a smaller number of obtained oocytes, their poorer quality and the nega-tive effect on endometrium during the period of im-plantation window.

An alternative to the start of ovarian stimulation in IVF program is surgical treatment of cyst enucleation. Such conduct does not raise any doubts in case of large size changes (more than 5 cm in diameter). The enucleation of smaller changes has its supporters and opponents.

The removal of the changes prior to stimulation is sug-gested by the above mentioned effects of joining IVD program with endometriosis. Opponents postulate that surgical treatment can have the effect of reducing ovar-ian reserve, which in turn can leads to lower respond to stimulation of ovulation. Furthermore, implementation of treatment associated with surgery postpones the de-cision on treatment with IVF method even by up to six months. For young women, this is more recommended proceedings than in case of women, in which endome-triosis was diagnosed at the age of about 40 years. In such cases, it is proposed to join immediately IVF pro-gram, in the absence of effective treatment in the first cycle the respond of the patient to stimulation and the course of embryonic development should be analyzed thoroughly. If these parameters do not diverge from standards for patients at this age, it is possible to con-sider joining the program again without surgery. In a situation of worse response to stimulation and lower number of embryos with unsatisfactory morphol-ogy, it is recommended to enucleate the endometrial cyst before next treatment program with use of assisted reproductive techniques.

In cases of joining the subsequent programs with use of assisted reproductive techniques by the patient with recurrent ovarian endometrial cysts it is possible to as-pire the cyst contents during follicles puncture. How-ever, this is done only after aspiration of the liquid from all the follicles. This procedure allows to avoid the toxic effects of the substances contained in endometrial cysts on the egg cell. This procedure is not generally as rec-ommended due to technical difficulties during the aspi-ration of „thick” contents of the cyst and the presence of strong pain after the puncture and the risk of infec-tion. Alternative to this procedure is to perform aspira-tion of cysts in the months preceding the stimulation with use of gonadotropins with application of pituitary gland desensitization with gonadotropin releasing hor-mone – GnRH. Such action makes it easier to carry out the procedure (smaller, more accessible ovary, less „thick” content of the cyst and the subsequent inclusion of stimulation in patient “without cyst”.

In younger patients, it is recommended to enucleate the endometrial cyst prior to IVF program joining. In case of stating minor endometriosis during diagnostic laparos-copy it is recommended to coagulate them, which in-volves small but statistically significant increase in fertility.

Literature:

1. Bagtharia S, Haloob AR. Is there a benefit from routine follicular flushing for oocyte retrieval? J Obstet Gynaecol 2005; 25 (4): 374-6.

2. Eisermann J, Yang V, Register K, Swank N, Strickler RC. Ovarian stimulation with pure follicle-stimulating hormone/human menopausal gonadotropin and improved laparoscopic aspiration needles influence the success of an in vitro fertilization program. Fertil Steril 1989; 51 (1): 112-6.

3. el Hussein E, Balen AH, Tan SL. A prospective study comparing the outcome of oocytes retrieved in the aspirate with those re-trieved in the flush during transvaginal ultrasound directed oocy¬te recovery for in-vitro fertilization. Br J Obstet Gynaecol 1992; 99 (10): 841-4.

4. Gembruch U, Diedrich K, Welker B, Wahode J, van der Ven H, Al-Hasani S, Krebs D. Transvaginal sonographically guided oocyte retrieval for in-vitro fertilization. Hum Reprod 1988; 3 Suppl 2: 59-63.

5. Haines CJ, Emes AL, O’Shea RT, Weiss TJ. Choice of needle for ovum pickup. J In Vitro Fert Embryo Transf 1989; 6 (2): 111-2.

6. Higgins JPT, Altman DG, Sterne JAC. Assessing risk of bias in included studies. In: Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. www.cochrane-handbook.org.

7. Hill MJ, Levens ED. Is there a benefit in follicular flushing in assisted reproductive technology? Curr Opin Obstet Gynecol 2010; 22 (3): 208-12.

8. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of rando-mized clinical trials: is blinding necessary? Control Clin Trials 1996; 17 (1): 1-12.

9. Kingsland CR, Taylor CT, Aziz N, Bickerton N. Is follicular flushing necessary for oocyte retrieval? A randomized trial. Hum Reprod 1991; 6 (3): 382-3.

10. Knight DC, Tyler JP, Driscoll GL. Follicular flushing at oocyte retrieval: a reappraisal. Aust N Z J ObstetGynaecol 2001; 41 (2): 210-3.

11. Levens ED, Whitcomb BW, Payson MD, Larsen FW. Ovarian follicular flushing among low-responding patients undergoing assisted reproductive technology. Fertil Steril 2009; 91 (4 Suppl): 1381-4.

12. Lozano DH, Fanchin R, Chevalier N, Feyereisen E, Hesters L, Frydman N, Frydman R. Optimising the semi natural cycle IVF: the importance of follicular flushing. J Indian Med Assoc 2006; 104 (8):423-7.

13. Mendez Lozano DH, Brum Scheffer J, Frydman N, Fay S, Fanchin R,Frydman R. Optimal reproductive competence of oocytes retrieved through follicular flushing in minimal stimulation IVF. Reprod Biomed Online 2008; 16 (1): 119-23.

14. Levy G, Hill MJ, Ramirez CI, Correa L, Ryan ME, DeCherney AH, Levens ED, Whitcomb BW. The use of follicle flushing during oocyte retrieval in assisted reproductive technologies: a systematic review and meta-analysis. Hum Reprod 2012; 27 (8): 2373-9.

15. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod 2011; 26 (7): 1768-74.

16. Nisolle M. Ovarian endometriosis and peritoneal endometriosis: are they different entities from a fertility perspective? Curr Opin Obstet Gynecol 2002; 14 (3): 283-8.

17. Kuivasaari P, Hippelainen M, Anttila M, Heinonen S. Effect of endometriosis on IVF/ICSI outcome: stage III/IV endometriosis worsens cumulative pregnancy and live-born rates. Hum Reprod 2005; 20 (11): 3130-5.

Piotr Marianowski, MD, PhD, Iwona Szymusik MD, PhD Department of Obstetrics and Gynaecology, Medical University of Warsaw, Pl. Starynkiewicza 1/3, Warsaw

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