15.1 Introduction

The context of premature ovulation does not exactly refer to premature luteinization or unpreventable LH surge that is discussed in the previous section. This topic is rather more relevant to premature follicle rupture, which can be observed before the planned oocyte retrieval or at the time of the retrieval procedure itself.

In women with diminished ovarian reserve (DOR) and/or advanced reproductive age (ARA), after triggering for final oocyte maturation, even if the oocyte retrieval is attempted at the conventional time interval of 35–36 hours, disappearance of especially the follicles at or above 18 mm can be observed. At times, such follicles can be so fragile that even the gentle introduction of the transvaginal ultrasound probe may lead to rupture of the follicles in front of the operator’s eyes. Other times, no follicles but only the fluid in the cul-de-sac can be observed leading to hopeless attempts of cul-de-sac fluid aspiration to find an oocyte. Considering the limited number of follicles in such patients and the corresponding small volume of fluid in the cul-de-sac, this attempt is usually unsuccessful and may potentially risk the case for especially bowel complications. Therefore, we mainly discuss preventive measures taken to prevent premature ovulation or follicle rupture, which is not associated with LH surge.

15.2 Earlier Performance of Oocyte Retrieval After the Administration of Trigger Agent

The groups focusing on patients with DOR and poor ovarian response (POR) are well aware of the phenomenon of early follicle rupture not related to LH surge. Therefore, after triggering for final oocyte maturation with either gonadotropin-releasing hormone (GnRH) agonist or human chorionic gonadotropin (HCG), such practices schedule oocyte retrieval in 32–34 hours when the trigger agent was administered with follicle size ≥18 mm [1]. Some others administer HCG at 5000 IU when the leading follicle size exceeds 16 mm and the oocyte retrieval is performed 34 hours after the HCG administration to mitigate follicle rupture before follicle aspiration [2].

Triggering final oocyte maturation in women with ARA at or above the age of 43 years to prevent premature luteinization of the follicles not related to LH surge is also discussed in minimal stimulation chapter. There is some data supporting the administration HCG 10,000 IU when the leading follicle size is between 16 and 18 mm in conventional IVF stimulation cycles without changing the timing of the retrieval. This may also be relevant to younger DOR patients as well although with smaller follicle diameters, cytoplasmic immaturity may be an issue, which may impact proper embryo development [3].

On the other hand, at least from the studies in general IVF population, it is reported that the best time interval for oocyte retrieval after triggering for final oocyte maturation should be between 35 and 38 hours to get the most metaphase II oocytes [4]. In the former years of IVF, earlier oocyte retrievals were mainly performed to minimize the effects of unprevented LH surge before the era of GnRH agonist protocols and GnRH antagonist use. From the earlier days of IVF to now, the data suggest the optimal time interval to be 36 hours [5].

It was also suggested that if the oocyte retrieval was scheduled earlier than 36 hours after the triggering for final oocyte maturation, perhaps delayed denudation of the oocytes from their surrounding cumulus granulosa cells may compensate for the earlier retrieval in conventional IVF stimulation cases planned for intracytoplasmic injection (ICSI). This hypothesis was tested in a cohort study in women <38 years of age undergoing conventional IVF stimulation for ICSI, and the HCG trigger was administered with at least three follicles >17 mm. This retrospective study included retrieval time intervals between 34 and 38 hours after triggering but assessed in two groups whether the retrieval was done before or after 36 hours. Cumulus cell denudation time after the retrieval ranged between 5 minutes and 7 hours (mean 2.3 ± 1.3 hours). This was examined in two groups whether denudation was performed in less or more than 2 hours after the oocyte retrieval. As the time interval from HCG administration is extended beyond 36 hours, ICSI outcomes improved. Despite the similar proportion of metaphase II oocytes in each group, fertilization rates and clinical pregnancy rates with similar number and quality of the embryos transferred were higher in the group with oocyte retrieval performed beyond 36 hours as compared to those undergoing earlier oocyte retrievals. Regardless of the HCG-retrieval interval, retrieval denudation interval did not show any impact on clinical pregnancy rates. In a similar fashion, denudation-ICSI interval (mean 1.2 ± 1.1 hours) did not affect ICSI outcome. The authors concluded that in patients with normal ovarian reserve undergoing ICSI, prolongation of the time for cumulus denudation while keeping the oocytes in culture or prolonging the ICSI time interval from denudation did not compensate the potential negative effects of performing oocyte retrievals earlier than 36 hours from the time of triggering for final oocyte maturation with HCG [6]. Certainly, many of such studies are from conventional IVF stimulation cycles and normal responders may not be relevant to minimal/mild stimulation or natural cycle approaches for women with POR, DOR, and/or ARA.

In the earlier years of our minimal stimulation IVF practice for patients with POR and DOR, we did observe disappearance of follicles or follicle collapse during the oocyte retrieval process if we sticked with the 36 hours interval from the time of HCG and/or GnRH agonist trigger. We then started to do the retrievals at 35 hours following the triggering. For some patients with oocyte maturation issues or problems in embryo progression after fertilization, we scheduled retrievals 35.5 hours after triggering. In patients with persistent early follicle collapse, performing oocyte retrievals as early as 34 hours may result in immature oocytes and issues with proper embryo progression. Therefore, we keep our retrieval times at 35 hours or 35.5 hours following the administration of the trigger agent. We take additional measures instead of doing earlier retrievals as described below.

15.3 Nonsteroidal Anti-inflammatory Agents

Indomethacin, one of the nonsteroidal anti-inflammatory drugs (NSAIDs), has been in use to prevent premature ovulation in IVF cycles [7]. Indomethacin found support especially in prevention of ovulation in natural cycles for IVF. This agent was shown to delay ovulation for a week when used as 50 mg orally three times daily for 7 days. Indomethacin is used in minimal stimulation IVF cycles at 50 mg dose provided on the day of GnRH agonist administration for triggering to prevent premature ovulation without adversely affecting LH surge-induced effects on oocyte maturation [1].

Inhibitory effects of indomethacin or aspirin on ovulation was first observed in rodents [8, 9]. It was then demonstrated that indomethacin does not prevent LH surge but acts directly on the ovary [10]. In pigs, it was reported that the inhibition of ovulation by the indomethacin given 24 hours after HCG trigger can be reversed by prostaglandin F2alpha administration [11].

In women, indomethacin at 50 mg orally three times daily used for 3 days or more started with the positive urinary LH testing was shown to delay ovulation without any ill effects on menstrual cycle length and FSH, LH, estradiol, and progesterone levels [12]. When used in modified natural IVF cycles as compared to the same treatment protocol without indomethacin use, while decreasing the rate of premature ovulation, indomethacin 50 mg orally three times daily started when follicles sizes reached 14 mm did not seem to have any adverse effects on embryo development and clinical pregnancy rates [13].

In summary, leukocytes, cytokines, and many inflammatory mediators including prostaglandins have a close relationship in the ovulation process [14]. NSAIDs, like indomethacin and ibuprofen, exert their actions by inhibiting the action of the cyclooxygenase enzymes (COX), which convert arachidonic acid to prostaglandin H2 (PGH2). Of the two isoforms, COX-1 and COX-2, COX-2 inhibition is the one thought to be involved in inhibiting the ovulation. The preovulatory rise in gonadotropins stimulates COX-2 in the granulosa cells, leading to an increase in PGH2 and other prostanoids. These in turn will act on granulosa and theca cells to induce secretion of matrix metalloproteinases (MMPs) that degrade the extracellular matrix, eventually leading to follicle rupture and ovulation [15]. LH surge itself induces this inflammatory cascade leading to follicle rupture through MMPs, which is inhibited by nonselective COX inhibitors like indomethacin and ibuprofen. However, such agents like ibuprofen may also have dose-related impact on platelet function which may resolve 24 hours after the last dose of ibuprofen [16].

In our practice, we use single 600 mg dose of oral ibuprofen, day after administration of HCG and/or GnRH analog, with lunch about 18 hours before the oocyte retrieval in select cases. These are typically women >40 years old with leading follicles >18 mm in sizes or with recent history of follicle rupture at the time of oocyte retrieval. We observed that ibuprofen single-dose regimen is adequate to prevent premature follicle rupture before or at the time of oocyte retrieval. In a small comparative within-patient study, 600 mg single dose of ibuprofen administered about 18 hours before oocyte retrieval was demonstrated to decrease the levels of interleukin (IL)-6, IL-8, eotaxin, granulocyte colony-stimulating factor, MMP-3, MMP-7, MMP-12, and MMP-13 as compared to the cycles of the same patients without ibuprofen use. Since in both consecutive cycles we did not observe premature follicle rupture in all patients with or without ibuprofen, at least this study shows that 600 mg single dose of ibuprofen does induce anti-inflammatory changes as reflected in the follicular fluid studies. We do not use higher doses or doses closer to the oocyte retrieval time to avoid potential bleeding tendency which may be associated with ibuprofen use [17, 18].

15.4 Conclusion

Prevention of premature ovulation or follicle rupture before or at the time of oocyte retrieval is an important issue affecting the oocyte yield especially in women with DOR and/or ARA undergoing minimal or mild stimulation protocols. We mainly discussed two strategies. One is planning oocyte retrieval earlier than the norm of 36 hours following the administration of the trigger agent. Some practitioners plan oocyte retrieval as early as 32 hours. However earlier retrievals can be associated with decrease in mature oocyte yield and embryo progression issues. Keeping the oocytes with their surrounding cumulus cells may not assist with mitigating such problems. NSAIDs have been use to prevent ovulation. Our preferred method of preventing premature ovulation is keeping oocyte retrieval time 35–35.5 hours after administration of the trigger agent while considering single oral dose of ibuprofen at 600 mg after lunch, about 18 hours before the oocyte retrieval procedure in select cases.