symptoms of egg rupture after hcg injection?

Successful prevention of follicular rupture at 45 h after hCG and GnRHa triggering by emergent administration of indomethacin: A case report
Author links open overlay panelHsin-YiChengaHsin-YangLiab
https://doi.org/10.1016/j.tjog.2018.08.029
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Abstract
Objective

To report the management and prevention of pre-operative ovulation before oocyte retrieval with emergent administration of indomethacin.
Case report

During in vitro fertilization (IVF) treatment, the patient described here mistakenly administered 6500 IU of hCG and 0.2 mg of triptorelin (GnRHa) 9 h earlier than scheduled triggering. To avoid emergent oocyte retrieval in the midnight, indomethacin was given (150 mg/day, there times a day) from 2 h after incorrect hCG and GnRHa injection to the night before ovum pickup. The oocyte retrieval was performed at originally scheduled time. The result showed that pre-operative ovulation was effectively prevented and we successfully collected the expected number Andersen et al., 1995 of oocytes at 45 h after triggering.
Conclusion

The presented case demonstrates that indomethacin can be used safely and effectively as an emergent prescription to prevent and postpone ovulation till up to 45 h after hCG and GnRHa triggering.

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Introduction

The mid-cycle surge of luteinizing hormone (LH) plays an important role in the resumption of oocyte meiosis, expansion of the cumulus cells and ovulation. The LH surge stimulates a series of crucial events for follicular rupture [1]. In the natural cycle, endogenous LH surge usually lasts for 48 h. The onset of the LH rise is considered a more reliable indicator than the LH peak in determining the time of impending ovulation [2]. Natural ovulation usually occurs between 37 and 39 h after the onset of LH surge [3], [4].

During controlled ovarian hyperstimulation (COH) of in vitro fertilization (IVF) treatment, human chorionic gonadotropin (hCG) is extensively used as a surrogate for the mid-cycle LH surge. As what endogenous LH surge has done, hCG triggers the resumption of meiosis in primary oocyte that had previously been arrested at prophase of the first meiotic division, and promotes the accomplishment of final oocyte maturation. However, the ideal time interval between hCG administration and ovum pickup varies among the literature. Generally, excessively short or long time intervals were both known to cause unfavorable outcome in egg collection. Droesch et al. [5] demonstrated that performing oocyte retrieval less than 35 h after hCG triggering resulted in low number of retrieved oocytes. Gudmundsson et al. [6] found that 39 h could be the critical time period for oocyte retrieval, and it was unavoidable to have preoperative ovulation if oocyte retrieval was delayed over 39 h after hCG administration.

Nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin or meloxicam have been found to prevent premature ovulation in previous retrospective studies [7], [8]. Because prostaglandin acts as an important mediator in ovulation process, NSAIDs which limit biosynthesis of prostaglandin by inhibition of cyclooxygenases can impede follicular rupture and oocyte release [9]. In some IVF studies [7], [10], NSAIDs have been utilized to prevent premature ovulation in case of subtle premature LH surge during COH. There is no report evaluating the efficacy of NSAIDs in postponing the timing of follicular rupture after hCG triggering.

Herein we report a case who wrongfully injected the triggering dose of hCG and GnRHa at 13:00 PM instead of scheduled 22:00 PM on the same day of trigger. To avoid ovum pickup at 1AM in the midnight, emergent administration of indomethacin was performed to prevent follicle rupture before scheduled ovum pickup at 10 AM, leading to successful retrieval of expected number of oocytes at 45 h after hCG triggering.
Materials and methods

Using medical records on our patient of interest from our hospital, we generated a description of a unique experience to undergo oocyte retrieval up to 45 h after the triggering of ovulation with the emergent use of indomethacin for preventing follicular rupture before egg retrieval. In accordance with Taipei Veterans General Hospital Institutional Review Board (IRB) policies, case reports are not considered to be research subject to IRB review and are thus except from formal IRB approval for publication. The written consent from the patient was not requested nor required absolutely because the report did not specifically involve individual's video, photography, image or illustration.
Case report

The patient was a 42-year-old woman with a 6-year history of primary infertility of unexplained etiology. She had regular menstrual cycles with intervals of 30–31 days. Her partner's semen analysis appeared approximately normal except occasional slight asthenozoospermia or oligozoospermia. Her past medical history was unremarkable except obesity, with BMI of 32 kg/m2 and body weight of 85 kg. Her obstetric history includes three previous pregnancies achieved by IVF at another hospital. One pregnancy through fresh embryo transfer resulted in live birth in 2011. However, the other two through subsequent frozen embryo transfer both ended up with first-trimester spontaneous abortions in 2014. Therefore, she turned to our clinic for further fertility treatment.

Ovarian stimulation was commenced by giving a single injection of 150 mcg corifollitropin alfa (Elonva®) on day 4 of the patient's menstrual cycle. Gonadotropin-releasing hormone antagonist (GnRH antagonist) (Cetrotide®) 0.25 mg/day was administered subcutaneously from cycle day 9 when the lead follicle reached 14 mm in size, and was continued until the day of triggering. Furthermore, daily 150 U of human menopausal gonadotropin (hMG) (Menopur®) and daily 150 U of follicle-stimulating hormone (FSH) (Gonal-F®) were added since cycle day 10 and day 11 respectively to ensure adequate follicle growth. On cycle day 12, the level of estradiol was 2252 pg/ml, and there were 4 follicles with mean diameter ≥17 mm and 11 follicles with mean diameter ≥11 mm. Final oocyte maturation was arranged to be done by co-administration of hCG (Ovidrel®) 6500 IU and triptorelin (Decapeptyl®) 0.2 mg at 10 PM on day 13.

However, the patient mistakenly administered hCG 6500 IU and triptorelin 0.2 mg at 13 PM on day 13. She found this mistake and contacted our reproductive center 1 h later. To prevent premature ovulation, 50 mg of indomethacin was given three times a day before scheduled ovum pickup at 10 AM on day 15, which is 45 h after triggering, from 2 h after incorrect hCG injection to the night before oocyte pickup. Then oocyte retrieval was carried out as original schedule at 10 AM of cycle day 15, using ultrasound-guided transvaginal needle aspiration with sedation of the patient. Fifteen oocytes we retrieved and inseminated by conventional IVF. All of these 15 oocytes were fertilized, and 10 of them cleaved into two and four-cell embryos on day 2 after IVF; among which 8 embryos had good morphology with minimal or no fragmentation. Subsequently, four 4-cell grade 1 embryos were transferred into the mid-uterine cavity under ultrasound guidance on day 2 after IVF. Progesterone gel (90 mg, once daily) and progesterone capsules (200 mg, twice daily) were administered vaginally from the day following oocyte retrieval for luteal phase support. However, she did not achieve pregnancy by checking serum β-HCG fourteen days after oocyte retrieval.
Discussion

During COH process in IVF, GnRH agonist or GnRH antagonist is often used to achieve adequate pituitary suppression so as to produce large cohorts of follicles and oocytes. In this way, endogenous gonadotropin fluctuations are almost eliminated. After meeting the sonographic criteria for ovulation triggering, hCG was administered. The ovulation timing after hCG injection may slightly differ from that after natural LH surge by reason of the drug's absorption lag time in the body. Through a real time record via laparoscopy, Testart et al. [4] demonstrated natural ovulation was frequently established at 34–38 h after the onset of LH rise. However, according to medical results from the studies designed with COH protocol, it typically takes 34–38 h to allow final maturation of the oocyte [11]. Ideal IVF performance can be obtained when oocyte retrieval was done more than 36 h after hCG priming. Nevertheless, there would be a possibility of preoperative ovulation as a result of prolonged exposure to hCG. Even though Nargund et al. [12] mentioned no women ovulated up to 41 h from hCG administration and Al-Mizyen ESS al [13]. demonstrated successful fertilization in vitro of oocytes retrieved 60 h after hCG injection, there was another prospective study [14] showing the mean time interval from HCG to first follicular rupture located around 38.3 h. Since the number of patients with the time interval of hCG-to-oocyte recovery more than 40 h was relatively small, we need more sufficient evidence to comprehensively substantiate the characteristics of preoperative ovulation after prolonged hCG exposure.

Based on reasons above, proper control over the interval between trigger and oocyte retrieval is absolutely crucial for women undergoing IVF, to maximize the number of mature oocytes retrieved and avoid the risk of canceling treatment cycles due to unexpected premature ovulation. In the present case, we were forced to handle the urgent situation resulting from patient's wrong injection far away from scheduled time. Here, we demonstrated emergent administration of indomethacin effectively postponed follicular rupture farther than 45 h after hCG triggering, and no oocyte escape seemed to occur in the case.

Oocyte maturation is a time-dependent phenomenon related to some mediators released after LH/hCG exposure, which catalyze the serial processes of luteinization, expansion of cumulus cells, and the resumption of oocyte meiosis. These known mediators include the final products of the renin angiotensin system, angiotensin II and vascular endothelial growth factor (VEGF), as well as other factors like interleukin 1 (IL-1), IL-6, IL-8, angiopoietin, and insulin-like growth factor (IGF). Prolonged hCG exposure has been proved to increase follicular maturation and oocyte quality. The benefit was especially remarkable in some specific subgroups like patients with polycystic ovarian syndrome and patients with history of immature oocytes repeatedly dominant in previous IVF stimulation [15], [16]. Wei Wang et al. [17] described the percentage of mature (MII) oocytes can be increased by prolonged hCG exposure, but the fertilization rate, implantation rate, and pregnancy rate was not improved. However, the majority of these studies were designed with the upper limit of 38–39 h for the time interval between hCG and egg collection, so there is not enough data showing whether an unduly prolonged hCG exposure would induce oocyte post-maturity. In the present case, the morphology and maturity of aspirated oocytes showed a normalized distribution. They did not display the appearance of post-mature oocytes, which is typically presented with extremely expanded cumulus masses, darkened corona radiate, accompanied with some atretic cumulus cells and apoptotic polar bodies.

High-dose NSAIDs administration in humans during the late follicular phase was recently explored as an effective method to control spontaneous ovulations during natural-cycle IVF [7], because NSAIDs is able to inhibit the production of prostaglandins which are essential for follicle rupture and ovulation. There were only a few studies [10], [18] suggesting that post-LH surge NSAIDs treatment may also be capable of preventing or delaying ovulation. Moreover, NSAIDs is used as an alternative method for emergency contraception [19], [20]. Jesam et al. [20] described that NSAIDs more effectively prevented ovulation when it was administered before the onset of the LH peak. However, in our case, indomethacin was administered 2 h after the wrong injection of hCG, but seemed to perfectly prevent premature follicular rupture before oocyte retrieval. It has also been shown that indomethacin interferes with the ovulatory process without having apparent effects on menstrual cycle length or FSH, LH, estradiol and progesterone concentrations [19], [21]. As to the effect of indomethacin on implantation, NSAIDs had been proved to induce decidualization defects and display anti-implantation effect in the animal study [22]. But in another human study, the implantation rate of embryos showed no statistical difference between the NSAIDs group and the control group [23]. More large-scale randomized trials are needed to further evaluate the effect of indomethacin on endometrium and implantation, thus providing advice on fresh or frozen embryo transfer for patients encountering the same condition in the future.
Conclusion

In summary, we conclude that indomethacin can be used safely and effectively as an emergent prescription to prevent and postpone ovulation till up to 45 h after hCG and GnRHa triggering.
Conflicts of interest

The authors declare no conflicts of interest.
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