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Factors contributing to good oocyte competence and utility rates for in vitro fertilization or intracytoplasmic sperm injection in high responders

Xue, Wei; Zhang, Duo-Duo; Zhen, Jing-Ran; Yu, Qi

Editor(s): Yin, Yan-Jie; Hao, Xiu-Yuan

Author Information
doi: 10.1097/CM9.0000000000001356
  • Open

To the Editor: The oocyte utility rate (OUR) describes the competence of oocytes to develop into usable embryos that can be transferred or cryopreserved. Except for maternal age, abnormalities due to intra-ovarian and/or extra-ovarian factors may affect the oocyte-granulosa cell interaction, maturation, and zygote development. In this study, we defined OUR as the number of applicable embryos (blastomere and blastocyst) divided by the number of oocytes retrieved from the corresponding stimulation cycle. We compared high and low OUR of cycles with at least 15 oocytes to determine the factors contributing to the huge gap between good and poor OUR to guide promising in vitro fertilization (IVF) outcomes.

The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. S-K1063), and the written consent forms were signed by the involved patients. This study analyzed IVF/intracytoplasmic sperm injection (ICSI) cycles performed at Peking Union Medical College Hospital between January 1, 2013 to December 31, 2019. Cycles harvesting of at least 15 oocytes were chosen and no fresh transfer was performed due to the consideration of ovarian hyperstimulation syndrome (OHSS). Each cycle was assessed using the OUR. After ranking all cases according to the OUR, we considered the highest 10% of cycles as group A and the lowest 10% of cycles as group B.

The ovarian stimulation protocol included the gonadotropin-releasing hormone (GnRH) agonist long protocol, GnRH antagonist protocol, and dual suppression protocol. The recombined follicle-stimulating hormone (rFSH) commencement dosage was determined based on the patient's age, body mass index (BMI), and ovarian reserve test results. Oocyte maturation was triggered by human chorionic gonadotropin (hCG). Oocytes were collected 36 h later. Embryo development was evaluated on day 3 and day 5 or day 6. On day 3, two fresh embryos with top grades were vitrified,[1] whereas the remaining embryos were cultured to blastocysts and then cryopreserved.

Finally, 453 patients were recruited. Group A and B included 43 and 47 patients, respectively. There were no differences in age, BMI, infertility duration, and basal hormone levels between the two groups [Table 1]. A higher proportion of group B have ovulatory disorders or endometriosis; 34% of their cycles were fertilized by ICSI in group B and only 14% in group A.

Table 1 - Clinical characteristics of the included patients performed IVF/ICSI.
Characteristics Group A (n = 43) Group B (n = 47) P value
Age (yr) 33.09 ± 2.61 32.37 ± 4.17 0.327
BMI (kg/m2) 21.61 ± 2.31 21.74 ± 2.54 0.811
Infertility duration (yr) 3 (2, 5) 4 (3, 5) 0.155
Primary infertility 72.1 (31/43) 74.5 (35/47) 0.799
Infertility factors 0.033
 Tubal 34.9 (15/43) 17.0 (8/47)
 Ovulatory obstacle 23.3 (10/43) 34.0 (16/47)
 Endometriosis 18.6 (8/43) 23.4 (11/47)
 Male 23.3 (10/43) 25.5 (12/47)
History of any previous IVF/ICSI 14.0 (6/43) 34.0 (16/47) 0.027
Rate of ICSI 20.9 (9/43) 40.4 (19/47) 0.046
Protocols for ovarian stimulation 0.013
 GnRH agonist long 20.9 (9/43) 31.9 (15/47)
 GnRH antagonist 23.3 (10/43) 42.6 (20/47)
 Dual suppression 55.8 (24/43) 25.5 (12/47)
Basal hormone profiles
 FSH (IU/L) 6.03 (4.95, 6.99) 6.00 (5.08, 6.84) 0.843
 LH (IU/L) 5.04 (2.72, 6.49) 4.44 (2.92, 5.71) 0.455
 E2 (pg/mL) 38.27 (26.58, 50.37) 43.78 (33.25, 54.54) 0.114
Hormone profiles on hCG day
 FSH (IU/L) 8.73 (6.24, 11.0) 10.57 (7.71, 13.48) 0.401
 LH (IU/L) 1.76 (1.35, 2.21) 1.59 (1.21, 2.04) 0.209
 E2 (pg/mL) 6715 (5136, 8222) 6000 (5143, 7436) 0.294
 P (ng/mL) 0.92 (0.69, 1.42) 1.1 (0.82, 1.59) 0.119
Gonadotropin consumption (ampul)
 rFSH starting dose 3 (2, 4) 3 (2.5, 4) 0.456
 Total rFSH 20.5 (12, 27) 20 (15, 28) 0.389
 Total HMG 3.5 (2.5, 5) 3 (2.5, 6) 0.990
 Total rLH 3 (2, 4) 2 (2, 3) 0.289
Days for ovarian stimulation 11 (10, 11) 10 (9, 11) 0.260
E2 decline during stimulation 30.2 (13/43) 42.6 (20/47) 0.038
Any suspension of rFSH except on the hCG day 23.3 (10/43) 44.7 (21/47) 0.033
No gonadotropins applied on hCG day 79.1 (34/43) 78.7 (37/47) 0.968
Laboratory results overview
 Oocytes retrieved 18 (16, 20) 20 (18, 22) 0.086
 MII oocytes 18 (16, 20) 18 (15, 20) 0.803
 Fertility rate 95.2 (689/776) 83.1 (726/874) <0.001
 Cleavage rate 100 (739/739) 96.0 (697/726) <0.001
Embryo on day 3
 Good-quality embryos 3 (1, 4) 0 (0, 1) <0.001
 Rate of good-quality embryos 15.8 (117/739) 3.7 (26/697) <0.001
 Eight-cell embryos 12 (9, 14) 3 (1, 5) <0.001
 Six-cell embryos 2 (0, 5) 4 (3, 6) 0.019
Blastocyst
 Embryos for blastocyst culture 15 (13, 18) 14 (12, 18) 0.346
 Numbers of blastocysts 12 (10, 13) 1 (0, 2) <0.001
 Blastocyst formation rate 78.1 (509/652) 7.9 (52/656) <0.001
 Numbers of 4BB+ embryos 6 (6, 9) 0 (0, 1) <0.001
 4BB+# embryo formation rate 46.5 (303/652) 3.4 (22/656) <0.001
Assisted reproductive outcomes
 Embryos cryopreserved (total) 14 (12, 14) 2 (2, 3) <0.001
 OUR 77.4 (601/776) 11.9 (104/874) <0.001
 CCPR 95.3 (41/43) 40.4 (19/47) <0.001
 CLBR 90.7 (39/43) 31.9 (15/47) <0.001
Data are presented as % (n/N), mean ± standard deviation or median (range).BMI: Body mass index; CCPR: Cumulative clinical pregnancy rate; CLBR: Cumulative live birth rate; IVF: In vitro fertilization; ICSI: Intracytoplasmic sperm injection; GnRH: Gonadotropin-releasing hormone; rFSH: Recombined follicle-stimulating hormone; rLH: Recombinant luteinizing hormone; HMG: Human menopausal gonadotropin; hCG: Human chorionic gonadotropin; MII: Metaphase 2; OUR: Oocyte utility rate. Each ampul equals 75 U of gonadotropin. #4BB+ embryos refer to blastocysts classified as stage 4–6 and BB, AB, BA, or AA according to the Gardner system.

We noticed that a higher proportion of patients in group B had experienced decreased E2 over the course of treatment. Furthermore, 44.7% of cycles in group B were suspended with rFSH during the stimulation before the trigger day. There were nearly equal numbers of retrieved oocytes and metaphase II oocytes. However, oocytes from the two groups demonstrated significant development potential. On day 3, 15.8% of embryos had good quality in group A; however, in group B, only 3.7% of embryos had good quality. Group A had more eight-cell blastomeres than group B. Although both groups had similar numbers of embryos for the blastocyst culture, group B had a much smaller formation rate (78.1% vs. 7.9%). Group A had an average of 14 embryos for cryopreservation; however, the average was only 2 in group B. Regarding frozen-thawed cycles, group A had a cumulative clinical pregnancy rate of 95.3% and a cumulative live birth rate of 90.7%; however, these two numbers were significantly lower in group B (31.9% and 40.4%, respectively).

Then we applied logistic regression to adjust each factor listed in Table 1 and selected beneficial or detrimental elements to OUR. Previously attempted IVF/ICSI (odds ratio (OR): 0.10, 95% confidence interval (CI): 0.01–0.81), infertility due to endometriosis (OR: 0.16, 95% CI: 0.03–0.84), and decreased E2 during the stimulation process (OR: 0.16, 95% CI: 0.04–0.64) were responsible for poorer OUR. On the contrary, longer ovarian stimulation durations (OR: 3.24, 95% CI: 1.25–8.42) led to better OUR. Compared to GnRH agonist long protocol, GnRH antagonist (OR: 1.39, 95% CI: 1.09–10.04) and dual suppression protocol (OR: 3.74, 95%CI: 1.06–26.86) contributed to promising OUR.

A high OUR is always expected by both physicians and patients. We noticed that previously attempted IVF/ICSI cycles were related to decreases in OUR. This could be attributed to previous improper luteal phase support or stimulation protocol. We also observed that the OUR was threatened when E2 decreased during the stimulation course. Additionally, this phenomenon was accompanied by the suspension of rFSH in the single factorial analysis. Similarly, a study that compared a reduction in rFSH and coasting concluded that the live birth rate remained the same, independent of the decrease in E2.[2] In another model, adding the GnRH antagonist induced a decrease in E2, which is commonly observed in clinical scenarios; the pregnancy rate did not vary according to decreases, plateaus, or increases in E2, but this study included normal and poor responders.[3] It should be emphasized that although it demonstrated contrary results, our study involved high responders who might have different oogenesis characteristics. Moreover, we allocated subjects to groups according to the OUR, whereas other studies separated patients based on the onset of E2 decline or withdrawal of rFSH.

The multifactorial analysis indicated that endometriosis was harmful to the OUR. In addition to the compromised number of oocytes, an impairment of oocyte competence has been demonstrated; several studies indicated that fertilization rates were lower with endometriosis than with tubal factor infertility.[4] Morphologically, oocytes from patients with endometriosis exhibit the loss of cortical granules and hardening of the zona pellucida, thus interfering with fertilization.[5] Although it does not have lethal effects on oocytes, physicians should remind patients of its complex threats to OUR.

For high responders, dual suppression and one cycle of oral contraceptives before the long conventional agonist protocol can lead to good OUR. Particularly for high responders with polycystic ovary syndrome, a cycle of contraceptives can induce a decrease in the luteinizing hormone/follicle-stimulating hormone ratio and serum dehydroepiandrosterone sulfate.[6] A non-randomized study also indicated that dual suppression does not disturb endometrial thickness or oocyte quality and number, but that it does dramatically prevent OHSS onset.[7] For endometriosis-associated infertility, pre-treatment with contraceptive pills is both cost-effective and non-inferior compared to long-term pituitary desensitization involved in the ultra-long protocol with a continuous GnRH agonist.[8]

Despite its retrospective nature and limited number, this study can guide future management of low OUR cases, especially for high responders. Patients with a history of IVF/ICSI and endometriosis should be considered at risk for unsatisfactory OUR. During ovarian stimulation, physicians should avoid suspending rFSH before the trigger day and prevent decreased E2. For high responders, dual suppression and GnRH antagonist can serve as an acceptable protocol, if possible.

Conflicts of interest

None.

References

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