Predictive Factors for Empty Follicle Syndrome in Infertile Patients Undergoing Assisted Reproductive Technology Treatment: A Retrospective Cohort Study and Brief Literature Review

Junichiro Mitsui^1,2, Kuniaki Ota^3,*, Hidetoshi Yamashita⁴, Toshio Sujino², Kenichiro Hiraoka², Shoko Katsumata^1,2, Yuko Takayanagi², Yurie Nako², Makiko Tajima², Kumi Ohuchi⁵, Masaru Hayashi⁵, Tomonori Ishikawa⁶, Kiyotaka Kawai^1,2,5

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¹ Comprehensive Reproductive Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8519 Tokyo, Japan

² Reproductive Medicine, Kameda IVF Clinic Makuhari, 261-8501 Chiba, Japan

³ Fukushima Medical Center for Children and Women, Fukushima Medical University, 960-1295 Fukushima, Japan

⁴ H.U. Group Research Institute G.K., Research Laboratory, 197-0833 Tokyo, Japan

⁵ Reproductive Medicine, Kameda Medical Center, 296-8602 Chiba, Japan

⁶ Department of Pediatrics, Perinatal and Maternal Medicine (Ibaraki), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8519 Tokyo, Japan

^*Correspondence: kuniakiota@gmail.com (Kuniaki Ota)

Clin. Exp. Obstet. Gynecol. 2023, 50(4), 80; https://doi.org/10.31083/j.ceog5004080

Submitted: 26 December 2022 | Revised: 22 February 2023 | Accepted: 6 March 2023 | Published: 17 April 2023

This is an open access article under the CC BY 4.0 license.

Abstract

Background: Empty follicle syndrome (EFS) is a rare complication in which no oocytes are retrieved in oocyte pick-up (OPU) despite adequate controlled ovarian hyperstimulation (COH). Various studies and systematic reviews have reported that EFS is mainly caused by diminished ovarian reserve (DOR) because EFS tends to occur in patients with a poor response to COH. However, these factors do not explain all cases. Current knowledge of these pathological factors is limited, and treatment is unknown. This study aimed to find out the clinical predictors of EFS before OPU. Methods: In this study, 2342 cycles of 1148 cases that underwent OPU between January 2015 and November 2020 in two reproductive clinics were retrospectively enrolled. Ninety-one and 2251 cycles were classified as EFS (no cultivatable oocytes retrieved) and non-EFS (cultivatable oocytes retrieved), respectively. Results: The EFS and non-EFS incidence was 3.9% and 96.1%, respectively. The mean patient age in the EFS group was higher than that in the non-EFS group (40.3 $\pm{}$ 3.4 years vs. 37.9 $\pm{}$ 4.5 years, p $<$ 0.001). Body mass indexes in the EFS and non-EFS groups were similar (21.7 $\pm{}$ 3.3 kg/m ${}^{2}$ vs. 22.0 $\pm{}$ 3.5 kg/m ${}^{2}$ , p = 0.52). The anti-Müllerian hormone (AMH) levels, antral follicle count (AFC), and the number of follicles were lower in the EFS group than in the non-EFS group (1.0 $\pm{}$ 1.2 ng/mL vs. 2.7 $\pm{}$ 2.5 ng/mL, p $<$ 0.001; 2.9 $\pm{}$ 2.2 vs. 8.5 $\pm{}$ 6.3, p $<$ 0.001; 1.9 $\pm{}$ 1.4 vs. 6.0 $\pm{}$ 4.1, p $<$ 0.001, respectively). However, unlike univariate analysis, logistic regression analysis showed no significant differences in age and AMH levels between the groups. The AFC and number of follicles were still significantly lower in the EFS than in the non-EFS group in multivariate analysis (odds ratio (OR), 1.301; 95% confidence interval (CI), 1.138–1.503; p $<$ 0.05 and OR, 1.832; 95% CI, 1.488–2.3; p $<$ 0.05, respectively). The EFS incidence rates for each follicle number just before OPU were 21.2%, 7.8%, 2.7%, and 1.2% with one, two, three, and four follicles, respectively. Not a single case of EFS was found among 410 cases with 10 or more follicles. Conclusions: The AFC and the number of follicles may be predictive of EFS.