Endometrial compaction after human chorionic gonadotrophin administration reduces ectopic pregnancy rate following fresh embryo transfer in vitro fertilization/intracytoplasmic sperm injection cycles in patients with non-thin endometrium: a retrospective cohort study

Study design and participants

This study retrospectively analyzed 3134 patients who underwent fresh IVF/ICSI ET in the Reproductive Center of the First Hospital of Lanzhou University from January 2019 to December 2021, including 3022 intrauterine, 112 ectopic cycles. This study has been approved by the Ethics Committee of the First Hospital of Lanzhou University. Exclusion criteria: did not reach the clinical pregnancy cycle, key data deletion cycle, heterotopic pregnancy cycle, or chromosome abnormality and uterine malformation cycle.

Definition of ectopic pregnancy and endometrial compaction

The main outcome index of this study was the EP rate. Ectopic pregnancy involves at least one sac outside the uterine cavity. The EP rate = the number of EP cycles/the number of ET cycles × 100%. The main measurement variables were endometrial thickness on the day of the HCG trigger and endometrial thickness on the day of ET. According to the difference in endometrial thickness on the day of ET and HCG administration, the patients were divided into two groups: the compaction group (the endometrium became thinner on the day of ET, compared with the endometrium on the day of HCG administration) and non-compaction group (the thickness of endometrium remains unchanged or thickened on the day of ET, compared with endometrium on the day of administration of HCG administration).

ART Program and Embryo Evaluation

According to the patient’s age, diagnosis of infertility, and ovarian reserve, a gonadotropin-releasing hormone (GnRH) antagonist regimen, GnRH agonist long regimen, or improved super-long regimen were selected for controlled superovulation.

The GnRH antagonist regimen: Gonadotropin (gonadotropin, Gn) (Gonafen, Merck Sherano, Switzerland; or Lishenbao, Zhuhai Lizhu Medicine) was given on day 2–3 of menstruation, or 2–3 day after withdrawal of the drug (oral contraceptive or progesterone), depending on the patient’s age, BMI, and ovarian reserve function. According to the results of transvaginal ultrasound combined with a serum hormone test, the follicular development was evaluated, and the dose and frequency of Gn was adjusted in time. When the diameter of the follicle was ≥ 12 mm or E2 ≥ 300 pg/mL, the GnRH antagonist (Ogali, Mercadon, USA; or Sizekai, Merck Sherano, Switzerland) at 0.25 mg was given daily. The GnRH agonist long regimen: Intramuscular injection of GnRH-a 3.75 mg in the mid-luteal phase of the previous menstrual cycle. Gn was used when the pituitary gland reached the down-regulation standard (endometrial thickness ≤ 5 mm, serum E2 < 50 pg/mL, bilateral ovarian sinus follicle diameter ≤ 5 mm). The specific starting dose depends on the patient’s age, BMI, and ovarian reserve function. After using Gn for 3–4 days, the follicular development was evaluated by transvaginal ultrasound combined with serum hormone detection, and the dose and frequency was adjusted in time. The improved super-long regimen: On the 7th day after ovulation or on the 18th day of oral administration of Diane-35 (starting on the 3rd day of the menstrual cycle in the previous month), GnRH-a leuprorelin acetate (Boennokang, Beijing Boente Pharmaceutical) was subcutaneously injected with the same dose 21 days after the treatment. Blood sampling and transvaginal ultrasound examination were performed 21 days after the last injection. After reaching the down-regulation standard (endometrial thickness ≤ 5 mm, serum E2 < 50 pg/mL, bilateral ovarian sinus follicle diameter ≤ 5 mm), domestic HMG (Zhuhai Lizhu Medicine) 150 ~ 225U/d was used to start. After 4–5 days, the dose was adjusted according to the transvaginal ultrasound results and blood hormone level. When the diameter of three or more follicles reached 18 mm, or the diameter of one dominant follicle reached 20 mm, human chorionic gonadotropin (HCG) was injected intramuscularly to induce oocyte maturation.

The transferred embryos were scored according to the rate of embryo development, the degree of fragmentation, and the equality of blastomeres. The high-quality cleavage stage embryos are grade I or grade II embryos with uniform cytoplasm and regular morphology, grade I embryos: fragments < 5%, grade II embryos: 5% < fragments < 10% [15]. The blastocysts were scored according to the Gardner scoring system [16]. The blastocysts were divided into six stages according to the volume of the blastocyst cavity and the degree of blastocyst incubation. Blastocysts in stage III ~ VI were divided into A, B, and C3 grades according to the number and structure of inner cell mass and trophoblast cells. Embryos with 4BB and above were adjudged to be high-quality embryos.

Measurement of endometrial thickness

Endometrial thickness was measured by transvaginal ultrasound on the day of the HCG trigger and the day of ET. When measuring the thickness of the endometrium, the sagittal plane of the uterus was taken to show the endometrial sonogram from the internal orifice of the cervix to the uterine floor, and the maximum distance between the myometrium and the junction of the endometrium on both sides was taken. Endometrial measurements are performed by experienced ultrasound physicians in millimeters (mm) and are accurate to 0.1 mm.

Statistical analysis

Statistical analysis was performed with Empower Stats software and R language. Continuous variables following the normal distribution were presented as mean ± SD, and continuous variables that did not conform to the normal distribution were presented as the median (25%–75%). Categorical variables were presented as N (%). T-test (normal distribution) and Kruskal–Wallis rank sum test (non-normal distribution) were used to compare the continuous variables between groups, and the chi-square test was used to analyze categorical variables. Univariate analysis was used to study the factors affecting EP. Multiple logistic regression analysis and stratified analysis were used to study the effect of endometrial compaction after HCG administration on EP in patients with a non-thin endometrium after adjusting for confounding factors. The difference was statistically significant (P < 0.05).

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