Clinical value of histologic endometrial dating for personalized frozen-thawed embryo transfer in patients with repeated implantation failure in natural cycles

Yuan Li, Xiao Feng Li, Jing Nan Liao, Xiang Xiu Fan, Yong Bin Hu, Runxin Gan, Guangxiu Lu, Ge Lin, Fei Gong, Yuan Li, Xiao Feng Li, Jing Nan Liao, Xiang Xiu Fan, Yong Bin Hu, Runxin Gan, Guangxiu Lu, Ge Lin, Fei Gong

Abstract

Background: Displacement of the window of implantation (WOI) has been proposed as an important factor contributing to repeated implantation failure (RIF). However, the use of histologic endometrial dating as a diagnostic tool of endometrial receptivity has been questioned.

Methods: This study is a prospective intervention trial that enrolled 205 infertile patients from July 2017 to December 2017. Endometrial biopsies from 50 patients with good prognoses were conducted on day 3 (n = 6), 5 (n = 6), 7 (n = 26), 9 (n = 6), or 11 (n = 6) post-ovulation (PO + 3/5/7/9/11) of the previous natural cycle before their conventional frozen-thawed embryo transfer (FET) cycle. We conducted endometrial biopsies for 155 RIF patients on day PO + 7.

Results: The verification of the Noyes criteria for endometrial dating was conducted at different times (PO + 3/+ 5/+ 7/+ 9/+ 11) on 41 patients with good prognoses who achieved an ongoing pregnancy in their first conventional FET cycle after endometrial biopsy. The agreement between two pathologists determining endometrial biopsy dating results in infertile patients was determined to be acceptable (weighted kappa = 0.672, P < 0.001). The rate of out-of-phase dating on day PO + 7 was significantly higher in RIF patients than in good- prognosis patients (31.6% vs. 3.8%, P = 0.003). pFET was performed in 47 RIF patients diagnosed to be out of phase, and the cumulative live-birth rate was 61.7%.

Conclusions: Histologic endometrial dating of RIF patients in natural cycles may be a biomarker for a receptive endometrium in diagnosing WOI displacement.

Trial registration: NCT03312309 Registered 17 October 2017. NCT03222830 Registered 19 July 2017.

Keywords: Endometrial receptivity; Histologic endometrial dating; Personal embryo transfer; Window of implantation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The patients recruited to the control and RIF groups
Fig. 2
Fig. 2
Bland–Altman plots of variability according to pathologists A and B. The x-axis depicts the mean endometrial sample dating for pathologist A and pathologist B; the y-axis is the difference from the mean endometrial dating between pathologists A and B. The upper and lower lines on the B–A plots represent the limits of agreement and the mean difference ± 1.96 times its standard deviation. Thus, the distance from 0 and the width of the limits of agreement both indicate the magnitude of disagreement between pathologists. Closer clustering to the mean indicates higher agreement. If the difference value for an endometrial dating is = 0, then the endometrial dating by pathologist A and pathologist B was identical
Fig. 3
Fig. 3
Endometrial dating in control and RIF groups. a Inner-group differences in endometrial biopsy dating in the control group at different times (PO + 3/5/7/9/11) were rare, as proven by two experienced pathologists. Using the mean ± SD as the lower and upper limits to define a reference range for endometrial biopsy dating, 1 of 50 control women were below the range. b The out-of-phase rate in the good-prognosis group was different from that for the RIF group. c Endometrial dating according to the Noyes criteria in RIF patients (X 400). Dating + 3, gland cytoplasm and nuclei above and vacuoles below (arrow); dating + 4, glandular nuclei are in the center of the cells and glycogen vacuoles are seen on two sides of the gland nuclei (arrow); dating + 5, vacuoles (arrow) remain in the basement membrane of the gland cells; dating + 10, pre-decidua (arrow) begin to differentiate and spiral arteries increase

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