Management strategies following implantation failure of euploid embryos

Abstract

Background: Euploid blastocyst implantation failure may result from embryonic factors undetectable by preimplantation genetic testing for aneuploidy (PGT-A); however, various nonembryonic factors can also intricately interfere with implantation. This review seeks to clarify evidence-based testing and treatments for implantation failure after euploid embryo transfer.

Methods: We conducted a review of the literature on implantation failure after euploid embryo transfer or multiple embryo transfer cycles, which mainly included systematic reviews and meta-analyses.

Results: The recommended tests for implantation failure include (1) hysteroscopy, (2) endometrial CD138 immunohistochemistry and bacterial culture, (3) serum 25-hydroxyvitamin D₃, and (4) thrombophilia screening. Based on diagnostic findings, the following treatments have been recommended: (1) antibiotics for chronic endometritis, (2) vitamin D replacement, (3) lifestyle modification, and (4) low-dose aspirin starting from the postimplantation period for thrombophilia. Moreover, frozen-thawed single euploid blastocyst transfer using assisted hatching and hyaluronan-enriched transfer medium may support embryo implantation.

Conclusion: To ensure a successful pregnancy in subsequent embryo transfers, simple, inexpensive, and evidence-based tests and treatments should be selected.

Keywords: euploid embryo; implantation failure; in vitro fertilization; infertility; preimplantation genetic testing.

FIGURE 1

Risk factors for implantation failure. Nonembryonic risk factors for implantation failure include intrauterine abnormalities, imbalance in maternal immunity, hydrosalpinx, and luteal phase deficiency. Hypothyroidism, thrombophilia, lifestyle habits mainly increase the risk of pregnancy loss but not implantation failure. Possible embryonic risk factors undetected by PGT‐A include false‐negative PGT‐A results, hardening of the zona pellucida, and impairment in cell adhesion at implantation.

FIGURE 2

Treatment protocols of chronic endometritis. When intrauterine organic lesions or a hydrosalpinx is present, hysteroscopic or laparoscopic surgery is initially performed. Endometrial CD138 immunostaining and bacterial culture tests are then repeated without antibiotic use in the subsequent menstruation cycle after surgery. When CE is detected in patients without intrauterine lesions, oral antibiotics based on bacterial culture test or doxycycline are administered. Should CE persist after ≥2 cycles of antibiotics, the inflamed endometrium is removed via gentle curettage. *Oral bacterium‐sensitive antibiotics or doxycycline are administered, according to the results of endometrial bacterial culture tests with or without specific bacteria except for Lactobacillus spp. or Bifidobacterium spp., respectively. If CE persisted with or without specific bacteria, bacterium‐sensitive antibiotics or ciprofloxacin and metronidazole are used as second‐line therapy. Figure in Kuroda et al. Reprod Med Biol 2023 was modified.

FIGURE 3

Drugs and supplements that may inhibit decidualization and implantation. During endometrial decidualization, stress‐resistant decidual endometrial cells emerge due to an acute stress response, whereas some decidual cells burdened by replication stress transform into senescent decidual cells. Given that uterine NK cells eliminate senescent decidual cells, endometrial cells transform into decidual cells. At implantation, the decidual endometrium modulates a local inflammatory reaction that allow trophoblast invasion by secreting proinflammatory cytokines. Throughout this multistep process, anti‐aging or anti‐inflammatory drugs or supplements may inhibit decidualization and implantation.