Case Report: The combined effect of endometrial receptivity array and laser assisted hatching on embryo implantation in repeated implantation failure case

Introduction

According to recent WHO studies, approximately 8-10% of couples are facing one or another kind of infertility problem, which means there are about 50-80 million people around the world who are tackling the issue of infertility.¹ Infertility can be referred to as “not being able to get pregnant or conceive after 12 months of unprotected sexual contact”.² In mammalian reproduction, the male gamete (sperm) fertilizes the female gamete (egg) to form an embryo that goes through various mitotic divisions before developing into the blastocyst. When an embryo arrives at the blastocyst stage, two sequential processes occur hatching and implantation, which initiate post-implantation development.³ These processes determine pregnancy outcomes and are established during the cleavage stage.

Physical factors such as molecular factors as well as the expansion of the blastocyst cavity are the factors on which the hatching process is dependent and that lead to the hatching of cells, which initiates rupture of the zona pellucida (ZP).⁴ Depending on the cause of infertility, several treatments such as intracytoplasmic sperm injection (ICSI) and assisted hatching (AH) have been developed to enable couples to have a greater chance of becoming pregnant and having a healthy baby.⁵ According to a previous study, progressive maternal age is one of the major factors affecting embryo hatching because of the hardening of ZP.⁶ Laser and light delivery systems are far superior to chemical or mechanical drilling methods because they provide a hands-free and precise method for delivering laser light to the target. This approach absorbs as little energy as possible from the embryos. Furthermore, the lasers currently being utilized for this purpose are inexpensive and can be easily added to any existing inverted microscope. Additionally, the laser focus is precisely managed during the reaction, indicating the capacity to produce an opening in the ZP without creating any mechanical, thermal, or mutagenic adverse effects.⁷ Repeated implantation failure (RIF) has become a prominent cause of infertility.⁸ In spite of many advances and achievements in reproductive medicine, they have ignored the fact that endometrium receptivity can also be the cause of infertility.⁹ Endometrial receptivity analysis (ERA) is an examination that ensures the best period for an embryo to be placed into a woman’s uterus for the embryo to implant, also known as the window of implantation (WOI). ERA can determine the timing of WOI, which can fall into the post-receptive or pre-receptive proliferative phases in the clinical context. WOI represents a brief phase during menses when the endometrium reaches its optimal efficiency. state, making it conducive for accepting a blastocyst for potential implantation.¹⁰

Treatment

The couple visited the infertility clinic situated in the rural area of the Vidarbha region for further treatment with all previous reports; these reports were then studied. After studying these reports, everything was observed to be normal, as mentioned above. Doctors advised the couple to undergo the conventional IVF protocol. The couple gave their consent for the same, the female partner underwent the pre-workup, and ovum pickup (OPU) was performed. Six oocytes were retrieved, of which one MI and five MII quality oocytes were retrieved. The oocytes were then injected with the husband’s sperm, and while performing ICSI, it was noticed that the zona pellucida of the oocytes was slightly thicker than normal. The blastocysts formed were of good quality, and we transferred the two embryos on day 5; however, the β-hCG test did not yield a positive result. Since we found that the zona was thick and the female did not conceive, we decided to consult with the patient. After consultation, the couple gave their consent, and it was decided to perform ERA and laser hatching. After studying the ERA results, we decided to perform a sequential embryo transfer.

The female patient was again stimulated with FSH for seven days for OPU. OPU was performed as scheduled, and this time we got 7 good-quality MII oocytes. The oocytes were then again injected with the husband’s sperm; on day 3, the embryos were frozen, and on day 5, two good embryos were formed and frozen. These embryos were frozen on two different cryofreezing devices, that is, 2+2, which means that two embryos were frozen in a single straw and another two were frozen in a different straw. After analyzing the ERA results, we decided to perform sequential embryo transfer. In the ERA report, blastocyst transfer was recommended at 135 ± 3 h of progesterone administration. For day-3 embryo(s), transfer should be performed two days earlier than indicated in the recommendation for blastocyst transfer. Thus, after studying the ERA results, we decided to perform sequential embryo transfer. Figure 1 shows the post-receptive results. Following the ERA results, embryo transfer (ET) was performed, a single blastocyst stage embryo was thawed, and after 1.5 hours, embryo laser hatching was performed. After 4 h, embryos were transferred as planned. Figure 2 showcases the hatching embryos that were transferred. After ET, the female partner was given bed rest for 6 hours, and the patient was advised to go home.

Figure 1. Shows the post-receptive ERA result.

Figure 2. Shows the transferred hatching embryo.

Discussion

Our case highlights the complications faced by the couple, including repeated implantation failure due to the post-receptive endometrium and thick zona. The decision was then made to perform ERA and personalized embryo transfer by performing laser-assisted hatching (LAH). In this case report, we discuss how ERA and laser-assisted hatching can lead to successful implantation.

In a study by Huy Phuong Tran et al., it was shown that the endometrial receptivity analysis did not enhance IVF outcomes, including pregnancy rates and implantation rates.¹¹ In our case, the ERA suggested a proper WOI and the correct time for ET, and pregnancy was accomplished following the ERA results. Hossein Razi et al. studied the impact of LAH. Their findings indicated that there was no significant increase in live births, clinical pregnancies, or the risk of congenital anomalies.¹² But in our case, LAH leads us to achieve a positive β-hCG level. Similarly, Da Li et al. reported that AH in ART resulted in a significant increase in clinical pregnancy and multiple pregnancy rates. The beneficial effect was especially seen in ICSI and when AH completely removed the zona pellucida.¹³ In a study by Wending Teng et al., sequential embryo transfer increased the pregnancy rate in patients with RIF.¹⁴

This study investigates the possible synergistic effect of combining two assisted reproductive technologies, ERA and LAH, in cases of RIF. ERA is a technique for measuring endometrial receptivity, whereas LAH involves making a small cut in the ZP around the embryo. The goal is to improve the potential for achieving effective embryo implantation in patients who have experienced repeat implantation failure. The goal of this study was to provide a vision for optimizing reproductive treatments for patients who have difficulty in generating successful pregnancies despite many attempts.

Conclusions

A couple facing primary infertility for nine years had a history of three failed IVF attempts. However, after transferring the two good-quality day 5 embryos by the conventional IVF protocol, the result was not positive. A decision to conduct the ERA test was made. In this attempt, seven good-quality MII oocytes were retrieved, which resulted in four good-quality day 5 blastocysts after performing ICSI. The embryos were then frozen in two different cryofreezing devices. After one month of ERA, three embryos were transferred, which led to a positive outcome with a β-hCG level of 245 mIU/mL after ET. This shows that the ERA test, along with LAH and sequential embryo transfer, helps achieve a successful pregnancy for couples with prolonged infertility.