Repeated IVF failure patient’s condition described.
The patient was 33 years old, married in 2005, living together after marriage, with normal sex life and no contraception. 2011-11-18 HSG: hysterosalpingogram showed no significant abnormality. 2011-11-16 male semen routine showed: sperm viability 33.1%, sperm motility 17.1%, sperm density 73.8 million/ml; 2012-1-6 repeat semen routine showed: sperm viability 40%, sperm motility 23.1%, sperm density 54.3 million/ml. The sperm morphology and acrosome reaction were not abnormal, and he had undergone AIH once at a hospital in Jiangmen at the end of 2011 without pregnancy.
Past history: no history of hypertension, diabetes mellitus, heart disease, etc. She has a history of allergy to alcohol.
Menstrual history: Menstruation was regular in the past, with menarche at the age of 14, 6-7 days/35-48 days. She was married at the age of 26, G1P0A1, and had one pedestrian abortion in 2004.
Physical examination: stable vital signs, no abnormalities in cardiopulmonary auscultation. Multiple lipomas were scattered under the skin of the lower limbs, ranging from 12.5px to 62.5px in diameter, height 163mm and weight 55Kg.
Gynecological examination: normal vulvar development, vaginal patency, smooth cervix, median uterus, normal size, medium texture, no pressure pain, no abnormality palpable in both adnexal areas.
Auxiliary examination: female basal sex hormone level: FSH 3.4IU/L, LH 2.73IU/L, E2 15pg/mL, PRL 37.86ng/mL, T 0.47 ng/mL.
Preliminary diagnosis: 1, secondary infertility; 2, ovulation disorder; 3, subcutaneous multiple lipomas.
Treatment history.
In February and March 2012, she underwent clomiphene + Gn and Gn ovulation regimen respectively at our center for 2 times without pregnancy. On May 21, 2012, FSH: 1.34 U/L, LH: 0.67 U/L, E2: less than 10 pg/ml, and 150 units of Gnapharm were given to start injection for 4 days. HCG day, FSH: 7.9U/L, LH: 0.41U/L, E2: >5000pg/ml; P: 0.5 ng/ml. 26 eggs were retrieved, fertilized 2PN: 8; 1PN: 5, Pb: 9; MI: 2; GV: 1. Two embryos were frozen by vitrification (2.2/8; 2.1/8). two frozen embryos failed to be transferred in a natural cycle on September 2, 2012, with an intima of 10.3 mm/A (the morphological score of the embryos was the same before and after thawing), LH: 4.92 U/L, E2: 92 pg/ml; P: 16 ng/ml on the day of transfer.
Chromosomes were normal on both sides in October 2012. The patient started short injection and long protocol cycle treatment on Oct 25, 2012 with Dafilin 0.1mg/qd down regulation, after 15 days of injection. on Nov 9, 2012 FSH was drawn: 1.18U/L, LH: 0.61U/L, E2: less than 10pg/ml, 150 units of Forteon was given to start, Gn dosage was adjusted according to follicle growth and HMG was added. On November 23, 2012, 15 days after superovulation, 10,000 units of HCG were given to trigger. on HCG day, FSH: 6.07U/L, LH: 0.57U/L, E2: 1336pg/ml; P: 0.2ng/ml. 19 eggs were retrieved, 11 mature MII eggs and 11 ICSI fertilized 2PN: 11 eggs. Six transferable blastocysts were raised and two freshly transferred blastocysts (4AA;4AA) were given progesterone 40mg/qd + Anchietan 200mg pv/qd + Tocopherol 2mg/qd luteal support, and the fresh cycle was infertile. Four frozen blastocysts (4AA; 4BB; 4CB; 5CB) were left and hysteroscopic examination on December 24, 2012 showed mild adhesions on both sides of the uterine cavity and at the base of the uterus. mm/A. Blood LH: 6.2 U/L, E2: 757 pg/ml; P: 6.1 ng/ml were checked on the day of transfer. 20mg bid of Darvon was added to enhance luteal support. One blastocyst (4AA) was transferred and was not pregnant.
Discussion notes.
Analyze the treatment process and present the treatment difficulties.
The patient had repeated AIH failures, three transfers of high quality embryos without pregnancy, and mild hysteroscopic adhesions had been separated.
The young patient had a history of pregnancy between husband and wife 8 years ago, good ovarian reserve, the cause of infertility was not completely clear, and she was infertile after three cycles of COS-AIH. In the first cycle, 26 eggs were retrieved by IVF with a long protocol. The fertilization rate was low, but two good quality embryos (2.2/8; 2.1/8) were formed, and no pregnancy occurred after transfer. Before the second cycle, both partners were found to have normal chromosomes, so we switched to ICSI for fertility treatment. 19 eggs were retrieved, 11 were fertilized, 6 good quality blastocysts were formed, and two good quality blastocysts (4AA,4AA) were transferred freshly, without any pregnancy. The use of luteal support should be adequate. After failed transfer of multiple good quality embryos, the patient underwent hysteroscopy suggesting mild uterine adhesions and separation was performed. After the procedure, TET with HRT protocol was performed and a 4AA blastocyst was transferred, which was still infertile. Progesterone 40mg*qd daily and oral Darvon 20mg*bid were used for progesterone support.
According to the case study, the quality of the transferred embryos was quite good, all three blastocysts were 4AA, and the cumulative pregnancy success rate of the transfer would be more than 90% according to the previous experience. Except for mild uterine adhesions, no specific abnormalities were detected in the patient. Therefore, the problem of endometrial tolerance is considered, what is the next step? Is treatment failure entirely due to odds?
Principles of treatment and presentation of relevant progress.
Reviewing the medical history, the patient had the indication of ICSI, repeated failed transfer of high quality embryos, good endometrial morphology under ultrasound, and mild endometrial adhesions under hysteroscopy had been separated. Repeated failed transfers of high quality embryos and normal endometrial ultrasound patterns caused confusion about the next step of treatment.
It is generally accepted that infertile women have undergone 2 to 6 IVF cycles without pregnancy and that more than 10 quality embryos have been transferred to the uterus in each of these cycles; secondly, 3 consecutive cycles of IVF treatment with quality embryos transferred but without pregnancy. Although this patient has not yet transferred 10 embryos, the cumulative pregnancy rate appears to be quite high due to the quality of the embryos, for example, three blastocysts with a score of 4AA have been transferred. Although the definition diagnosis of repeated implantation failure was not met, it can no longer be explained simply by the chances of embryo implantation alone and its causes should be fully explored before the next treatment.
Since the classical D3 oogenesis and D5 blastocyst stage embryo scores combined with normal chromosomes on both sides do not appear to be the cause of the patient’s three IUIs and three embryo transfer failures, the most likely cause is the embryo tolerance problem.
In a natural cycle, implantation of blastocysts in the endometrium occurs only within a limited period of time, i.e., d 20-24 (i.e., LH peak + 7-11 d) of a normal 28-day menstrual cycle. During this period, the endometrium is receptive to the embryo and accepts its implantation, which is known as the implantation window. Many studies have concluded that it is mainly the reduced endometrial tolerance that causes 2/3 of implantation failures.
When endometrial tolerance is suspected, the clinical test of choice is hysteroscopy, and the patient underwent hysteroscopy, which resulted in mild uterine adhesions, and a separation was performed. Generally speaking, in cases like mild adhesions with basically normal endometrial morphology, the embryo implantation rate can be slightly affected and the endometrium can be thickened as much as possible by hormone replacement program to fit the embryo for implantation. However, the result is still not satisfactory. There are few means to improve endometrial tolerance, so what else is there?
Lightly invasive endometrial surgery is now becoming recognized as a clinical treatment for abnormal endometrial tolerance, performed after multiple failed transfers of quality embryos to rule out embryo-derived implantation failure. The study of light invasion of the human endometrium dates back to 2003, when Baresh et al. suggested that performing light invasive endometrial procedures in the first cycle of IVF could increase pregnancy rates exponentially. The improvement of embryo implantation and pregnancy rate by light endometrial invasion lies in both structural reconstruction of endometrial tissue and expression of endometrial tolerance-related factors. The removal of inhomogeneous endometrium and endometrial polyps by mechanical stimulation facilitates the growth of new endometrium and completes the structural reconstruction of endometrial tissue. Secondly, endometrial metaplasia was promoted by raising factors associated with endometrial tolerance after endometrial light trauma, including leukemia inhibitory factor (LIF), osteopontin (OPN), and satiation synapse. Recent studies suggest that endometrial light trauma can upregulate the expression of important factors, urothelial plaque proteins, which have important implications for endometrial tolerance.
The focus of endometrial light invasive surgery is on light and invasive, requiring that the operation must be gentle and the scratching should be comprehensive to achieve stimulation of the endometrium, and not to make light invasive into heavy invasive, which can result in serious consequences of uterine adhesions and endometrial philtrum once the endometrial basal layer is damaged. With regard to the timing of endometrial debridement, there are reports in the literature of good pregnancy outcomes in the menstrual, follicular and luteal phases, but this is determined by the patient’s condition. There are also a few reports in the literature that endometrial light invasive surgery is not effective in improving embryo implantation rates, which may be related to patient cohort selection. Patients undergoing similar treatment should be selected for repeated transfer of quality embryos, especially in patients with failed quality blastocysts. The patient in this case is suitable for further course and outcome of endometrial I would like to be quite flattering and telephone benzyl bath.
On May 26, 2013, her menstrual period started, and on May 27, she underwent mild scratching of the four walls of the endometrium, and was also given Cilixin 0.25mg bid*3 days to prevent infection. on June 18, 2013, she underwent frozen embryo transfer on HRT protocol (Tocopherol 3mg/bid + Fenmatone 1# pv/qd + Progesterone 60mg/qd + Daphne 10mg bid), and her endometrium before progesterone injection Thickness 9.0mm/A type. On the day of transfer, blood LH: 1.28U/L, E2: 637pg/ml; P: 12.4ng/ml. two blastocysts were transferred (5CB, 4BB). On July 18, 2013, the vaginal ultrasound showed a single live intrauterine pregnancy, equivalent to more than 6 weeks of gestation. On August 16, 2013, the repeat ultrasound showed a single live intrauterine pregnancy, equivalent to more than 10 weeks of gestation. On January 31, 2014, she delivered a son prematurely and was in good health.