Obesity Affects Endometrial Receptivity by Displacing the Window of Implantation.

Our aim was to determine prospectively whether increased body mass index (BMI) affects endometrial receptivity through displacement of the window of implantation (dWOI) using the endometrial receptivity analysis (ERA), and whether this effect is BMI-dependent. We recruited a population of 170 infertile women with a normal uterus and no clinical history of recurrent miscarriage or implantation failure. These women were divided into four groups according to BMI: normal weight (18.5-24.9 kg/m2; n = 44), overweight (25-29.9 kg/m2; n = 29), class I obese (30.0-34.9 kg/m2; n = 54), and class II and III obese (> 35 kg/m2; n = 43). We also assigned the patients to one of two larger BMI cohorts: non-obese (normal weight and overweight; n = 73) and obese (class I, II, and III obese; n = 97). We compared analytical and clinical data and dWOI in these categories, finding significant metabolic differences in glycemia, TSH, insulin, HDL cholesterol, LDL cholesterol, triglycerides, and systolic and diastolic blood pressure among the different BMI groups. One-day dWOI increased significantly with BMI, and significant differences were observed in the non-obese versus obese categories (9.7% vs 25.3 %, respectively (p = 0.02)). dWOI was most pronounced in patients with class II-III obesity. In addition, displacement was longer as BMI increased since ERA revealed a higher proportion of displacements of 1 day than of 12 h and showed they were predominantly pre-receptive. In conclusion, obesity has a negative effect on endometrial receptivity through delaying of the WOI, which increases in function of BMI as well as the metabolic disturbances of the patient.

Impact of low serum progesterone levels on the day of embryo transfer on pregnancy outcome: a prospective cohort study in artificial cycles with vaginal progesterone.

STUDY QUESTION: Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER: Serum P levels <8.8 ng/ml on the day of ET lower ongoing pregnancy rate (OPR) in both own or donated oocyte cycles. WHAT IS KNOWN ALREADY: We previously found that serum P levels <9.2 ng/ml on the day of ET significantly decrease OPR in a sample of 211 oocyte donation recipients. Here, we assessed whether these results are applicable to all infertile patients under an artificial endometrial preparation cycle, regardless of the oocyte origin. STUDY DESIGN, SIZE, DURATION: This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE: Women with serum P levels <8.8 ng/ml (30th percentile) had a significantly lower OPR (36.6% vs 54.4%) and live birth rate (35.5% vs 52.0%) than the rest of the patients. Multivariate logistic regression showed that serum P < 8.8 ng/ml was an independent factor influencing OPR in the overall population and in the three treatment groups. A significant negative correlation was observed between serum P levels and BMI, weight and time between the last P dose and blood tests and a positive correlation was found with age, height and number of days on HRT. Multivariate logistic regression showed that only body weight was an independent factor for presenting serum P levels <8.8 ng/ml. Obstetrical and perinatal outcomes did not differ in patients with ongoing pregnancy regardless of serum P levels being above/below 8.8 ng/ml. LIMITATIONS, REASONS FOR CAUTION: Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS: This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NCT03272412.

Autologous mitochondrial transfer as a complementary technique to intracytoplasmic sperm injection to improve embryo quality in patients undergoing in vitro fertilization-a randomized pilot study.

OBJECTIVE: To study if autologous mitochondrial transfer (AUGMENT) improves outcome in patients with previously failed in vitro fertilization (IVF). DESIGN: Randomized, controlled, triple-blind, experimental study. SETTING: Private infertility center, Valencian Institute of Infertility (IVI-RMA), Valencia, Spain. PATIENT(S): Infertile women ≤42 years of age, body mass index <30 kg/m2, antimüllerian hormone ≥4 pmol/L, >5 million/mL motile sperm, at least one previous IVF with at least five metaphase oocytes (MIIs) collected, and low embryo quality. INTERVENTIONS(S): An ovarian cortex biopsy was performed to isolate egg precursor cells to obtain their mitochondria. Sibling MIIs were randomly allocated to AUGMENT (experimental) or intracytoplasmic sperm injection (Control). In AUGMENT, mitochondrial suspension was injected along with the sperm. Viable blastocysts from both groups were biopsied for preimplantation genetic testing for aneuploidy. MAIN OUTCOME MEASURE(S): Pregnancy, embryo quality. RESULT(S): An interim analysis was conducted. The patients' mean age was 36.3 ± 3.6 years, and they had an average of 2.5 ± 1.5 previous IVF cycles. Two of the 59 enrolled patients spontaneously conceived (one miscarried). Fifty-seven patients had ovarian biopsies and underwent stimulation. Oocyte retrieval was performed in 56 patients (premature ovulation; n = 1). A total of 253 MIIs were inseminated in AUGMENT and 250 in Control; fertilization rates were 62.7 ± 30.0% and 68.7 ± 29.1%, respectively. Statistical differences were observed in day 5 blastocyst formation rates (23.3 ± 32.0% vs. 41.1 ± 36.9%). Neither the euploid rate per biopsied blastocyst (43.8 ± 41.7% vs. 63.8 ± 44.1%) nor the euploid rate per MII (9.8 ± 20.5% vs. 11.9 ± 16.1%) between AUGMENT and Control achieved statistical significance. Moreover, no differences were seen regarding mitochondrial DNA content and relevant morphokinetic variables. Thirty patients were able to undergo embryo transfer. Cumulative live birth rates per transferred embryo were 41.6% in AUGMENT and 41.2% in Control. CONCLUSION(S): AUGMENT does not seem to improve prognosis in this population. Therefore, the study has been discontinued. CLINICAL TRIAL REGISTRATION NUMBER: NCT02586298.

Does optimal follicular size in IUI cycles vary between clomiphene citrate and gonadotrophins treatments?

OBJECTIVE: To evaluate pregnancy-related leading follicles during ovulation induction and superovulation with clomiphene citrate (CC) or gonadotropin. DESIGN: Retrospective cohort. PATIENTS: Five hundred and forty-two women who underwent a total of 615 treatment cycles with CC or gonadotropin. INTERVENTION: We evaluated the effects of CC and gonadotropin on the leading follicles, clinical pregnancy rates and miscarriage rate. RESULTS: The number of follicles larger than 15 mm in the different protocols was comparable. In those treated with CC, the diameter of the dominant follicles before human chorionic gonadotropins (hCG) trigger in the conception cycles (20.4 ± 1.2 mm) was significantly larger than in the non-conception cycles (18.8 ± 1.9 mm). In women treated with gonadotropin, the diameter of the leading follicle in the conception cycles (18.5 ± 1.7 mm) was comparable to that in the non-conception cycles (18.2 ± 1.7 mm). The pregnancy-related diameter of the leading follicle in CC cycles (20.4 ± 1.2 mm) was significantly larger than that in gonadotropin cycles (18.8 ± 1.9 mm; p = 0.001; 95% CI, -2.2 to -0.9). CONCLUSION: Pregnancy-related diameter of the leading follicle in CC cycles is significantly larger than that in gonadotropin cycles and the best time for hCG trigger in the CC cycle is when the leading follicle reaches 20 mm.

Future developments to minimize ART risks.

The most important complications of assisted reproductive techniques are the risk of ovarian hyperstimulation syndrome (OHSS) and the high incidence of multiple pregnancies. Two new strategies are effective in preventing OHSS: the use of anti-müllerian hormone as a marker and the use of dopamine agonists. Genetic markers and vascular endothelial growth factor levels do not predict OHSS. In vitro oocyte maturation treatment should be considered in high responders and in women at risk of OHSS. For prevention of multiple pregnancies, the most effective method is transfer of a single embryo. Preimplantation genetic screening with comparative genomic hybridization, genetic expression of cumulus cells, time-lapse imaging, and respiration rate are emerging technologies for embryo selection that require further study.

Redefining reproductive surgery.

With the availability of and improvements in in vitro fertilization (IVF), the role of reproductive surgery has been questioned. Yet, the scope of reproductive surgery today is much larger than in the past. Hysteroscopic correction of intrauterine disease is an important endoscopic procedure in women with infertility. Evidence suggests that correction of intrauterine disease is often followed by spontaneous pregnancy and improved IVF outcome. Hysteroscopic examination should be considered after 1 failed IVF. Today, it is clear that removal of the hydrosalpinx leads to a higher IVF-related live birth rate. The procedure should be performed thoroughly without compromising the ovarian blood supply. The IVF pregnancy rate is not affected by the presence of ovarian endometriomas, and small endometriomas need not be removed; however, large and symptomatic endometriomas that interfere with oocyte retrieval should be excised. When excision of the cyst wall is difficult, fenestration and ablation should be considered. This might lead to an increased recurrence rate, but is associated with less interference of the ovarian reserve. Although the role of reproductive surgery as primary treatment for tuboperitoneal infertility is limited, it has an important role in enhancing the outcome of IVF treatment and in preservation of fertility. Surgical preservation of fertility consists of ovarian suspension, ovarian excision for cryopreservation, and ovarian tissue transplantation.

Effects of different body mass indices on in vitro maturation in women with polycystic ovaries.

OBJECTIVE: To evaluate the effect of body mass index (BMI) on in vitro maturation (IVM) outcomes in women with polycystic ovaries. DESIGN: Retrospective, cohort study. SETTING: Tertiary IVF unit. PATIENT(S): One hundred thirteen women with polycystic ovaries. INTERVENTION(S): One hundred sixteen cycles of IVM. Patients were divided into subgroups according to their BMI: underweight, normal weight, overweight, obese, and morbidly obese. We evaluated the effects of BMI on the number of oocytes matured in vivo, maturation rate in vitro, fertilization and cleavage rates, number of embryos transferred, implantation rates, pregnancy rates, and delivery rates. MAIN OUTCOME MEASURE(S): Pregnancy rate and delivery rate. RESULT(S): The number and quality of oocytes among women with different BMIs were similar. There was no significant difference in the endometrial thickness and rates of implantation, pregnancy, and delivery among women with different BMIs. The pregnancy rate in underweight women was 50%, normal weight 47.9%, overweight 29.1%, obese 27.2%, and in morbidly obese women was 30.7%. The miscarriage and delivery rates were also similar. CONCLUSION(S): The results of IVM are independent of BMI.