Immunomodulation for unexplained recurrent implantation failure: where are we now?

In brief: Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies. Abstract: Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.

Among high responders, is oocyte development potential different in Rotterdam consensus PCOS vs non-PCOS patients undergoing IVF?

PURPOSE: To evaluate the oocyte potential to develop to blastocyst in Rotterdam consensus PCOS in women with hyper-responses requiring freeze-all embryos. METHODS: Retrospective, single-academic center, cohort study of 205 patients who underwent freeze-all antagonist IVF cycles for OHSS risk between 2013 and 2019. Women in the PCOS group (n = 88) were diagnosed per the 2003 Rotterdam criteria. Control patients (n = 122) had no evidence of hyperandrogenism or menstrual disturbance. Data was compared by t-tests, chi-squared tests, or multivariate logistic regression (SPSS). Frozen blastocysts were Gardner's grade BB or better. RESULTS: There was no difference in terms of number of oocytes collected (PCOS vs non-PCOS 27.7 ± 9.4 vs 25.9 ± 8.2, p = 0.157), number of MII (20.7 ± 8.0 vs 19.1 ± 6.6, p = 0.130), number of 2PN fertilized (15.6 ± 7.4 vs 14.4 ± 5.9, p = 0.220), and number of frozen blastocysts (7.8 ± 4.9 vs 7.1 ± 3.8, p = 0.272). In addition, fertilization rates (74 ± 17% vs 75 ± 17%, p = 0.730), blastulation rates per 2PN (51 ± 25% vs 51 ± 25%, p = 0.869), and blastulation rates per mature oocytes (37 ± 18% vs 37 ± 15%, p = 0.984) were all comparable between PCOS and controls, respectively. Moreover, there was no difference when comparing PCOS and controls in pregnancy rates (45/81 vs 77/122, p = 0.28) and clinical pregnancy rates (34/81 vs 54/122, p = 0.75), respectively. Multivariate logistic regression controlling for confounders failed to alter these results. CONCLUSION: PCOS subjects do not seem to have altered oocyte potential as measured by number of MII oocytes collected, fertilization, and blastulation rates when compared to high-responder controls, with similar magnitude of stimulation.

Does increasing estrogen dose during frozen embryo transfer affect pregnancy rate?

OBJECTIVE: To assess the effect of increasing estrogen doses during hormone therapy frozen embryo transfer (HT-FET) cycles on endometrial thickness and success rates compared to patients who received fixed estrogen dose. MATERIALS AND METHODS: A retrospective study from a university-based fertility clinic during the years 2008-2021. We compared two groups: the fixed-dose group (i.e., received 6 mg estradiol dose daily until embryo transfer) and the increased-dose group (i.e., the initial estradiol dose was 6 mg daily, and was increased during the cycle). PRIMARY OUTCOME: clinical pregnancy rate. RESULTS: The study included 5452 cycles of HT-FET: 4774 cycles in the fixed-dose group and 678 cycles in the increased-dose group. Ultrasound scan on days 2-3 of the cycle showed endometrial thickness slightly different between the two groups (4.2 mm in the fixed-dose and 4.0 mm in the increased-dose group, P = 0.003). The total estrogen dose was higher, and the treatment duration was longer in the increased than the fixed-dose group (122 mg vs. 66 mg and 17 days vs. 11 days, respectively; P < 0.001). The last ultrasound scan done before the addition of progesterone showed that the endometrial thickness was significantly thicker in the fixed than the increased-dose group (9.5 mm vs. 8.3 mm; P < 0.001). The clinical pregnancy rates were 35.8% in the increased-group vs. 34.1% in the fixed-dose group; P = 0.401. CONCLUSIONS: The increased-dose group had thinner endometrium despite the higher doses of estrogen and longer treatment duration than the fixed-dose group. However, the pregnancy rates were similar between the two groups.

The Maternal Age Cut-Off for an Increase in Composite Adverse Outcomes.

OBJECTIVE: To investigate whether there is a specific maternal age cut-off at which there is an increase in maternal and neonatal adverse outcomes. METHODS: A retrospective study comparing maternal and neonatal outcomes between nulliparous women of different ages. The receiver operating characteristic model with the Youden index was used to find the best age cut-off using cesarean delivery (CD) and composite adverse outcomes. A multivariable logistic regression analysis was calculated after adjusting for smoking, induction of labour, epidural use, hypertensive disorders, gestational diabetes, and birth weight. RESULTS: The study included 11 343 nulliparous women. Age 28 years was found to be the cut-off age at which we found a significant increase in adverse outcomes. Women older than age 28 years had a higher risk of CD than women younger than 28 years (35.7% vs. 21.3%, P < 0.0001). They were also more likely to deliver prematurely (11.9% vs. 7.9%; P < 0.0001) and had higher rates hypertensive disorders (2.3% vs. 1.1%; P < 0.0001) and gestational diabetes mellitus (0.4% vs. 0.1%; P = 0.001). Furthermore, their babies were more likely to be growth restricted (1.1% vs. 0.3%; P < 0.0001). There were no differences in the rates of induction of labour or macrosomia. After adjusting for confounders, we found that women older than 28 years had higher risks of CD and adverse outcomes than younger women (aOR 1.9 [95% CI 1.744-2.1] and aOR 1.6 [95% CI 1.6-1.77], respectively). CONCLUSION: Increasing maternal age is independently associated with adverse maternal and neonatal outcomes with an age cut-off of 28 years. Women older than age 28 years are at higher risk for composite adverse outcomes than younger women.

The effect of LH rise during artificial frozen-thawed embryo transfer (FET) cycles.

PURPOSE: To evaluate the association between a rise in serum luteinizing hormone (LH) levels during artificial frozen-thawed embryo transfer (FET) cycles and clinical pregnancy rate. METHODS: A retrospective cohort study of women undergoing artificial FET cycles. We compared cycles in which LH double itself from the early follicular phase and further (group A) to cycles without a rise in LH (group B). Endometrium preparation was achieved by administration of 2 mg three times per day estradiol valerate tablets. Embryo transfer (ET) was conducted after achieving endometrial thickness > 7 mm and vaginal progesterone was added according to the embryo's age. A beta-hCG was measured 13-14 days after ET. Clinical pregnancy was diagnosed on transvaginal ultrasound. RESULTS: Data from 984-FET cycles were retrieved. LH, exogenous estradiol (E2), progesterone values, endometrial thickness, and pregnancy outcomes were available in all patients. From 984-FET cycles, 629 (63.9%) had a doubling, and 355 (36.07%) had no rise in LH. Patients mean age was 30 years, similar in both groups. A multivariable logistic regression analysis was calculated to assess the effect of LH rise and pregnancy outcomes, after adjusting for confounders including a rise in E2 level and endometrial thickness. In this model, there was no association between doubling LH values and pregnancy rates (adjusted odds ratio: 1.06, 95% CI: 0.75-1.5, P = 0.74). CONCLUSION: LH rise during artificial FET cycles does not alter pregnancy rates. Apparently, hormonal monitoring of LH levels may not yield useful information in the artificial FET cycle and may be omitted. LAY SUMMARY: Supplementation of estradiol, a hormone produced by the ovaries, starting at the beginning of the menstrual cycle of an artificially frozen embryo transfer (FET) can lead to a rise in luteinizing hormone (LH), the hormone that induces ovulation. Such a rise in LH may interfere with embryo implantation, the process where the embryo attaches to the inner lining of the uterus and, therefore, could affect the chances of pregnancy. The current study is the first to assess the effect of a dynamic rise in LH levels during FET cycles on pregnancy rates. This study found no difference in pregnancy rates between FET cycles where the LH doubled compared to cycles without such a rise in LH. Larger, prospective studies should be conducted to assess the impact of LH elevation on pregnancy outcomes.

Primary Papillary Serous Carcinoma of the Fallopian Tube Presenting as a Vaginal Mass: A Case Report and Review of the Literature.

BACKGROUND There is now evidence to support that some cases of high-grade serous papillary carcinoma arise from the fallopian tubes rather than the ovaries. Common symptoms at presentation include abdominal pain and swelling, vomiting, altered bowel habit and urinary symptoms. To our knowledge, this is the first case of serous papillary carcinoma presenting as a vaginal mass lesion. CASE REPORT A 41-year-old woman was referred to the Bnai-Zion Medical Center with the main complaint of irregular vaginal bleeding, vaginal mucous discharge, and suspected pelvic mass. Physical examination showed a soft, painless mass, measuring about 10 cm in diameter located mainly in the recto-vaginal septum, but not involving the uterus. Ultrasound examination showed no abnormal ovarian or uterine findings. Transvaginal biopsies of the mass showed a poorly differentiated serous papillary carcinoma of ovarian, tubal, or peritoneal origin. The physical examination and imaging findings strongly indicated an inoperable tumor, and the patient was treated with neoadjuvant (pre-surgical) chemotherapy. Pre-operative computed tomography (CT) imaging showed the partial involvement of the colon, and so surgical treatment included total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, partial vaginectomy, anterior rectal resection, and lymph node dissection. Histopathology of the surgical specimens showed a poorly differentiated serous carcinoma originating from the fimbria of the right fallopian tube. CONCLUSIONS To the best of our knowledge, this is the first report to describe primary fallopian tube papillary serous carcinoma presenting as a vaginal mass. Therefore, physicians should be aware of this possible diagnosis.