Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss.

PROBLEM: Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune-mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6 year-outcomes and to develop a framework for IVIg use in RPL. METHOD OF THE STUDY: Retrospective, single-center cohort study. All patients having received IVIg for unexplained RPL at the McGill Reproductive Immunology Clinic (MRIC) from January 2014 to December 2020 were included if maternal age was <42 years, body mass index (BMI) < 35 kg/m2 , non-smoker and having had ≥3 consecutive RPL despite previous treatment with aspirin and progesterone. IVIg 0.6-0.8 g/kg was given prior to conception and monthly during pregnancy until 16-20 weeks' gestation. We compared IVIg treated patient's outcomes to a separate "natural history cohort". This cohort was composed of patients consulting at the McGill recurrent pregnancy loss clinic and the MRIC over a 2-year period (January 2020 to December 2021) with similar inclusion criteria as the treatment cohort but did not receive IVIg or other immunomodulatory treatments. The association of IVIg with outcomes (compared to no IVIg) was evaluated among the groups of patients with primary RPL and secondary RPL. The primary outcome was live birth rate (LBR), secondary outcomes included IVIg safety, obstetrical, and neonatal complications. RESULTS: Among 169 patients with unexplained RPL that were included in the study, 111 had primary RPL (38 exposed to IVIg and 83 controls) and 58 had secondary RPL (nine exposed to IVIG and 49 controls). Among patients with primary RPL (n = 111), the LBR was 64.3% (18/28) among patient exposed to IVIg compared to 43.4% (36/83) in controls (p = 0.079); regression analysis adjusting for BMI and number of previous miscarriages showed benefit favoring the use of IVIg (OR = 3.27, CI 95% (1.15-10.2), p = 0.03) when evaluating for live birth. In the subgroup of patients with ≥5 previous RPL and primary RPL (n = 31), IVIg was associated with higher LBR compared to control (10/15 (66.7%) vs. 3/16 (18.8%); p = 0.0113) but not the in the sub-group of patients with <5 miscarriages and primary RPL (8/13 (61.5%) vs. 33/67 (49.3%); p = 0.548). IVIG treatment did not improve LBR in patients with secondary RPL in our study (3/9 (33.3%) vs. 23/49 (47%); p = 0.495). There were no serious adverse events in the IVIg treatment group, obstetrical/neonatal complications were similar between groups. CONCLUSION: IVIg may be an effective treatment for patients with RPL if appropriately used in specific groups of patients. IVIg is a blood product and subject to shortages especially with unrestricted off-label use. We propose considering IVIg in well-selected patients with high order RPL who have failed standard medical therapy. Further mechanistic studies are needed to understand immune-mediated RPL and IVIg's mode of action. This will enable further refinement of treatment criteria and the development of standardized protocol for its use in RPL.

Ovarian stimulation and intrauterine insemination in women aged 40 years or more.

Fertility decreases with advancing age. This study retrospectively reviewed the results of ovarian stimulation and intrauterine insemination (IUI) in women 40 years old with diminished ovarian reserve or unexplained infertility who underwent treatment with ovarian stimulation/IUI with clomiphene citrate or gonadotrophin and compared them with the results of IVF and in-vitro maturation (IVM) treatments. The main outcome measures were pregnancy and live-birth rates. The profiles of the patients in ovarian stimulation, IVM and IVF groups were comparable. There were no clinical pregnancies in the clomiphene citrate and IVM groups. The clinical-pregnancy rates in the gonadotrophin and IVF groups were 2.6% and 16.9% and the live-birth rates were 2.6% and 13.7%, respectively. Compared with ovarian stimulation, IVF is most effective for women aged 40 years or more. Attempting success with ovarian stimulation or IVM will delay conception unnecessarily.

How old is too old for in vitro maturation (IVM) treatment?

OBJECTIVE: Fertility declines with age. A study of the outcomes of in vitro maturation (IVM) in women of different ages has not been reported to date. The aim of our study was to evaluate the impact of age on treatment response and on pregnancy rates after IVM treatment. STUDY DESIGN: We reviewed the data of all IVM cycles and recorded the total number of oocytes, total metaphase II (MII) oocytes, the number and quality of embryos as well as pregnancy rates. The main outcome measures were number and maturity of retrieved oocytes and pregnancy rates. RESULTS: Compared to cycles in women ≤25 years, the number of oocytes and total MII oocytes were significantly lower in women over 40 years. The number of good quality embryos in women ≤25 years (3.6±1.7) was higher than in women aged 40 years (0.8±1.2, P<0.0001). The ongoing pregnancy rates in women aged 20-25 years were 36.8%, 26-35 years were 30.0% and in those 36-39 years were 31.9%. No clinical pregnancy was observed in women over the age of 40. CONCLUSION: Women over 40 years are poor candidates for IVM treatment.

Controversies in IVM.

PURPOSE: To explore four areas of controversy: the benefits of gonadotropin priming, benefits and timing of hCG trigger as well as the ideal protocols for endometrial preparation and luteal support. METHODS: A literature review was performed to explore the current evidence RESULTS: Current evidence suggests that Gonadotropin priming in combination with hCG prior to collection benefits patients with normal ovaries. In PCOS patients 10,000 IU hCG 38 h before retrieval increases the total number and rate of oocyte maturation. Gonadotropin priming may also benefit PCOS patients. The ideal timing of hCG trigger appears to be when the leading follicle is 10-12 mm. Sparse data exists regarding luteal support protocols. CONCLUSIONS: There is still a need for well-designed studies to establish ideal methods for oocyte priming, timing of retrieval, endometrial preparation and luteal support. Further studies must incorporate both clinical and basic science principles of ovarian, follicular and endometrial physiology.

Comparison of automated and manual follicle monitoring in an unrestricted population of 100 women undergoing controlled ovarian stimulation for IVF.

BACKGROUND: Ovarian response to gonadotrophin stimulation is monitored with serial ultrasound (US) examinations. Sonography-based Automated Volume Count (SonoAVC) is a relatively new three-dimensional (3D) US technology, which automatically generates a set of measurements including the mean follicular diameter (MFD) and a volume-based diameter (d(V)) for each follicle in the ovaries. The present study aimed to assess the applicability and reproducibility of this automated follicle measurement method in an IVF programme. METHODS: For this prospective method comparison study, 100 women undergoing US monitoring of a controlled ovarian stimulation cycle were recruited. Each follicle was manually measured by taking the mean of maximal diameters on three orthogonal planes with two-dimensional (2D) US. A 3D volume of each ovary was then captured. The ovarian volumes were later analysed using SonoAVC. The agreement between the two methods for the numbers of follicles and the size of the leading follicle was assessed with the Bland-Altman method. The reproducibility of SonoAVC measurements was assessed with the intraclass correlation coefficient (ICC). RESULTS: Both SonoAVC-generated MFD and d(V)-based follicle counts, as well as the leading follicle diameter, had good agreement with conventional 2D US measurements. SonoAVC measurements had very good reproducibility, with ICC ≥0.8 for most evaluations. CONCLUSIONS: Automated follicle monitoring with SonoAVC can replace or be used interchangeably with conventional 2D measurements. Automated follicle monitoring can save time, provide a method of quality control and create opportunities for developing HCG criteria based on follicular volume or for monitoring patients from a distance.