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Background and objectivesPatients with multiple sclerosis (MS) may seek fertility treatment (FT)-including in vitro fertilization (IVF). Variable relapse risk after IVF has been reported in small historical cohorts, with more recent studies suggesting no change in annualized relapse rate (ARR). The objective of this study was to evaluate ARR 12 months pre-FT and 3 months post-FT in a multicenter cohort and identify factors associated with an increased risk of relapse.MethodsPatients with clinically isolated syndrome (CIS) or MS aged 18-45 years with at least 1 FT from January 1, 2010, to October 14, 2021, were retrospectively identified at 4 large academic MS centers. The exposed period of 3 months after FT was compared with the unexposed period of 12 months before FT. FTs included controlled ovarian stimulation followed by fresh embryo transfer (COS-ET), COS alone, embryo transfer (ET) alone, and oral ovulation induction (OI). The Wilcoxon signed rank test and mixed Poisson regression models with random effects were used to compare ARR pre-FT vs post-FT, with the incidence rate ratio (IRR) and 95% CI reported.ResultsOne hundred twenty-four FT cycles among 65 patients with MS (n = 56) or CIS (n = 9) were included: 61 COS-ET, 19 COS alone, 30 ET alone, and 14 OI. The mean age at FT was 36.5 ± 3.8 years, and the mean disease duration was 8.2 ± 5.0 years. Across 80 cycles with COS, only 5 relapses occurred among 4 unique patients within 3 months of treatment. The mean ARR after COS and before was not different (0.26 vs 0.25, p = 0.37), and the IRR was 0.95 (95% CI: 0.52-1.76, p = 0.88). No cycles with therapeutic disease-modifying therapies (DMTs) during COS had 3 months relapse (ARR 0 post-COS vs 0.18 pre-COS, p = 0.02, n = 34). Relapse rates did not vary by COS protocol. Among COS-ET cycles that achieved pregnancy (n = 43), ARR decreased from 0.26 to 0.09 (p = 0.04) within the first trimester of pregnancy. There were no relapses 3 months after ET alone and 1 relapse after OI.DiscussionIn this modern multicenter cohort of patients with MS undergoing diverse FTs, which included 43% on DMTs, we did not observe an elevated relapse risk after FT.

PurposeAs the paradigm shifts towards improving cancer survivorship, an important concern for reproductive-aged women diagnosed with cancer is how their disease and its treatment will affect their future fertility. We sought to characterize pregnancy attempts and outcomes in breast cancer patients following chemotherapy.MethodsWe conducted a prospective cohort study of women diagnosed with breast cancer seen between 2010 and 2019. A questionnaire was administered following cancer treatment with questions regarding oncologic and reproductive history and attempts and method of conception.ResultsOf 181 participants, 46 (25.4%) attempted to conceive following chemotherapy. Thirty-five patients (76.1%) had return of ovarian function. Of those, 34 patients (mean age 32.8 years) first attempted to conceive by intercourse, and 22 (64.7%) became pregnant, resulting in 17 live births. Of the remaining 12 who did not successfully conceive through intercourse, eight went on to try other methods, resulting in five additional pregnancies and one live birth. Twelve patients (mean age 34.6 years) proceeded directly to ART; of those, eight (66.7%) became pregnant, resulting in six live births.ConclusionIn breast cancer patients with return of ovarian function after chemotherapy, half were able to conceive by intercourse alone. In order to maximize reproductive potential in patients who have return of ovarian function, providers should offer natural conception as a reasonable option prior to the use of cryopreserved tissue. For those who did not attempt to conceive on their own, the use of pre-treatment cryopreserved eggs or embryos had a high likelihood of success.

Study questionAre follicular fluid (FF), arsenic (As), mercury (Hg), cadmium (Cd) and lead (Pb) concentrations associated with IVF outcomes among women undergoing IVF?Summary answerThere was a non-linear association between higher FF Hg concentration and a lower likelihood of biochemical pregnancy and live birth. Higher FF Pb concentration was also associated with a lower probability of live birth.What is known alreadyPrevious research suggests that toxic elements may affect fertility among couples conceiving with and without assistance. However, the results have been inconsistent, possibly related in part to exposure misclassification. Very few studies have used ovarian FF to measure toxic elements, as it requires an invasive collection procedure, yet it may offer a more accurate estimate of a biologically effective dose than blood or urine.Study design size durationThis is a prospective study of 56 women undergoing IVF, from October 2015 to June 2017. FF was collected for analysis on the day of oocyte retrieval.Participants/materials setting methodsAs, Cd, Hg and Pb were determined in 197 FF specimens, using inductively coupled plasma tandem mass spectrometry. FF glutathione peroxidase, glutathione reductase, total glutathione-S-transferase, superoxide dismutase, arylesterase and paraoxonase (PON1p) activities were measured using kinetic enzyme assays.Main results and the role of chanceNon-linear associations were detected, in which the probabilities of biochemical pregnancy (P = 0.05) and live birth (P = 0.05) were lower in association with FF Hg greater than ∼0.51 µg/l Hg, adjusted for age, race, cigarette smoking and recent seafood consumption. Higher FF Pb was also associated with a lower likelihood of live birth (relative risk (RR) = 0.68, 95% CI: 0.46, 1.00; P = 0.05). We also found a suggestive, although imprecise, antagonizing mediating effect of PON1p activity on the association between FF Pb and live birth (-28.3%; 95% CI: -358%, 270%).Limitations reasons for cautionThe results should be interpreted judiciously given the limited sample size and difficulty accounting for correlated data in generalized additive models and mediation analyses. Additionally, women undergoing IVF are highly selected with respect to age and socioeconomic status, and so the generalizability of the results may be limited.Wider implications of the findingsOverall, the results suggest that FF Hg was associated with a lower likelihood of biochemical pregnancy and live birth, with a potential threshold effect, and that higher FF Pb was associated with a lower probability of live birth. These results may help to guide clinical recommendations for limiting the exposure of patients to Hg and Pb and ultimately improve IVF success rates.Study funding/competing interestsThis work was funded in part by the National Institute of Environmental Health Sciences (NIEHS), grant number 1R56ES023886-01, to the University at Albany (M.S.B.), and in part by the National Institute of Environmental Health Sciences (NIEHS), grant number 1U2CES026542-01, to the Wadsworth Center (P.J.P.). The authors declare no competing interests.Trial registration numberN/A.

Phthalates are reproductive toxicants in experimental animal studies and exposure has been associated with infertility in human populations, although the results have been inconsistent. To help to address the data gap, we conducted a hypothesis-generating investigation of associations between urinary phthalate metabolites and reproductive outcomes among women (n = 56) and their male partners (n = 43) undergoing in vitro fertilization (IVF). Urine was collected from participants on the day of oocyte retrieval. Samples were analyzed for a series of phthalates, MEP, MBP, MPP, MHxP, MEHP, MEHHP, MECPP, MiNP, MiDP, MCHP, and MBzP, using liquid chromatography-tandem mass spectrometry. We employed Poisson regression with robust variance estimation to estimate associations between urinary phthalate levels and biochemical pregnancy and live birth, adjusted for partner's concentration and confounding factors. Doublings in women's MBP (relative risk (RR) = 0.32, 95 % CI: 0.13, 0.78), and men's MEHP (RR = 0.28, 95 % CI: 0.09, 0.83), were associated with a lower likelihood for pregnancy. Doublings in women's (RR = 0.08, 95 % CI: 0.01, 0.67) and men's (RR = 0.13, 95 % CI: 0.02, 0.92) MHxP were associated with a lower likelihood of live birth. Our results suggest that phthalate exposure may impact IVF outcomes, and underscore the importance of including male partners when investigating the impact of phthalate exposure on IVF. These results also suggest that clinical recommendations should include male partners for limiting phthalate exposure. Still, a larger and more comprehensive investigation is necessary to more definitively assess the risks.

PurposeThe purpose of this study was to compare ovarian stimulation and pregnancy outcomes between transgender men (1) with and without a history of testosterone use (HRT) and (2) to cisgender women.MethodsRetrospective chart review between January 1st 2015 and March 1st, 2019 of transgender men and cisgender women seeking ovarian stimulation (OS) matched by BMI and age. Outcomes were compared using Fisher's exact or Wilcoxon's rank sum tests.ResultsThirteen transgender men presented for OS, 7 who used HRT. When comparing transgender men with and without a history of HRT, there were no differences in the baseline follicle count, cycle length, or FSH and hmG used (p = 0.193, 0.306, 0.200, and 0.197, respectively). Transgender men who used HRT had lower peak estradiol and oocytes retrieved compared to transgender men with no HRT use; peak estradiol levels of 1175 pg/mL IQR [559.5-2684]) vs 2713.5 pg/mL IQR [2335-3105]; oocytes retrieved 12 IQR [4-26]) vs. 25.5 [18-28] (p = 0.046. and 0.038, respectively). There were no differences in the estradiol level per oocyte, meiosis II oocyte yield, or maturity rate (MII/oocytes) between the two groups (p = 1.000, 0.148, and 0.147, respectively). Peak estradiol levels were lower among transgender men compared to cisgender women (p = 0.016), but the remaining cycle characteristics were similar between the two groups. Three successful pregnancies were conceived using the oocytes of transgender men who used HRT.ConclusionHRT use may not negatively impact ovarian stimulation outcomes. Clinical pregnancies are possible from the oocytes of transgender men with a history of HRT.

PurposeTo evaluate the feasibility of utilizing back-to-back random-start ovarian stimulation to increase oocyte yield for fertility preservation prior to cancer treatment.MethodsA case series of 15 patients who underwent back-to-back random-start stimulation cycles prior to chemotherapy.ResultsOf the 15 back-to-back random-start stimulation cases, 13 had breast cancer and 2 had other cancers. The average age was 38 years (range 30-43) and average AFC was 8 (range 3-14). Fourteen of the 15 women (93%) who underwent two ovarian stimulation cycles completed both of them. The average time to complete back-to-back random-start ovarian stimulation was 33 days (range 13-43 days). The average time between the first cycle completion and the second cycle start in our back-to-back random-start stimulations was 9 days (range 0-14 days). Two of the women underwent back-to-back random-start ovarian stimulation prior to starting neoadjuvant chemotherapy for breast cancer. Eleven of our 15 women at least doubled their oocyte or embryo yield relative to their first cycle. Only 1 of the 15 second cycles was canceled. The mature oocyte rate, fertilization rate, and embryo yield were similar among the first and second cycles.ConclusionsBack-to-back random-start ovarian stimulation may be an effective way to maximize fertility preservation, even in time-limited settings.