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Purpose: Supraphysiologic serum estradiol levels may negatively impact the likelihood of conception and live birth following IVF. The purpose of this study is to determine if there is an association between serum estradiol level on the day of progesterone start and clinical outcomes following programmed frozen blastocyst transfer cycles utilizing oral estradiol., Methods: This is a retrospective cohort study at an academic fertility center analyzing 363 patients who underwent their first autologous single (SET) or double frozen embryo transfer (DET) utilizing oral estradiol and resulting in blastocyst transfer from June 1, 2012, to June 30, 2018. Main outcome measures included implantation, clinical pregnancy, live birth, and miscarriage rates. Cycles were stratified by quartile of serum estradiol on the day of progesterone start and separately analyzed for SET cycles only. Poisson and Log binomial regression were used to calculate relative risks (RR) with 95% confidence intervals (CI) for implantation, clinical pregnancy, live birth, and miscarriage with adjustments made for age and BMI., Results: Cycles with the highest quartile of estradiol (mean 528 pg/mL) were associated with lower risks of implantation (RR 0.66, CI 0.50-0.86), ongoing pregnancy (RR 0.66, CI 0.49-0.88), and live birth (RR 0.70, CI 0.52-0.94) compared with those with the lowest estradiol quartile (mean 212 pg/mL). Similar findings were seen for analyses limited to SETs. There was no significant difference in miscarriage rate or endometrial thickness between groups., Conclusion: High levels of serum estradiol on the day of progesterone start may be detrimental to implantation, pregnancy, and live birth following frozen blastocyst transfer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To investigate assisted reproductive technology (ART) outcomes among adolescent and young-adult female cancer survivors., Methods: The Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) data were linked to the Massachusetts Cancer Registry for 90,928 ART cycles in Massachusetts to women ≥ 18 years old from 2004 to 2013. To estimate relative risks (RR) and 95% confidence intervals (CI), we used generalized estimating equations with a log link that accounted for multiple cycles per woman and a priori adjusted for maternal age and cycle year. The main outcomes of interest were ART treatment patterns; number of autologous oocytes retrieved, fertilized, and transferred; and rates of implantation, clinical intrauterine gestation (CIG), live birth, and pregnancy loss., Results: We saw no difference in number of oocytes retrieved (aRR: 0.95 (0.89-1.02)) or proportion of autologous oocytes fertilized (aRR: 0.99 (0.95-1.03)) between autologous cycles with and without a history of cancer; however, cancer survivors required a higher total FSH administered (aRR: 1.12 (1.06-1.19)). Among autologous cycle starts, cycles in women with a history of cancer were less likely to result in CIG compared to no history of cancer (aRR: 0.73 (0.65-0.83)); this relationship was absent from donor cycles (aRR: 1.01 (0.85-1.20)). Once achieving CIG, donor cycles for women with a history of cancer were two times more likely to result in pregnancy loss (aRR: 1.99 (1.26-3.16))., Conclusions: Our analysis suggests that cancer may influence ovarian stimulation response, requiring more FSH and resulting in lower CIG among cycle starts., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: We previously developed a subfertile comparison group with which to compare outcomes of assisted reproductive technology (ART) treatment. In this study, we evaluated whether insurance claims data in the Massachusetts All Payers Claims Database (APCD) defined a more appropriate comparison group., Methods: We used Massachusetts vital records of women who delivered between 2013 and 2017 on whom APCD data were available. ART deliveries were those linked to a national ART database. Deliveries were subfertile if fertility treatment was marked on the birth certificate, had prior hospitalization with ICD code for infertility, or prior fertility treatment. An infertile group included women with an APCD outpatient or inpatient ICD 9/10 infertility code prior to delivery. Fertile deliveries were none of the above. Demographics, health risks, and obstetric outcomes were compared among groups. Multivariable generalized estimating equations were used to calculate adjusted relative risk (aRR) and 95% confidence intervals (CI)., Results: There were 70,726 fertile, 4,763 subfertile, 11,970 infertile, and 7,689 ART-treated deliveries. Only 3,297 deliveries were identified as both subfertile and infertile. Both subfertile and infertile were older, and had more education, chronic hypertension, and diabetes than the fertile group and less than the ART-treated group. Prematurity (aRR = 1.15-1.17) and birthweight (aRR = 1.10-1.21) were increased in all groups compared with the fertile group., Conclusion: Although the APCD allowed identification of more women than the previously defined subfertile categorization and allowed us to remove previously unidentified infertile women from the fertile group, it is not clear that it offered a clinically significantly improved comparison group.

Purpose: Among infants following ART-treated, subfertile, and fertile deliveries to determine (1) the presence and magnitude of sex differences in health outcomes and (2) whether the presence of sex differences varied among maternal fertility groups., Methods: Retrospective cohort analysis of infants born in Massachusetts (MA) in 2004-2013 who were conceived by ART. The Society for Assisted Reproductive Technology Clinic Outcome Reporting System was linked to the Pregnancy to Early Life Longitudinal data system, which links birth certificates to hospital discharge records for MA mothers and infants. Included were singletons born via ART-treated, subfertile, and fertile deliveries. Multivariable logistic regression was used to model the association between infant sex and health outcomes, controlling for maternal demographic and health characteristics., Results: A total of 16,034 ART-treated, 13,277 subfertile, and 620,375 fertile singleton live births were included. For all three groups, males had greater odds of being preterm (AOR range 1.15-1.2), having birth defects (AOR range 1.31-1.71), experiencing respiratory (AOR range 1.33-1.35) and neurologic (AOR range 1.24-1.3) conditions, and prolonged hospital stay (AOR range 1.19-1.25) compared to females. The interaction between maternal fertility group and infant sex for all infant outcomes was nonsignificant, denoting that the presence of sex differences among fertile, subfertile, and ART groups did not vary., Conclusion: Sex differences in birth outcomes of infants following ART-treated, subfertile, and fertile deliveries exist but the magnitude of these differences does not vary among these maternal fertility groups.

Purpose: It is known that delivery rates from spontaneous conception vary according to season which may be due to cultural or environmental factors; however, conflicting data exist regarding whether outcomes from IVF are also seasonally dependent. The present study was designed to test the hypothesis that the season at oocyte retrieval is associated with livebirth after fresh transfer., Methods: Dates of oocyte retrieval for all autologous cycles in our IVF program between January 2012 and December 2017 were categorized by season. Dates were linked to local temperature (min, max, average) and day length obtained from meteorological records. Average maximum temperature and day length were categorized into tertiles. Multivariable logistic regression, adjusted for age and quadratic age, were used to model odds (aOR) of implantation, clinical pregnancy, spontaneous abortion, and livebirth., Results: Patient characteristics were similar across seasons. As expected, temperature and day length varied by season. When compared with cycles started during winter, there was no difference in the age-adjusted odds of livebirth for the other three seasons (spring: aOR: 0.97, 95% CI: 0.82-1.13; summer: aOR: 1.05, 0.90-1.23; fall: aOR: 0.98, 0.84-1.15). There was a positive linear trend between temperature and odds of implantation, and clinical pregnancy (p value, test for linear trend (implantation, p = 0.02; clinical pregnancy, p = 0.01)) but no association with livebirth for temperature or day length., Conclusions: We found that season at oocyte retrieval was not associated with livebirth, contrary to patterns seen in naturally conceived populations. However, our data did suggest modestly higher odds of clinical pregnancy for retrievals in June and July, and that higher temperature at time of retrieval was associated with higher odds of clinical pregnancy but not livebirth.

Purpose: To determine whether the presence of endometriosis in infertile women without prior ovarian surgery influences markers of ovarian reserve, AMH and FSH., Methods: A retrospective cohort study included three groups of women who presented for IVF treatment at our tertiary care center from 04/27/2015 to 05/31/2017: women with endometriosis and prior ovarian surgery (EnSx), women with endometriosis without prior ovarian surgery (En), and women with a primary diagnosis of male factor infertility (MF; reference group)., Results: There were 671 patients that met inclusion criteria (78 EnSx, 60 En, and 533 MF). Compared to the MF group (3.6 ± 3.0), a lower mean AMH level (ng/mL) was observed in the EnSx group (2.5 ± 2.5; aβ - 1.21; 95% CI [- 1.79, -0.62]) and in the En group (2.5 ± 2.2; aβ - 1.11; 95% CI [- 1.68, - 0.54]). Both endometriosis groups had a statistically significantly higher proportion of patients with an AMH < 1 (EnSx, 24.4%; OR, 2.39 [95% CI, 1.31, 4.36]; En, 28.3%; OR, 2.67 [95% CI, 1.41, 5.08]) compared to the MF group (13.9%). The mean baseline FSH level (lU/L) was statistically significantly higher in both endometriosis groups (EnSx, 8.6 ± 4.3; β, 1.37 [95% CI, 0.39, 2.34]; En, 8.4 ± 3.7; β, 0.96 [95% CI, 0.04, 1.87]) compared to the MF group (7.3 ± 2.2)., Conclusions: Among infertility patients with endometriosis, with and without a history of ovarian surgery, ovarian reserve markers were worse (lower AMH and higher FSH) and a higher proportion had decreased ovarian reserve as measured by AMH compared to women with MF.

Purpose: Despite studies focused on the association between embryo morphology and implantation potential, it is unknown how the collective quality of the supernumerary embryos in a cohort is associated with the implantation rate (IR) of the transferred embryo. This study tested the hypothesis that a relationship exists between the quality of the supernumerary cohort and IR., Methods: A retrospective cohort study of first fresh autologous IVF cycles from 05/2012 to 09/2016, with ≥ 3 blastocysts, resulting in a single blastocyst transfer (n = 819) was performed. Cohorts were grouped in two ways: by mean priority score (PS; 1 being best) of supernumerary embryos and by percent supernumerary embryos with low implantation potential. The relationship between cohort quality and IR was assessed using logistic regression., Results: As mean cohort PS increased, IR of the transferred embryo decreased (test for linear trend, p = 0.05). When ≥ 75% of the supernumerary cohort was predicted to have low implantation potential, IR of the transferred embryo was significantly lower compared to when < 75% of the cohort was predicted to have low implantation potential (OR 0.71; 95% CI (0.53-0.94)). All associations were attenuated when adjusting for PS of the transferred embryo., Conclusions: Our findings suggest that quality of supernumerary embryos is associated with IR of the transferred embryo, among patients with ≥ 3 blastocysts available on day 5. As cohort quality declines and the proportion of low implantation potential embryos increases, the IR of the transferred embryo declines. These associations are attenuated when controlling for quality of the transferred embryo, suggesting that the relationship between embryo cohort quality and implantation is not independent of the transferred embryo quality.

Purpose: To determine the expected out-of-pocket costs of IVF with preimplantation genetic testing for aneuploidy (PGT-A) to attain a 50%, 75%, or 90% likelihood of a euploid blastocyst based on individual age and AMH, and develop a personalized counseling tool., Methods: A cost analysis was performed and a counseling tool was developed using retrospective data from IVF cycles intended for PGT or blastocyst freeze-all between January 1, 2014 and August 31, 2017 (n = 330) and aggregate statistics on euploidy rates of > 149,000 embryos from CooperGenomics. Poisson regression was used to determine the number of biopsiable blastocysts obtained per cycle, based on age and AMH. The expected costs of attaining a 50%, 75%, and 90% likelihood of a euploid blastocyst were determined via 10,000 Monte Carlo simulations for each age and AMH combination, incorporating age-based euploidy rates and IVF/PGT-A cost assumptions., Results: The cost to attain a 50% likelihood of a euploid blastocyst ranges from approximately $15,000 U.S. dollars (USD) for younger women with higher AMH values (≥ 2 ng/mL) to > $150,000 for the oldest women (44 years) with the lowest AMH values (< 0.1 ng/mL) in this cohort. The cost to attain a 75% versus 90% likelihood of a euploid blastocyst is similar (~ $16,000) for younger women with higher AMH values, but varies for the oldest women with low AMH values (~ $280,000 and > $450,000, respectively). A typical patient (36-37 years, AMH 2.5 ng/mL) should expect to spend ~ $30,000 for a 90% likelihood of attaining a euploid embryo., Conclusions: This tool can serve as a counseling adjunct by providing individualized cost information for patients regarding PGT-A.

Purpose: We examined whether short-term exposure to in vitro maturation (IVM) medium of cumulus-oocyte complexes (COCs) from a stimulated cycle increases the yield of metaphase II (MII) oocytes and usable embryos., Methods: Retrospective review of two consecutive autologous IVF/ICSI cycles per patient between 2007 and 2015 in which cycle 1 did not result in live birth. Patients with short-term exposure of COCs to IVM medium (3-5 h before standard insemination or ICSI) in cycle 2 (treated) were matched 1:4 on %MI and %MII to patients without use of IVM in cycle 2 (untreated). The proportions of mature oocytes, two pronucleate (2PN) zygotes, number of usable embryos, and clinical outcomes were compared between groups with regression modeling., Results: The treated (n = 43) and untreated (n = 163) groups had similar demographic characteristics and similarly high proportions of immature oocytes (48.2 vs. 41.3%, respectively) in cycle 1. There were no significant differences between the treated and untreated groups in the change in %MII (48.1 to 68.9% vs. 50.5 to 72.5%, respectively) or mean number of usable embryos (2.2 to 3.4 vs. 2.0 to 3.3, respectively) from cycle 1 to cycle 2., Conclusions: These findings suggest that short-term IVM incubation of COCs may not provide any additional benefit in patients with a prior unsuccessful cycle notable for a high proportion of immature oocytes. Further randomized studies are warranted to determine whether there is a subset of patients who may have improved clinical outcomes with this "rescue IVM" intervention.

Purpose: The purpose of this study is to investigate whether abnormal hCG trends occur at a higher incidence among women conceiving singleton pregnancies following transfer of multiple (two or more) embryos (MET), as compared to those having a single embryo transfer (SET)., Methods: Retrospective cohort study was performed of women who conceived singleton pregnancies following fresh or frozen autologous IVF/ICSI cycles with day 3 or day 5 embryo transfers between 2007 and 2014 at a single academic medical center. Cycles resulting in one gestational sac on ultrasound followed by singleton live birth beyond 24 weeks of gestation were included. Logistic regression models adjusted a priori for patient age at oocyte retrieval and day of embryo transfer were used to estimate the Odds Ratio of having an abnormal hCG rise (defined as a rise or < 66% in 2 days) following SET as compared to MET., Results: Among patients receiving two or more embryos, 6.1% (n = 84) had abnormal hCG rises between the first and second measurements, compared to 2.7% (n = 17) of patients undergoing SET (OR 2.16, 95% CI 1.26-3.71). Among patients with initially abnormal hCG rises who had a third level checked (89%), three-quarters had normal hCG rises between the second and third measurements., Conclusions: Patients who deliver singletons following MET were more likely to have suboptimal initial hCG rises, potentially due to transient implantation of other non-viable embryo(s). While useful for counseling, these findings should not change standard management of abnormal hCG rises following IVF. The third hCG measurements may clarify pregnancy prognosis.

Purpose: The purposes of this study were to evaluate public opinion regarding fertility treatment and gamete cryopreservation for transgender individuals and identify how support varies by demographic characteristics., Methods: This is a cross-sectional web-based survey study completed by a representative sample of 1111 US residents aged 18-75 years. Logistic regression was used to calculate odd ratios (ORs) and 95% confidence intervals (CIs) of support for/opposition to fertility treatments for transgender people by demographic characteristics, adjusting a priori for age, gender, race, and having a biological child., Results: Of 1336 people recruited, 1111 (83.2%) agreed to participate, and 986 (88.7%) completed the survey. Most respondents (76.2%) agreed that "Doctors should be able to help transgender people have biological children." Atheists/agnostics were more likely to be in support (88.5%) than Christian-Protestants (72.4%; OR = 3.10, CI = 1.37-7.02), as were younger respondents, sexual minorities, those divorced/widowed, Democrats, and non-parents. Respondents who did not know a gay person (10.0%; OR = 0.20, CI = 0.09-0.42) or only knew a gay person without children (41.4%; OR = 0.29, CI = 0.17-0.50) were more often opposed than those who knew a gay parent (48.7%). No differences in gender, geography, education, or income were observed. A smaller majority of respondents supported doctors helping transgender minors preserve gametes before transitioning (60.6%) or helping transgender men carry pregnancies (60.1%)., Conclusions: Most respondents who support assisted and third-party reproduction also support such interventions to help transgender people have children.

Purpose: The aim of this study was to determine if zona pellucida thickness variation (ZPTV) is associated with implantation and if this relationship changes with use of assisted hatching (AH)., Methods: Day 3 embryos from single or double embryo transfers (DETs) performed between 2014 and 2016 were included. ZPTV was assessed by examining photographs taken before transfer using an automated image processing platform to segment the zona pellucida (ZP) with an active contour technique. One hundred points were obtained of ZP thickness (ZPT) of each embryo to calculate ZPTV ([maximum ZPT-mean ZPT]/mean ZPT). Logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) of implantation by tertile of ZPTV. Maternal age and AH were adjusted for a priori. Other cycle and embryo characteristics were adjusted for if they altered the continuous effect estimate by >10%., Results: There was no statistically significant association between ZPTV and implantation across tertiles although embryos with greater ZPTV showed a trend of decreased implantation (Tertile 2 (T2) versus Tertile 1 (T1), OR = 0.80, CI = 0.50-1.28; Tertile 3 (T3) versus Tertile 1 (T3), OR = 0.75, CI = 0.47-1.20). While similar nonsignificant trends for the association between ZPTV and implantation were observed across tertiles after stratification of embryos hatched or not, embryos with the greatest ZPTV had slightly higher odds for implantation when AH was utilized (T3 vs. T1: with AH, OR = 0.89, CI = 0.49-1.62; without AH, OR = 0.61, 0.29-1.27)., Conclusion: ZPTV was not associated with implantation after day 3 transfer. This finding did not vary by use of AH.

Purpose: Several time-lapse imaging (TLI) systems for non-invasive continuous monitoring of developing embryos are currently available. The present study explored the prevalence, means of acquisition, and clinical application of TLI systems in USA in vitro fertilization (IVF) laboratories., Methods: An online cross-sectional survey of 294 USA IVF laboratory directors was conducted in February and March 2016. Those directing more than one laboratory were asked to complete the survey for their home program and for their smallest laboratory by number of IVF/intracytoplasmic sperm injection (ICSI) cycle starts. Use of TLI was analyzed using logistic regression to calculate odds ratios (OR)., Results: Of 294 directors surveyed, 162 (55%) reported data on 204 laboratories. Thirty-five laboratories (17%) possessed at least one TLI system (median 2, interquartile range 1-4, total range 1-11). The more oocyte retrievals a laboratory performed annually, the more likely the laboratory was to possess a TLI system. Fifteen laboratories (43%) purchased their own systems, while others leased, loaned, or received donated systems. Twenty-five laboratories (71%) reported using TLI for embryo selection; all used TLI always, or usually, in combination with standard morphology evaluation. Twenty laboratories (80%) offered TLI to all patients. Some laboratories charged patients for TLI. Directors with TLI systems were more inclined to believe that TLI has value for embryo selection in clinical IVF., Conclusions: TLI system possession in USA IVF laboratories is low, although positively associated with the number of retrievals performed and with directors' opinions on the technology's utility. Over 70% of laboratories with TLI systems use them clinically, and less than half purchased their systems.

Purpose: The aim of this study is to investigate the clinical predictors of failure of a single dose of methotrexate (MTX) for management of ectopic pregnancy after in vitro fertilization (IVF)., Methods: A retrospective cohort study was performed of women who conceived ectopic pregnancies following fresh or frozen IVF cycles at an academic infertility clinic between 2007 and 2014, and received intramuscular MTX (50 mg/m 2 ). Successful single-dose MTX treatment was defined as a serum beta-human chorionic gonadotropin (hCG) decline ≥15% between days 4 and 7 post-treatment. Logistic regression models adjusted for oocyte age, number of embryos transferred, and prior ectopic pregnancy were used to estimate the adjusted odds ratio (OR) (95% confidence interval [CI]) of failing one dose of MTX., Results: Sixty-four patients with ectopic pregnancies after IVF were included. Forty required only one dose of MTX (62.5%), while 15 required additional MTX alone (up to four total doses, 23.4%), and 9 required surgery (14.1%). By multivariable logistic regression, the highest tertiles of serum hCG at peak (≥499 IU/L, OR = 9.73, CI 1.88-50.25) and at first MTX administration (≥342 IU/L, OR = 4.74, CI 1.11-20.26), fewer embryos transferred (OR = 0.37 per each additional embryo transferred, CI 0.19-0.74), and adnexal mass by ultrasound (OR = 3.65, CI 1.10-12.11) were each correlated with greater odds of requiring additional MTX and/or surgery., Conclusion: This is the first study to report that in women with ectopic pregnancies after IVF, higher hCG-though well below treatment failure thresholds previously described in spontaneous pregnancies-fewer embryos transferred, and adnexal masses are associated with greater odds of failing one dose of MTX. These findings can be used to counsel IVF patients regarding the likelihood of success with single-dose MTX.

Purpose: Many practices are moving away from cleavage-stage transfer in favor of blastocyst transfer. The purpose of this study is to evaluate how the overall live birth rate for fresh IVF cycles may increase by optimizing the day of transfer for each patient., Methods: This is a retrospective cohort study of 1225 first fresh autologous IVF cycles performed between May 2012 and November 2013. Stepwise logistic regression was used to determine characteristics associated with live birth following cleavage-stage versus blastocyst transfer. The optimal transfer day (i.e., the day that maximized the odds of live birth) was determined for each patient, and the actual live birth rate was compared with the projected rate had each patient undergone transfer on her optimal day., Results: With transfer on the optimal day for each patient, the overall birth rate would have increased from its actual value of 34.8 % to a projected 43.0 %, a 24 % increase. The majority of this increase (21 %) was due to optimization of patients who underwent cleavage-stage transfer but had a higher projected birth rate from blastocyst transfer. These patients were older (37.8 versus 36.0 years, p < 0.01) and had more follicles ≥18 mm than patients who should have remained with a cleavage-stage transfer., Conclusions: A model can be built enabling patient-specific identification of optimal transfer day; within this discovery cohort, such optimization was estimated to increase live birth following a fresh transfer by 24 %. This study suggests blastocyst transfer should be more widely offered; however, there remain patients for whom a cleavage-stage transfer may yield better outcomes., Competing Interests: Compliance with ethical standards Funding LF is supported by T32HD060454 in reproductive, perinatal, and pediatric epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health. Ethical approval For this type of study, formal consent is not required. Conflict of interest The authors declare that they have no conflicts of interest.