Successful reproduction requires proper ovarian follicular development, synchronized ovulation, and adequately mature oocytes. The immune system plays a significant role in promoting and controlling the necessary physiologic changes in reproductive tissues. While inflammation, angiogenesis, and cytokine/chemokine release play a crucial role in successful follicular growth and ovulation, a dysregulated immune system can impair proper reproductive function. Immune cells within the ovary, specifically T cells populations, are responsible for the initiation, propagation, and regulation of the inflammatory response associated with follicular growth and successful release of oocytes. Many signaling pathways within these cells are controlled by G-protein-coupled receptors (GPCRs). The molecules responsible for rapidly turning off GPCR signaling are known as regulator of G protein signaling (RGS) proteins. A specific regulator of downstream signaling, RGS2, has been found to have various roles in oocyte function such as prevention of premature oocyte activation, proper meiotic spindle formation and chromosome segregation during oocyte maturation. Previous studies have shown an upregulation in RGS2 in peripheral CD4 T cells in patients with pre-eclampsia, a disease of pregnancy associated with a dysregulated immune cell response [1]. While other studies have investigated the roles of RGS2 and CD4 T cells individually in reproduction, no study has evaluated the impact of loss of RGS2 function specifically in CD4 T cells on ovarian function.

PURPOSE:This study aims to know what proportion of culture day 5 pre-blastocyst-stage embryos develop into blastocysts by culture day 6 and what patient and cycle characteristics are associated with delayed blastocyst formation.METHODS:A retrospective observational cohort analysis was performed including a total of 9886 embryos from 1008 IVF cycles in 835 patients, who underwent treatment between January 1, 2016, and December 31, 2018. Autologous fresh in vitro fertilization (IVF) cycles at a single academic center were included in the analysis. Embryos were group-cultured using single-step culture media. Blastulation was defined as the presence of a new blastocyst. Usable blastulation was defined as the presence of a new good or excellent quality, expanded, hatching, or hatched blastocysts.RESULTS:The mean blastulation rate between days 5 and 6 of extended embryo culture was 30.9%. The mean percentage of embryos developing into usable blastocyst-stage embryos was 19.8%. The factors associated with blastulation on day 6 included the total number of embryos and the number of pre-blastocysts on day 5, as well as the use of ICSI. Age, the number of total embryos, those remained in culture and pre-blastocysts, as well as the blastulation rate on day 5 were associated with usable blastulation.CONCLUSION:It is important to know the usable blastocyst development rate between culture days 5 and 6 in order to adequately counsel patients debating whether to proceed with fresh ET on day 5 or forego ET with the expectation that embryos will be biopsied for PGT and/or cryopreserved on culture day 6. Our findings provide evidence to help guide patients in this difficult decision.

Objective: To study the birth rates of normal vs. high responders after dual trigger of final oocyte maturation with gonadotropinreleasing hormone (GnRH) agonist and human chorionic gonadotropin in fresh in vitro fertilization (IVF) cycles in which ovarian stimulation was achieved by a flexible GnRH antagonist protocol. Design: Retrospective cohort study. Setting: University hospital. Patient(s): In women < 35 years of age, 290 fresh IVF cycles using the dual trigger protocol with day 5 embryo transfers from January 2013 to July 2018 were included. Cycles excluded were those with preimplantation genetic testing, gestational carriers, donor oocytes, and fertility preservation. Intervention(s): IVF with dual trigger. Main Outcome Measure(s): Clinical pregnancy rate, live birth rate. Result(s): Comparing normal responders, defined as < 30 oocytes retrieved, and high responders, defined as >= 30 oocytes retrieved, the clinical pregnancy rates (67.0% vs. 69.3%, respectively) and live birth rates (60.5% vs. 60.0%, respectively) were not significantly different. No cases of ovarian hyperstimulation syndrome were reported in either group. Conclusion(s): Ovarian stimulation by a fl exible GnRH antagonist protocol followed by dual trigger yields comparable outcomes between normal and high responders in fresh IVF cycles. (Fertil Steril Rep (R) 2021;2:314-9. (c) 2021 by American Society for Reproductive Medicine.)

Many IVF clinics use endometrial thickness as a predictive factor for IVF outcomes, as research has shown a positive association between endometrial thickness and favorable IVF outcomes. A thickness of 6-8 mm is often used as a cut-off in for the decision of whether or not to transfer an embryo in both fresh and frozen cycles. However, prior studies investigating the relationship between a thin endometrium and IVF outcomes have overwhelmingly been performed in fresh cleavage stage embryo transfers. Given the recent trend toward the transfer of frozen blastocyst transfers, we aimed to determine whether endometrial thickness predicts live birth in both fresh and frozen blastocyst stage single embryo transfers.

Dual trigger protocol using a combination of GnRH agonist and hCG for final oocyte maturation has been shown to minimize ovarian hyperstimulation syndrome (OHSS) risk without compromising fresh embryo transfer outcomes1. However, other evidence suggests that patients with good ovarian reserve may benefit from freeze-all cycles due to supraphysiologic hormone levels affecting the uterine environment during the fresh cycle2. Therefore, we sought to determine if any cycle characteristics were associated with lower clinical pregnancy rates in the fresh cycle. Retrospective cohort study. All patients who underwent the dual trigger protocol and had a fresh embryo transfer 5 days after oocyte retrieval were included. Maternal age, BMI, gravidity, parity, antral follicle count (AFC), oocytes retrieved, endometrial thickness, number of embryos transferred and frozen were compared for subjects who achieved clinical pregnancy, defined as an intrauterine gestational sac confirmed by ultrasound, and those who did not. Mann Whitney-U test was used to compare demographic, cycle characteristics, and outcome data between groups. Medians with interquartile ranges are presented with p-values. Additional analysis between subjects who had <30 and ≥30 oocytes retrieved was conducted. Logistic regression was used to identify predictors of clinical pregnancy. A clinical pregnancy was confirmed for 196 (67%) of the 291 patients who underwent the dual trigger protocol with fresh embryo transfer. The cohort achieving clinical pregnancy had significantly lower age and a higher number of embryos cryopreserved (Table 1). After stratifying for number of oocytes retrieved, 216 (74%) patients had <30 oocytes and 75 (26%) had ≥30 oocytes, there was no difference in clinical pregnancy rates of 66.8% and 69.2% respectively. Logistic regression analysis identified number of embryos cryopreserved as the only parameter to predict clinical pregnancy, with an odds ratio of 1.079. There were no cases of OHSS in patients that underwent a fresh embryo transfer. This data supports the use of dual trigger to both minimize ovarian hyperstimulation risk as well as obtain appreciable pregnancy rates in the fresh cycle. The high number of oocytes obtained was not associated with lower pregnancy rates in the fresh cycle supporting fresh embryo transfers in this good prognosis group of patients.Table 1Cohort characteristicsClinical pregnancy (N=196) Median (IQR)No clinical pregnancy (N=95) Median (IQR)p-valueAge30.0 (28.0-33.0)31.0 (29.0-33.0)0.033BMI26.0 (22.8-31.9)25.8 (22.6-32.2)0.719Gravida0.0 (0.0-1.0)0.0 (0.0-1.0)0.733Para0.0 (0.0-0.0)0.0 (0.0-0.0)0.507Antral follicle count36.0 (29.0-41.0)37.0 (28.0-40.0)0.416Oocytes retrieved24.0 (19.0-30.0)23.0 (18.0-28.0)0.209Endometrial thickness (mm)10.9 (9.5-12.5)10.3 (9.2-12.1)0.060Fresh embryos transferred1.0 (1.0-1.0)1.0 (1.0-1.0)0.369Embryos frozen5.0 (2.0-8.0)3.0 (1.0-7.0)0.007 Open table in a new tab

Prior studies investigating the relationship between a thin endometrium and IVF outcomes have overwhelmingly been performed in fresh, cleavage stage embryo transfers. Given the recent trend toward frozen blastocyst transfers, we aimed to determine whether endometrial thickness predicts live birth rate in both fresh and frozen blastocyst stage embryo transfers. Retrospective cohort study. First fresh or frozen IVF blastocyst transfers at the University of Iowa between 9/2011 and 9/2017 were included in this study. Donor cycles, PGS cycles, and cycles with incomplete information were excluded. Endometrial thickness was measured on the day of hCG trigger +/- 1 day (for fresh cycles) or at the end of estrogen priming (just prior to progesterone administration) in a frozen transfer cycle. Statistical analysis was performed using a generalized linear mixed model. We controlled for potential confounding variables including age, weight/BMI, embryo quality, days of stimulation, number of embryos transferred, and parity. In fresh blast transfers (n=1042), endometrial thickness (median=10.9 mm; range 2.6-22 mm) was significantly correlated with live birth rate when controlling for other confounding factors. For every 1 mm increase in endometrial thickness, the odds of live birth increased by 7.9% (p<0.0001). The fresh live birth rate was negatively affected by female age and increasing days of stimulation, and positively affected by higher blastocyst stage and trophectoderm grade (A better than B/C). In frozen blast transfers (n=566), endometrial thickness (median 8.7 mm; range 4.9-18.9 mm) was not significantly correlated with live birth rate when controlling for the same factors. Increasing female age negatively affected, and increasing number of embryos transferred positively affected the live birth rate after frozen blastocyst transfers. Patient weight and BMI did not affect either the live birth rate or endometrial thickness in either dataset. We have shown that a thicker endometrium on the day of trigger is associated with improved live birth rates after fresh blastocyst transfer. In frozen transfers, there was a trend toward improved live birth rate with increasing endometrial thickness, but this was non-significant. These data suggest that endometrial thickness is more important in fresh than in frozen embryo transfers. However, these results could be explained by the fact that frozen transfers are generally not performed at our institution until an endometrial thickness of >6.0 mm is achieved. Further studies will be required to clarify these differences.

agonist versus antagonist cycles for patients <35 years who were overweight (BMI 25.0-29.9kg/m 2 ) or had class II (BMI 35.0-39.9kg/m 2 ) or class III (BMI R40 kg/m 2 ) obesity; comparisons for older ages were not significant.Among non-Hispanic white and non-Hispanic black women with class II or class III obesity, LBRs were also higher for agonist versus antagonist cycles.Among women with a prior spontaneous abortion, LBRs were significantly higher for those using agonist vs antagonist protocol for all BMI categories.Cycle cancellation rates were higher for antagonist versus agonist cycles for each BMI category; however, cancellation due to ovarian hyperstimulation occurred less frequently in the antagonist cycles for each BMI category.CONCLUSIONS: Overall, pregnancy and live birth rates were higher in agonist versus antagonist cycles in all BMI categories.Among women who had class II or III obesity, use of agonist protocol resulted in higher LBRs in those who were <35 or were non-Hispanic white or non-Hispanic black.Cancellation due to hyperstimulation was less frequent in the antagonist than agonist cycles, as expected, but this must be weighed with improved IVF outcomes with the agonist protocol.

To compare live birth and multiple birth rates among women who underwent eSET versus DET in the first frozen embryo transfer (FET) cycle following a failed fresh mSET. Retrospective cohort study. All patients at our institution from 1/1/2012-9/14/2017 who met criteria for mSET (age <38, good quality blastocyst, and no previous failed fresh cycle), did not have a live birth following their first fresh transfer, had at least 2 remaining cryopreserved blastocysts, and subsequently underwent FET were included. Primary outcomes were live birth per transfer and multiple birth per delivery. Secondary outcomes were clinical pregnancy rate, miscarriage rate, ectopic pregnancy rate, term vs. preterm delivery, vaginal delivery vs. cesarean section, and infant birth weight. Exclusion criteria were preimplantation genetic testing (PGT) cycles, FET cycles in which only 1 embryo survived the thaw process, mSET due to maternal condition (e.g. unicornuate uterus), cycles in which birth data were not available, and donor oocyte cycles. Chi-squared tests and t-tests were used to compare demographic, cycle characteristics, and outcome data between groups. Medians with interquartile ranges, means with standard deviation, or percentages are presented. Of the 731 patients who underwent an initial mSET and had outcome data available, 450 had a live birth (61.5%). Of the 281 that failed their fresh mSET, 218 of these went on to have a FET within our time frame (77.6%). Of those, 54 patients were excluded due to no outcome data available (n=9), <2 blastocysts frozen (n=15), only 1 surviving embryo available to transfer after warming (n=27), or mSET due to maternal condition (n=3). This left 164 patients, of which 88 (53.7%) chose to transfer 1 embryo and 76 (46.3%) chose to transfer 2 embryos in their FET. Demographic and cycle characteristics were similar between eSET and DET patients (Table 1). DET patients had a significantly higher live birth rate and clinical pregnancy rate than eSET patients. However, DET patients also had a significantly higher multiple birth rate, C-section rate, and lower birth weight (Table 1). There was no other differences in outcomes seen between groups. In a group of good prognosis patients with an unsuccessful mandatory single embryo transfer, DET in the subsequent cycle resulted in a higher live birth rate than SET, but also was associated with a much higher multiple birth rate. When deciding on the number of embryos to transfer in this group, patients and providers should consider both the higher pregnancy rate and the significant risk of multiples with DET vs. SET.Tabled 1Demographic and Cycle CharacteristicsceSET (n=88)DET (n=76)pAge31 (29-34)32 (29-34)0.248BMI26.7 (21.9-31.5)25.4 (22.6-32.7)0.618Number of oocytes retreived18 (13-25)18 (13-30)0.377Number of blastocysts cryopreserved3 (2-6)4 (2-7)0.345Parity0 (0-0)0 (0-1)0.586Live birth39 (44.3%)52 (68.4%)0.002Multiple birth1 (2.6%)19 (35.8%)<0.001Clinical pregnancy53 (60.2%)57 (75.0%)0.045Preterm delivery5 (12.8%)13 (25.0%)0.149C-section13 (33.3%)29 (55.8%)0.034Birth weight (grams)3540 (3090-3720)3090 (2584-3443)0.003 Open table in a new tab

Background: Heterotopic pregnancy is a rare complication of in vitro fertilization (IVF) and diagnosis and treatment can be challenging, particularly with unusual ectopic sites and desire to maintain the intrauterine pregnancy. Case: We review the case of a 29-year-old female who presented with a cornual heterotopic pregnancy following IVF treated with exploratory laparotomy and ultrasound guided resection of the cornual pregnancy, resulting in an ongoing viable singleton intrauterine pregnancy. Conclusion: The management of cornual heterotopic pregnancies is limited by lack of data regarding ideal treatment although several surgical and non-surgical strategies have been described. This case uses abdominal resection of cornual ectopic pregnancy using intraoperative ultrasound as an optimal approach to remove the ectopic pregnancy without disrupting the viable intrauterine pregnancy, which was in close proximity of the cornual ectopic.

Objective: To determine the effect of elective single ET (eSET) on live birth and multiple birth rates by a cycle-level and clinic-level analysis.Design: Retrospective cohort study.Setting: Not applicable. Patient(s): Patient ages <35 and 35-37 years old.Intervention(s): None.Main Outcome Measure(s): Clinics were divided into groups based on eSET rate for each age group and aggregate rates of live birth per ET and multiple birth per delivery were calculated. A cycle-level analysis comparing eSET and double ET (DET) live birth and multiple birth rates was also performed, stratified based on total number (2, 3, or 4+) of embryos available, embryo stage, and patient age.Result(s): There was a linear decrease in multiple birth rate with increasing eSET rate and no significant difference in clinic-level live birth rates for each age group. Cycle-level analysis found slightly higher live birth rates with double ET, but this was mainly observed in women aged 35-37 years or with four or more embryos available for transfer, and confirmed the marked reduction in multiple births with eSET.Conclusion(s): Our study showed a marked and linear reduction in multiple birth rates, and important, little to no effect on clinic-level live birth rates with increasing rates of eSET supporting the growing evidence that eSET is effective in decreasing the high multiple birth rates associated with IVF and suggests that eSET should be used more frequently than is currently practiced. (C) 2016 by American Society for Reproductive Medicine.

Purpose To assess human fertilization and preimplantation embryo development in the presence and in the absence of carbon filtration Methods This is a retrospective cohort analysis of fresh, controlled ovarian hyperstimulation cycles as well as previously cryopreserved pronuclear stage embryo transfer cycles in a single IVF center. Embryo development and cycle-based outcomes were compared among three groups: 1) when carbon filtration was present, 2) when carbon filtration was absent, and 3) when carbon filtration had been restored. Results A total of 524 fresh cycles and 156 cryopreserved embryo cycles were analyzed. Fertilization, cleavage, and blastocyst conversion rates for fresh cycles all declined during the period of absent carbon filtration and recovered after the restoration of carbon filtration. Cryopreserved embryos that were thawed and cultured during the period of absent filtration did not have changes in cleavage or blastocyst conversion rates compared to periods where carbon filtration was present. Clinical pregnancy and live birth rates were unchanged among the three time periods. Conclusions The absence of carbon filtration in an IVF laboratory air handler is associated with poor fertilization and early embryo development for fresh cycles. Because development of previously frozen pronuclear stage embryos was unaffected, the lack of carbon filtration may preferentially affect embryos in the peri-fertilization period. Carbon filtration is an integral part to a successful human in-vitro fertilization laboratory.

Laboratory air quality may aff5ct outcomes of assisted reproductive technologies (ART) (1, 2). Much of the published data is anecdotal or limited to pregnancy outcomes (3, 4). Additionally, improvement of IVF outcomes with the introduction of an air filter may be coincident with other improvements in the laboratory over time. To examine parameters of embryo development before, during, and after a period when carbon filtration was unknowingly removed from our IVF laboratory air handler. In this retrospective study, we analyzed fresh ART cycles from three periods: 1) February – July 2010, when the IVF lab air handler contained carbon filtration ("Carbon 1"), 2) February – July 2011, when carbon filtration was absent ("Absent"), and 3) February – July 2012, after carbon filtration had been restored ("Carbon 2"). HEPA filtration was in place throughout the study period, and no auxiliary (in-line or free-standing) air purification systems were employed. All embryo cultures were performed in 5.5-6.0% CO2 in air at 37°C in sequential culture media. The patient demographics and the rates of fertilization, cleavage, and blastocyst conversion per zygote following IVF or ICSI were compared. We also compared cleavage rates of PN stage embryos thawed during the three periods. Cleavage was defined as an embryo having ≥2 cells by 42 hours post insemination. One-way ANOVA was used to compare means with Games-Howell post-hoc analysis to confirm differences among groups. Chi-square tables were used to compare proportions. P values < 0.05 were considered statistically significant. We reviewed 524 fresh ART cycles and 164 PN-stage thaw cycles. There were no statistically significant demographic differences between the Absent group and either of the Carbon groups (Table 1). More ICSI was performed during the Absent and Carbon 2 periods, in response to poor fertilization rates with conventional insemination during the Absent period, which helped maintain fertilization rates. Fertilization and fresh embryo cleavage rates were adversely aff5cted when carbon filtration was absent (Absent group). However, the cleavage rate of frozen PN embryos in the three groups did not differ significantly (Figure 1, Figure 2). The absence of carbon filtration negatively aff5cted fertilization and cleavage rates in fresh IVF cycles. Cleavage rate was significantly aff5cted in fresh but not frozen cycles, suggesting that volatile organic compounds may negatively aff5ct oocytes and zygotes preferentially.

To assess clinical outcomes and embryo efficiency between day 3 and day 5 embryo transfer (ET) in women with 6 zygotes to culture. Retrospective cohort analysis. We analyzed all women 36 years or younger who had 6 zygotes following IVF at our program between 2003 and 2013. Per policy, in women with 6 embryos to culture, fresh ETs were performed on culture day 3 before 2009 (day 3 ET group) and on culture day 5 after 2009 (day 5 ET group). In both groups, non-transferred embryos were cultured to day 5 or 6 and cryopreserved if they reached the blastocyst stage. Main outcome measures were fresh and cumulative live birth rate, and embryo efficiency. Cumulative live birth rate was censored for delivery and calculated on a per patient basis. Embryo efficiency was calculated based on proportion of live born babies during both fresh and frozen cycles per total number of embryos. Number of embryos transferred, implantation rate and cumulative twin delivery rate were also analyzed. Chi-square, Fisher’s exact and Mann-Whitney U tests were used for statistical analysis. A total of 185 patients were included, 95 in day 3 ET group and 90 in day 5 ET group. From this total, 23 women have remaining cryopreserved embryos, 3 women in day 3 group with 5 embryos cyropreserved and 20 women in day 5 group with 40 embryos cryopreserved. Results are summarized in the table.Tabled 1Day 3Day 5P valueAge31.0±3.230.9±2.70.472BMI27.6±7.527.1±6.60.954Average embryos transferred (fresh)2.0±0.31.3±0.5<0.001Implantation rate (fresh)0.460.470.900Fresh live birth rate65.3%50.0%0.036Embryos cryopreserved0.52±1.01.1±1.2<0.001Implantation rate (cryo)0.500.530.780Cumulative live birth rate68.4%65.6%0.680Embryo efficiency15.9%14.4%0.490Cumulative twin delivery rate25.0%10.8%0.032 Open table in a new tab Numbers represent mean ± standard deviation or percentage. Clinical pregnancy is defined by ultrasonographic demonstration of fetal cardiac activity. Implantation rate is defined as total gestational sacs divided by total embryos transferred in each category. These data suggest that extended embryo culture to day 5 does not adversely affect embryo efficiency in a select group of women with only 6 zygotes and does not pose a detrimental effect on cumulative live birth rate. Additionally, a significant decrease in cumulative twin delivery rate is achieved by this strategy if single embryo transfer is used frequently for day 5 ETs. This may translate to a safer IVF practice strategy in prevention of multiple pregnancies, including twins.

Up to 30% of cases of infertility will be categorized as “unexplained” after a thorough evaluation, yet there are few randomized clinical trials to guide treatment decisions for these couples. When compared to expectant management, the efficacy of either controlled ovarian hyperstimulation (COH) or IUI used alone has been challenged (1Bhattacharya S. Harrild K. Mollison J. Wordsworth S. Tay C. Harrold A. et al.Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomized controlled trial.BMJ. 2008; 337: a716Crossref PubMed Scopus (125) Google Scholar). A comprehensive review of prospective randomized trials concluded that the combination of COH and IUI results in a statistically significant, but clinically small, increase in pregnancy rates (PRs) compared with COH with timed intercourse (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.13–2.5). These results suggest that as many as 13 couples would have to be treated with one to three cycles of COH and IUI to produce one additional pregnancy. The review (2Pandian Z. Gibreel A. Bhattacharya S. In vitro fertilization for unexplained subfertility.Ochrane Database Syst Rev. 2012 Sept 12; 9: CD001838PubMed Google Scholar) also noted that the quality of the included studies was rather poor. In contrast, IVF has been found in the single published trial (3Veltman-Verhulst SM, Cohlen BJ, Hughes E, Heineman MJ. Intra-uterine insemination for unexplained subfertility. The Cochrane Library 2012. CD001838. Cochrane Menstrual Disorders and Subfertility Group. The Cochrane Collaboration.Google Scholar) to be vastly more effective than expectant management (OR 22, 95% CI 2.56–189.4) for couples with unexplained infertility. In patients with this diagnosis who failed to conceive with clomiphene citrate (CC) and IUI, IVF also resulted in a significantly higher PR than COH using gonadotropin injections combined with IUI (OR 12.78, 95% CI 7.54–21.65) (4Reindollar R.H. Regan M.M. Neumann P.J. Levine B.S. Thornton K.L. Alper M.M. et al.A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial.Fertil Steril. 2009; 94: 888-899Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Important, women in these aforementioned studies had a mean age of 30–33 years, with women aged 39 years and older generally excluded (3Veltman-Verhulst SM, Cohlen BJ, Hughes E, Heineman MJ. Intra-uterine insemination for unexplained subfertility. The Cochrane Library 2012. CD001838. Cochrane Menstrual Disorders and Subfertility Group. The Cochrane Collaboration.Google Scholar). With the trend toward delayed childbearing, clinicians are increasingly advising and caring for women of relatively advanced maternal age. At present, there has been little in the literature to guide this advice. The underlying pathophysiology behind unexplained infertility may differ between women aged 38–42 years and younger women, challenging the propriety of broadly using treatment strategies suggested by past studies such as those listed. Indeed, it is likely that the higher prevalence of oocyte chromosomal defects with advancing age contributes significantly to “unexplained” infertility in older women. This calls into question the relative utility of IUI for these couples. The Forty and Over Treatment Trial (FORT-T) is an important trial of treatment strategies for unexplained infertility in couples in which the female partner is between the ages of 38 and 42 years. The investigators conclude that a strategy of immediate IVF results in superior PRs with fewer treatment cycles and a shorter time to pregnancy in these couples when compared to two cycles of COH/IUI followed by up to six cycles of IVF (5Goldman M.B. Thornton K. Ryley D. Alper M.M. Fung J.L. Hornstein M.D. et al.A randomized clinical trial to determine optimal infertility treatment in older couples: the forty and over treatment trial (FORT-T).Fertil Steril. 2014; 101: 1574-1581Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). The FORT-T trial has many strengths, including its prospective randomized design and, due in part to mandated infertility coverage, its low drop-out rates allowing for analysis of long-term outcomes for the different treatment strategies. One must also recognize some of the limitations in applying this trial's findings to general clinical infertility care. The investigators included a highly selected group (∼2%) of all the women assessed for eligibility. Readers are left to wonder how many women were screened out because of diminished ovarian reserve (based on an abnormal CC challenge test in this study), a common issue in this age group. Because the findings of this study should only be applied to women with advanced maternal age and normal ovarian reserve, clinicians are still lacking data that suggest the best strategy for the many women in this age range with diminished ovarian reserve. Also, although the age range of women included in this study was relatively narrow, live birth rates are very different in 38- to 40-year-old women compared with 41- to 42-year-old women. National IVF data from 2012 show the percentage of cycles resulting in live births in 38- to 40-year-old women was twice that of 41- to 42-year-old women (e.g., 22.2% vs. 11.8%; www.SART.org). In the FORT-T study, couples were stratified by the woman's age. However, enrollment was stopped after reaching approximately one-third of the original planned sample size due to slow enrollment and the findings of an unplanned interim analysis. We suspect the data were not in fact analyzed using this stratification because the final sample size was not sufficient. This represents another trial limitation and begs the question of why enrollment was so difficult. Perhaps it was due to the challenge of finding women with a normal CC challenge tests in this age group? Readers are also left without resolution of whether there are differences in the most appropriate treatment strategy for women aged 38–40 versus 41–42 years. Although the investigators chose clinical PR as their primary outcome, we believe that live birth rate is the outcome of most importance to patients and should be the primary outcome of such trials. When looking at live birth rate outcomes after two treatment cycles, it appears that IVF affords higher rates per cycle (15.3% vs. 5.1%) and per couple (27.7% vs. 7.9%) compared with COH/IUI (CC/IUI and FSH/IUI combined). Within the latter treatment group, the investigators suggest that CC/IUI has an equivalent live birth rate to FSH/IUI. However, it is interesting to note that five of eight (62%) live births conceived in the CC/IUI arm were treatment-independent versus only one of seven pregnancies in the FSH/IUI arm. One of the remarkable findings in this article is that 20% of all live births were treatment-independent (n = 14), a higher proportion than was achieved with COH/IUI (n = 9, 13%). This raises the question of the relative efficacy of expectant management versus COH/IUI in unexplained infertility, even in this older infertile population. Although this study demonstrates the superiority of IVF compared with COH/IUI in short-term efficacy, it is interesting to note that the three studied strategies were ultimately equivalent based on live birth rate per randomized couple by the end of the study. This suggests that couples electing to start simpler and less expensive treatment than IVF are not harming their ultimate chances of having a child. This observation also raises the important question of cost effectiveness of these treatment options, an analysis that has not yet been reported from these data. The investigators are congratulated on a very important study that will help guide treatment of older infertile couples in the United States. We call on them and other clinical investigators to use these findings to elucidate future inquiries into comparative efficacy and cost-effectiveness of infertility treatment options. A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T)Fertility and SterilityVol. 101Issue 6PreviewEarn online CME credit related to this document at www.asrm.org/elearn Full-Text PDF Treatment for couples with unexplained infertility: the female partner at the end of reproductive yearsFertility and SterilityVol. 101Issue 6PreviewWe are writing this letter in response to the editorial by Van Voorhis et al. (1). We thank the authors for their interest in our manuscript and their positive comments about the importance of the FORT-T trial (2). There are several points in the editorial that we address in this letter. With respect to the observation that we studied a highly selected group of patients, we would point out that all well-designed randomized clinical trials have specified inclusion and exclusion criteria. These criteria enable the study to enroll a homogeneous population with the condition of interest. Full-Text PDF

Pregnancies achieved by in vitro fertilization (IVF) may be complicated by miscarriage or abnormal implantation (ectopic and heterotopic pregnancies). Identification of early predictors of these conditions may help build a cost-efficient strategy for their management. We aimed to identify and compare early predictors of poor early pregnancy outcome (PEPO: miscarriage, ectopic, and heterotopic pregnancies) following an IVF cycle. We conducted a retrospective cohort study of all IVF pregnancies between 1995 and 2013. Patient complaints of vaginal bleeding, and/or pelvic/abdominal pain, as well as information on the diagnosis and management of PEPO were abstracted from our IVF database, and medical records. All patients at our center are scheduled for an initial serum hCG level 15 days after oocyte retrieval (first hCG), followed by a repeat hCG level (second hCG) 48 hours later. Binary forward stepwise logistic regression (LogRes) models were built to determine early predictors of PEPO. First and second hCG levels, age, vaginal bleeding, pain, the rate of increase in hCG (i.e. slope of the hCG parabola, hCGslope), and day of embryo transfer (ET, day3 vs. day 5) were included in the analysis. Receiver operating characteristics (ROC) curves were constructed to assess and compare the predictive capacity of the parameters chosen by LogRes models. Out of 3904 IVF pregnancies evaluated, there were 651 cases of PEPO (16.7%). LogRes models identified the following independent predictors for PEPO: age, vaginal bleeding, pain, first hCG, second hCG, and hCGslope (Nagelkerke r2: 0.149, df: 6, p<0.001). The ROC curves and the results of the ROC curve analysis are displayed in Figure 1 and Table 1, respectively.Table 1Predictor of PEPOArea Under the Curve95% Confidence IntervalsSecond hCG level0.7040.690-0.719First hCG level0.6940.679-0.709Age0.6000.584-0.616hCGslope0.5640.548-0.580Vaginal bleeding0.5500.534-0.566Pain0.5210.505-0.536 Open table in a new tab Combined use of clinical symptoms and early quantitative hCG assessments may help predict PEPO after IVF, although no single reliable predictor was identified.

Ectopic pregnancy (EP) occurs in 2.1% of all pregnancies achieved by in vitro fertilization1 (IVF). Identification of early predictors of this condition may help build a cost-efficient strategy for its management. We aimed to identify and compare early predictors of EP following an IVF cycle. We conducted a retrospective cohort study of all IVF pregnancies between 1995 and 2013. Our IVF database, paper and medical records of the patients were evaluated for patient complaints of vaginal bleeding and/or pelvic/abdominal pain occurring between the day of embryo transfer and the first obstetric ultrasound, as well as for information on diagnosis and management of EP. All patients at our center are scheduled for an initial serum hCG level 15 days after oocyte retrieval (first hCG), followed by a repeat hCG level (second hCG) 48 hours later. Due to a variety of logistic constraints, this schedule is could not be precisely followed in all cases. To overcome the resulting heterogeneity in timing of the first hCG assessment, a projected hCG level (PhCG) was calculated based on the existing hCG levels as well as the rate of increase in hCG (i.e. slope of the hCG parabola, hCGslope) to correspond with the 15th day after oocyte retrieval for cases as needed. Binary forward stepwise logistic regression (LogRes) models were built to determine early predictors of EP. First and second hCG levels, age, tubal factor, vaginal bleeding, pain, hCGslope, day of embryo transfer (ET, day3 or day 5) and PhCG were included in the analysis. Receiver operating characteristics (ROC) curves were constructed to assess and compare the predictive capacity of the parameters chosen by LogRes models. Out of 3904 IVF pregnancies evaluated, there were 31 cases of EP (0.8%). The variation in the day of first hCG is shown in Figure 1. LogRes models identified the following independent predictors for EP: tubal factor infertility, vaginal bleeding, pain, PhCG (Nagelkerke r2: 0.373, df: 4, p<0.001). The results of the ROC curve analyses are summarized in Figure 2 and Table 1. First hCG level plots a fine ROC curve exhibiting reliable predictability of EP.Figure 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Cut-offSensitivity (%)Specificity (%)PPV∗ (%)NPV+ (%)First hCG≤50 U/L67.793.17.399.7Projected hCG≤72 U/L74.285.54.099.8Any symptom-80.767.82.099.8Tubal factor-46.776.02.099.3∗PPV: positive predictive value.+NPV: negative predictive value. Open table in a new tab ∗PPV: positive predictive value. +NPV: negative predictive value. Combined use of history, clinical symptoms and early quantitative hCG drawn approximately 15 days after oocyte retrieval is an effective means to predict EP after IVF. The first hCG level is a useful tool to predict EP after IVF.

ObjectiveWe sought to evaluate fresh and frozen cycle outcomes of all patients undergoing policy SET. At our institution SET is mandatory for all women < 38 years of age with at least 7 zygotes, no history of a failed fresh cycle at our center, and at least one good quality blastocyst available for transfer.DesignRetrospective cohort study.Materials and MethodsData from our program's clinical database were reviewed. We included all women undergoing policy SET in a fresh cycle and subclassified them as donor oocytes, age < 35, and age 35-37. If patients did not achieve live birth, we analyzed subsequent frozen cycle ongoing pregnancy/live birth rate (OP/LBR). During frozen embryo transfer (FET) cycles, patients were eligible for double blastocyst transfer. We calculated overall cryo-augmented OP/LBR and multiple gestations.ResultsTabled 1Fresh LBRFrozen embryos1 FET OP/LBR2 FET OP/LBR3 FET OP/LBRCryo-augmented OP/LBR% multiple rate of OP/LBDonor n = 7855%100%16/283/50/179%21%<35 n = 50466%92%81/11712/222/785%8%35-37 n = 13058%85%19/342/31/175%7%ALL n = 71263.1%91.7%64.8%56.7%33.3%82.2%9% Open table in a new tab ConclusionIn a favorable prognosis patient group, cumulative cryo-augmented OP/LBRs are very high, despite mandatory SET in fresh cycle. Although double embryo transfer is done in subsequent FET cycles, the overall multiple gestation rate is relatively low. This information is useful in counseling patients on the significant advantages of SET when compared to the risk of not achieving a pregnancy from fresh cycle embryo cohort. ObjectiveWe sought to evaluate fresh and frozen cycle outcomes of all patients undergoing policy SET. At our institution SET is mandatory for all women < 38 years of age with at least 7 zygotes, no history of a failed fresh cycle at our center, and at least one good quality blastocyst available for transfer. We sought to evaluate fresh and frozen cycle outcomes of all patients undergoing policy SET. At our institution SET is mandatory for all women < 38 years of age with at least 7 zygotes, no history of a failed fresh cycle at our center, and at least one good quality blastocyst available for transfer. DesignRetrospective cohort study. Retrospective cohort study. Materials and MethodsData from our program's clinical database were reviewed. We included all women undergoing policy SET in a fresh cycle and subclassified them as donor oocytes, age < 35, and age 35-37. If patients did not achieve live birth, we analyzed subsequent frozen cycle ongoing pregnancy/live birth rate (OP/LBR). During frozen embryo transfer (FET) cycles, patients were eligible for double blastocyst transfer. We calculated overall cryo-augmented OP/LBR and multiple gestations. Data from our program's clinical database were reviewed. We included all women undergoing policy SET in a fresh cycle and subclassified them as donor oocytes, age < 35, and age 35-37. If patients did not achieve live birth, we analyzed subsequent frozen cycle ongoing pregnancy/live birth rate (OP/LBR). During frozen embryo transfer (FET) cycles, patients were eligible for double blastocyst transfer. We calculated overall cryo-augmented OP/LBR and multiple gestations. ResultsTabled 1Fresh LBRFrozen embryos1 FET OP/LBR2 FET OP/LBR3 FET OP/LBRCryo-augmented OP/LBR% multiple rate of OP/LBDonor n = 7855%100%16/283/50/179%21%<35 n = 50466%92%81/11712/222/785%8%35-37 n = 13058%85%19/342/31/175%7%ALL n = 71263.1%91.7%64.8%56.7%33.3%82.2%9% Open table in a new tab ConclusionIn a favorable prognosis patient group, cumulative cryo-augmented OP/LBRs are very high, despite mandatory SET in fresh cycle. Although double embryo transfer is done in subsequent FET cycles, the overall multiple gestation rate is relatively low. This information is useful in counseling patients on the significant advantages of SET when compared to the risk of not achieving a pregnancy from fresh cycle embryo cohort. In a favorable prognosis patient group, cumulative cryo-augmented OP/LBRs are very high, despite mandatory SET in fresh cycle. Although double embryo transfer is done in subsequent FET cycles, the overall multiple gestation rate is relatively low. This information is useful in counseling patients on the significant advantages of SET when compared to the risk of not achieving a pregnancy from fresh cycle embryo cohort.

REI fellowship programs must include 18 months of research; the impact of this extended break in clinical training on IVF cycle outcomes has not been evaluated. The study objective is to compare clinical pregnancy rate (CPR) following embryo transfer (ET) performed by REI fellows before and after an 18 month lapse in clinical training. Retrospective cohort (2004-2012) at academic training program. Cycle outcomes after fellow ET were evaluated using data from a prospectively collected IVF database. Each fellow had an 18 month lapse in clinical training mid-way through fellowship while on a research rotation. The primary outcome was CPR (sonographic presence of gestational sac) for the last 50 ETs performed prior to training lapse and the first 50 ETs performed upon return to clinical training. CPRs for each fellow were compared using McNemar's test. Ongoing analyses will include the secondary outcomes of implantation and live birth rate and will use multivariate regression models adjusting for potential confounders including patient age, attempt number, and cycle type. Analyses included 4 fellows who performed a total of 822 ETs during the study period. Cumulative per fellow CPR during fellowship ranged from 54%-63%. Patient age was similar before and after the training lapse. Unadjusted analyses revealed no difference in CPR when comparing the 50 ETs prior to and after the training lapse (all p>0.1).Tabled 1Fellow 1Fellow 2Fellow 3Fellow 4Before lapse (n = 50)Mean pt age34.4233.733.5734.7CPR66%64%50%52%After lapse (n = 50)Mean pt age33.8533.6133.4334.11CPR58%56%54%48%p-value0.100.100.890.68 Open table in a new tab A research rotation is common in the middle of REI training programs. This length of leave from clinical training does not appear to negatively impact CPR following fellow ET.