Fresh In Vitro Fertilization Research Articles

The role of frozen–thawed embryo replacement cycles in assisted conception

Key content Recent years have seen a dramatic rise in the number of frozen–thawed embryo replacement (FER) cycles. Improved embryo cryopreservation techniques have resulted in outcomes for FER that are similar to fresh embryo transfer. FER maximises the cumulative live‐birth rate of a fresh in vitro fertilisation (IVF) cycle by using excess embryos and encourages a policy of single embryo transfer; this has contributed to a fall in the multiple pregnancy rate associated with IVF. Freezing all suitable embryos in a fresh cycle reduces the risk of ovarian hyperstimulation syndrome. The endometrium is prepared for FER by a natural or medicated protocol; the optimum method is unknown. Learning objectives To appreciate the importance of FER in IVF practice. To understand the current debate surrounding fresh versus frozen IVF. To understand the indications for, and methods of, embryo cryopreservation. To understand the commonly used methods of endometrial preparation for FER. To be able to date an FER pregnancy. Ethical issues Funding from the National Health Service (NHS) for embryo storage and FER varies widely across the UK; where funding is limited, this can result in viable embryos being discarded. When an embryo is created by a couple, the consent of both partners is required before transferring the embryo.

Live birth outcomes of vitrified embryos generated under growth hormone stimulation are improved for women categorized as poor-prognosis.

ObjectiveTo determine the clinical pregnancy (CP) and live birth (LB) rates arising from frozen embryo transfers (FETs) that had been generated under the influence of in vitro fertilization (IVF) adjuvants given to women categorized as poor-prognosis.MethodsA registered, single-center, retrospective study. A total of 1,119 patients with first FETs cycle include 310 patients with poor prognosis (109 treated with growth hormone [GH], (+)GH group vs. 201 treated with dehydroepiandrosterone, (–)GH group) and 809 patients with good prognosis (as control, (–)Adj (Good) group).ResultsThe poor-prognosis women were significantly older, with a lower ovarian reserve than the (–)Adj (Good) group, and demonstrated lower chances of CP (p<0.005) and LB (p<0.005). After adjusting for confounders, the chances of both CP and LB in the (+)GH group were not significantly different from those in the (–)Adj (Good) group, indicating that the poor-prognosis patients given GH had similar outcomes to those with a good prognosis. Furthermore, the likelihood of LB was significantly higher for poor-prognosis women given GH than for those who did not receive GH (p<0.028). This was further confirmed in age-matched analyses.ConclusionThe embryos cryopreserved from fresh IVF cycles in which adjuvant GH had been administered to women classified as poor-prognosis showed a significant 2.7-fold higher LB rate in subsequent FET cycles than a matched poor-prognosis group. The women with a poor prognosis who were treated with GH had LB outcomes equivalent to those with a good prognosis. We therefore postulate that GH improves some aspect of oocyte quality that confers improved competency for implantation.

Does assisted hatching affect live birth in fresh, first cycle in vitro fertilization in good and poor prognosis patients?

To assess the effect of assisted hatching (AH) on live birth rate (LBR) in first cycle, fresh in vitro fertilization (IVF) in good and poor prognosis patients. Retrospective cohort using cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Live birth rate was compared in women who underwent first cycle, autologous, fresh IVF cycles with (n = 48,858) and without (n = 103,413) AH from 2007 to 2015. The propensity-weighted LBR was 39.2% with AH versus 43.9% without AH in all patients. The rate difference (RD) with AH was - 4.7% ([CI - 0.053, - 0.040], P < 0.001) with the calculated number needed to harm being 22. AH affected live birth in both good prognosis and poor prognosis patients. The propensity-weighted monozygotic twinning (MZT) rate was 2.3% in patients treated with AH as compared to 1.2% patients that did not receive AH. The RD with AH on MZT in fresh, first IVF cycles was 1.1% ([0.008, 0.014], P < 0.001). AH may affect LBR across all patients and in poor prognosis patients in fresh IVF cycles. Caution should be exercised when applying this technology. More prospective research is needed.

Investigating the effect of lifestyle risk factors upon number of aspirated and mature oocytes in in vitro fertilization cycles: Interaction with antral follicle count.

IntroductionThere is evidence demonstrating that certain lifestyle factors have a detrimental effect on fertility. Since such factors often coexist, possible synergistic effects merit further investigation. Thus we aimed to examine the cumulative impact of lifestyle factors on in vitro fertilization (IVF) early reproductive treatment outcomes and their interaction with measures of ovarian reserve.Materials and methodsBy following women who were starting their first fresh IVF cycle in 2 cohorts, the “Lifestyle study cohort” (hypothesis generating cohort, n = 242) and the “UppSTART study” (validation cohort, n = 432) in Sweden, we identified two significant risk factors acting independently, smoking and BMI, and then further assessed their cumulative effects.ResultsWomen with both these risk factors had an Incidence Rate Ratio (IRR) of 0.75 [(95% CI 0.61–0.94)] regarding the number of aspirated oocytes compared to women without these risk factors. Concerning the proportion of mature oocytes in relation to the total number of aspirated oocytes, the interaction between BMI and Antral Follicle Count (AFC) was significant (p-value 0.045): the lower the value of AFC, the more harmful the effect of BMI with the outcome.ConclusionsData shows that there is an individual as well as a cumulative effect of smoking and BMI on the number of aspirated and mature oocytes in fresh IVF treatment cycles. AFC might modify associations between BMI and the proportion of mature oocytes in relation to the total number of aspirated oocytes. These results highlight the importance of lifestyle factors on IVF early reproductive outcomes and provide additional evidence for the importance of preconception guidance for the optimization of IVF cycle outcome.

The combined impact of maternal age and body mass index on cumulative live birth following in vitro fertilization

It is critical to evaluate the combined impact of age and body mass index on the cumulative likelihood of live birth following invitro fertilization, as achieving a lower body mass index before infertility treatment often is recommended for women with overweight and obesity. It is important to consider whether achieving a particular body mass index, thus resulting in an older age at invitro fertilization cycle start, is beneficial or harmful to the likelihood of live birth. To evaluate the combined impact of age and body mass index on the cumulative live birth rate following invitro fertilization to inform when delaying invitro fertilization treatment to achieve a lower body mass index may be beneficial or detrimental to the likelihood of live birth. This is a retrospective study using linked fresh and cryopreserved/frozen cycles from January 2014 to December 2015 from the Society for Reproductive Technology Clinic Outcome Reporting System, representing >90% of invitro fertilization cycles performed in the United States. The primary outcome was live birth as measured by cumulative live birth rate. Secondary outcomes included implantation rate, clinical pregnancy rate, and miscarriage rate. Poisson and logistic regression were used to calculate risk and odds ratios with 95% confidence intervals to determine differences in implantation, clinical pregnancy, and miscarriage, as appropriate, among first fresh invitro fertilization cycles compared across age (years) and body mass index (kg/m2) categories. Cox regression was used to calculate hazard ratios with 95% confidence intervals to determine differences in the cumulative live birth rate using fresh plus linked frozen embryo transfer cycles. There were 51,959 first fresh cycles using autologous eggs and 16,067 subsequent frozen embryo transfer cycles. There were 21,395 live births, for an overall cumulative live birth rate of 41.2% per cycle start. The implantation rate, clinical pregnancy rate, and cumulative live birth rate decreased with increasing body mass index and age, and the miscarriage rate increased with increasing body mass index and age (linear trend P<.001 for all). Body mass index had a greater influence on live birth at younger ages as compared with older ages. Age-related decline in fertility has a greater impact than body mass index on the cumulative live birth rate at older ages, suggesting that taking time to achieve lower body mass index before invitro fertilization may be detrimental for older women with overweight or obesity. Delaying conception to lose weight before invitro fertilization should be informed by the combination of age and body mass index.

An enhanced clot growth rate before in vitro fertilization decreases the probability of pregnancy

BackgroundThe shift towards hypercoagulation during in vitro fertilization (IVF) can lead to the impairment of embryo implantation and placental blood circulation, which is believed to be a factor in an unsuccessful IVF cycle.ObjectivesTo assess coagulation in women with infertility before the start of an IVF cycle and during treatment to reveal the association between coagulation imbalance and IVF outcome.Patients/MethodsWe conducted a prospective cohort observational study including 125 participants who underwent fresh IVF cycles. Blood samples were collected at five time points: before IVF, one week after the start of controlled ovarian stimulation (COS), on the day of follicular puncture, on the day of embryo transfer (ET) and one week after ET. Coagulation tests (clotting times: activated partial thromboplastin time (APTT) and prothrombin; fibrinogen and D-dimer concentrations; thrombodynamics) were performed.ResultsWomen with an elevated clot growth velocity (>32.3 μm/min, detected by thrombodynamics) before IVF demonstrated a higher risk of negative IVF outcomes (adjusted RR = 1.38; 95% CI 1.28–1.49; P<0.001). During the procedure, we observed increases in prothrombin, fibrinogen and D-dimer concentrations, a slight shortening of APTT and a hypercoagulation shift in the thrombodynamics parameters. The hemostasis assay values during COS and after ET had no associations with IVF outcomes.ConclusionsHypercoagulation in the thrombodynamics before the start of IVF treatment was associated with negative IVF outcomes. After the start of COS, all tests demonstrated a hypercoagulation trend, but the hypercoagulation did not influence IVF outcome. This research is potentially beneficial for the application of thrombodynamics assay for monitoring hemostasis in infertile women prior to an IVF procedure with the goal of selecting a group requiring hemostasis correction to increase the chances of pregnancy.

Interleukin-3 Polymorphism is Associated with Miscarriage of Fresh in Vitro Fertilization Cycles.

The aim of this study was to examine the association between interleukin (IL) genes polymorphisms and in vitro fertilization (IVF) outcome. A prospective cohort analysis was performed at a Women’s Hospital IVF centre of 1015 female patients undergoing fresh non-donor IVF cycles. The effects of the following six single nucleotide polymorphisms (SNPs) in five IL genes on IVF outcomes were explored: IL-1α (rs1800587 C/T), IL-3 (rs40401 C/T), IL-6 (rs1800795 C/G), IL-15 (rs3806798 A/T), IL-18 (rs187238 C/G) and IL-18 (rs1946518 G/T). The main outcome measures included clinical pregnancy, embryo implantation, abortion and live birth rates. There were no statistically significant differences in clinical pregnancy, embryo implantation and live birth rates in the analysis of 1015 patients attempting their first cycle of IVF. Infertile women with IL-3 homozygous major genotype had a higher abortion rate than those with heterozygous and homozygous minor genotype (16.5% vs. 7.9%, P = 0.025). In conclusion, our results indicated that the IL-3 rs40401 polymorphism is associated with increased risk of abortion of IVF patients. Future studies with inclusion of other ethnic populations must be conducted to confirm the findings of this study.

Anti-Müllerian Hormone Gene Polymorphism is Associated with Clinical Pregnancy of Fresh IVF Cycles.

The aim of this study was to examine the effects of single-nucleotide polymorphisms (SNPs) in the anti-Müllerian hormone (AMH) and AMH type II receptor (AMHRII) genes on in vitro fertilization (IVF) outcomes. In this prospective cohort study, we genotyped the AMH 146 T > G, AMHRII −482 A > G and AMHRII IVS1 +149 T > A variants in 635 women undergoing their first cycle of controlled ovarian stimulation for IVF. DNA was extracted from the peripheral blood of all participants, and the SNPs were genotyped by real-time polymerase chain reaction. The distributions, frequencies of genes, and correlation with clinical pregnancy of IVF were analyzed. The AMH 146 T > G G/G genotype in women was associated with a lower clinical pregnancy rate (T/T: 55.0%, T/G: 51.8%, G/G: 40.0%; p < 0.05). Women with the AMH 146 T > G GG genotype were half as likely to have a clinical pregnancy compared with women with TT genotypes (OR = 0.55, 95% CI: 0.34–0.88, p = 0.014). With multivariate analysis, the AMH 146 T > G GG genotype remains as a significant independent factor to predict clinical pregnancy (p = 0.014). No significant difference was found between AMHRII polymorphisms and clinical pregnancy outcomes of IVF. In conclusion, our results show that AMH 146 T > G seems to be a susceptibility biomarker capable of predicting IVF pregnancy outcomes. Further studies should focus on the mechanism of these associations and the inclusion of other ethnic populations to confirm the findings of this study.

Transcutaneous electrical acupuncture point stimulation improves pregnancy outcomes in patients with recurrent implantation failure undergoing in vitro fertilisation and embryo transfer: a prospective, randomised trial.

To evaluate the effect of transcutaneous electrical acupuncture stimulation (TEAS) on pregnancy outcomes in patients with recurrent implantation failure (RIF) undergoing in vitro fertilisation (IVF). A total of 122 women with RIF undergoing fresh embryo transfer cycle IVF were randomly allocated to a TEAS or mock TEAS (MTEAS) group. Gonadotrophin therapy using a long protocol was provided in both groups. TEAS consisted of 30 min of stimulation (9-25 mA, 2 Hz) at SP6, CV3, CV4 and Zigong from day 5 of the ovarian stimulation cycle once every other day until the day of embryo transfer. The patients in the control group received MTEAS. Implantation, clinical pregnancy and live birth rates were compared. In the TEAS group, the implantation rate, clinical pregnancy rate and live birth rate (24.3%, 32.8% and 27.9%, respectively) were significantly higher than in the MTEAS group (12.1%, 16.4% and 13.1%, respectively). TEAS significantly improves the clinical outcomes of subsequent IVF cycles among women who have experienced RIF. ChiCTR-TRC-14004730.

The effects of acupuncture on the secondary outcomes of anxiety and quality of life for women undergoing IVF: A randomized controlled trial.

Studies have shown in vitro fertilization (IVF) treatment to have a significant impact on women's quality of life. In addition, anxiety is experienced during IVF treatment and prior to knowing the outcome from a treatment cycle. Although support services are available at many IVF clinics, the uptake of these opportunities may not be high. Acupuncture is used by women undertaking IVF treatment in the belief that it improves their reproductive outcomes, and some studies suggest that it may reduce anxiety. The objective of this study was to examine the effects of acupuncture compared with sham acupuncture on quality of life and anxiety for women undergoing an IVF cycle. A multicenter randomized controlled trial was conducted in Australia and New Zealand. Women were eligible if they were aged 18-42years, undergoing a fresh IVF cycle and not using acupuncture. Recruitment occurred between June 2011 and October 2015. Women were randomized to acupuncture or a sham acupuncture control group and three treatments were administered, the first treatment between day 6 and 8 of ovarian stimulation, and two treatments were given on the day of embryo transfer. The primary outcome was livebirth. Secondary outcomes included quality of life and anxiety, and were assessed at baseline, on the day of embryo transfer and 14weeks from trial entry. In all, 848 women were randomized to the trial, 608 women underwent an embryo transfer, of which 526 (86%) received all three treatments. Adjusted analysis found that women receiving acupuncture reported reduced anxiety following embryo transfer (mean difference [MD] -1.1, 95% CI -2.2 to -0.1, P=0.03). Unadjusted analysis of quality of life did not differ between groups following embryo transfer. Adjusted analyses by per protocol found a significant positive change for the acupuncture group for the general health MOS Short Form 36 (SF36) domain (MD 2.6, 95% CI 0.5-4.7, P=0.01) following embryo transfer. The benefit was not sustained at 14weeks (MD 0.1, 95% CI -2.7 to 2.9). Acupuncture may reduce anxiety at embryo transfer. Quality of life did not differ between the groups. Women experience reduced emotional well-being 3months following the IVF cycle, highlighting ongoing unmet psycho-social needs.

Comparative Study of Serum Progesterone Levels at the Time of Human Chorionic Gonadotropin Trigger and Ovum PickUp in Predicting Outcome in Fresh in vitro Fertilization Cycles.

Background:Studies have shown that premature rise of progesterone in controlled ovarian stimulation (COS) at the time of human chorionic gonadotropin (hCG) trigger is negatively associated with in vitro fertilization (IVF) outcome in fresh IVF cycles. Some authors have failed to demonstrate this. One large single centre retrospective cohort study has compared the pre and post hCG progesterone and observed that the ratio of the rise in progesterone could be a positive predictor. There is paucity of literature on this aspect.Aims and Objectives:To compare the serum progesterone at hCG trigger and ovum pick-up (OPU) with IVF outcome by estimating the respective paired hormone levels.Material and Methods:Serum progesterone levels at hCG trigger and OPU are compared retrospectively in 301 fresh IVF cycles with IVF outcome by long protocols with GnRH agonists for two years. Parametric and nonparametric testing of null hypothesis is performed. P value <0.05 is taken as significant.Results:There is no predictive association of IVF outcome with either progesterone levels. The ratio of rise in progesterone is strongly positively associated with IVF outcome (P < 0.001). However, after adjusting for confounders and modifiers the retrieved number of oocytes are positively associated with IVF outcome (P = 0.044).Conclusions:The ratio of rise in progesterone is significantly associated with number of oocytes retrieved which in turn is associated with successful IVF outcome in fresh cycles. Ratio of rise in progesterone seems to be therefore an indirect parameter for predicting successful IVF outcome in fresh cycles.

Patient experience in a randomized trial of a weekly progesterone vaginal ring versus a daily progesterone gel for luteal support after in vitro fertilization

To assess patient experience and convenience of using progesterone vaginal ring (VR) versus vaginal gel for women requiring luteal phase support during invitro fertilization (IVF). Post hoc analysis of a prospective, randomized, single-blind, multicenter, phase 3 clinical trial. Twenty-two U.S. IVF centers. Women undergoing IVF (N = 1,297). Randomization to weekly VR or daily gel the day after egg retrieval for up to 10weeks, with fresh embryo transfer IVF per site-specific procedures. Patient satisfaction questionnaire completed at final study visit. In the women who were taking ≥1 dose of either VR (n = 647) or gel (n = 650), >97% reported that learning to use the formulation, remembering to take it at the correct time, and using it as prescribed was "easy" or "somewhat easy." More VR than gel users reported noninterference with daily activity (93.3% vs. 74.7%, P<.001), sexual comfort (80.3% vs. 67.8%, P<.001), and sexual desire (73.8% vs. 61.8%, P<.001), as well as not being bothered during sexual intercourse (66.9% vs. 39.2%, P<.001). More gel than VR users reported no difficulty with application (97.4% vs. 80.9%, P<.001). Among women who had previously used progesterone during IVF, more VR users than gel users preferred their currently assigned treatment to their previous treatment (91.4% vs. 83.0%, P=.03). Weekly progesterone VR and daily progesterone gel were easy to use, with limited impact on quality of life. Overall, the VR appeared to interfere less with daily life, social activities, and sexual activity although the gel was less difficult or stressful to apply. NCT00615251.

External validation of a prediction model to select the best day-three embryo for transfer in in vitro fertilization or intracytoplasmatic sperm injection procedures

To evaluate the multivariate embryo selection model by van Loendersloot etal. (2014) (VL) in a different geographical context. This is a retrospective external validation study of a 5-year cohort of women undergoing invitro fertilization or intracytoplasmatic sperm injection. Two outpatient fertility clinics. A total of 1,197 women who underwent 1,610 fresh invitro fertilization or intracytoplasmatic sperm injection cycles with single embryo transfer were included. None. The area under the receiver operating characteristics curve for diagnostic efficacy was used to assess the discriminative value of the model. Calibration for testing the validity of the VL model was performed using the Hosmer-Lemeshow goodness-of-fit test and a calibration plot. Three hundred thirty-three patients (21%) achieved a viable pregnancy of at least 11weeks. The area under the receiver operating characteristics curve using the VL model was 0.68. No significant difference between the predicted implantation rate and the observed implantation rates was showed using the Hosmer-Lemeshow (X2= 6.70). The calibration plot showed an intercept of the regression line of 0.34 and the estimated slope was 0.72. The investigated VL model was able to distinguish between higher and lower implantation potential of embryos in our clinical setting.

Time-Varying Exposure to Fine Particulate Matter and Black Carbon and Outcomes of In Vitro Fertilization

Background/Aim: Air pollution has been linked to decreased fertility yet the specific mechanisms and windows of susceptibility remain unclear. We examined the association between time-varying exposure to fine particular matter (PM2.5) and black carbon (BC) on in vitro fertilization (IVF) outcomes.Methods: We included 356 women (537 cycles) for the PM2.5 analysis (2005-2016) and 234 women (343 cycles) for the BC analysis (2005-2011) enrolled in a prospective cohort study of couples undergoing a fresh IVF cycle in New England. We used spatiotemporal models to estimate daily PM2.5 and BC exposures (based on residential address) throughout the IVF cycle. Multivariable discrete time Cox proportional hazards models with 3 time periods (cycle initiation to embryo transfer (ET), ET to implantation, implantation to live birth) were used to estimate odds ratios (OR) and 95% confidence intervals (CI) of failing at IVF. Time-dependent interactions between exposures and IVF time windows were used to identify vulnerable periods.Results: An interquartile range (IQR) increase in PM2.5 (3 µg/m3) and BC (0.2 µg/m3) throughout the IVF cycle was associated with a non-significant, elevated odds of failing at IVF prior to live birth (OR&amp;#61;1.15, 95% CI 0.96, 1.38 for PM2.5 and OR&amp;#61;1.25, 95% CI 0.87, 1.78 for BC). The effect of PM2.5 and BC exposure on IVF failure was strongest during the earliest windows of IVF. Specifically, an IQR increase in PM2.5 and BC exposure was associated with 1.30 (95% CI 1.01, 1.67) and 1.55 (95% CI 1.15, 2.10) times the odds of failing prior to ET, 1.07 (95% CI 0.82, 1.39) and 1.18 (0.77, 1.80) times the odds of failing between ET and implantation, and 1.05 (0.59, 1.88) and 0.82 (0.43, 1.59) times the odds of failing between implantation and live birth.Conclusion: Increased exposure to PM2.5 and BC during ovarian stimulation is associated with higher odds of IVF failure prior to ET. Acute exposure to PM2.5 and BC may have adverse effects on oocyte development.

Freezing of all embryos in in vitro fertilization is beneficial in high responders, but not intermediate and low responders: an analysis of 82,935 cycles from the Society for Assisted Reproductive Technology registry

To assess invitro fertilization (IVF) and pregnancy outcomes in patients having their first frozen embryo transfer (FET) after a freeze-all cycle versus similar patients having their first fresh embryo transfer (ET). Retrospective cohort study. None. Registry data on 82,935 patient cycles from the Society for Assisted Reproductive Technology (SART). All first fresh autologous IVF cycles were analyzed and compared to first FET cycles after a freeze-all first IVF stimulation. The cycles were subdivided into cohorts based upon the number of oocytes retrieved (OR): 1-5 (low), 6-14 (intermediate), and 15+ (high responders). Univariate analyses were performed on cycle characteristics, and multivariable regression analyses were performed on outcome data. Clinical pregnancy rate (CPR) and live-birth rate (LBR). Of the 82,935 cycles analyzed, 69,102 patients had their first fresh transfer, and 13,833 had a first FET. High responders were found to have a higher CPR and LBR in the FET cycles compared with the fresh ET cycles (61.5 vs. 57.4%; 52.0 vs. 48.9%). In intermediate responders, both CPR and LBR were higher after fresh ET compared with FET (49.6% vs. 44.2%; 41.2 vs. 35.3%). Similarly, in low responders, CPR and LBR were higher after fresh compared with FET (33.2% vs. 15.9%; 25.9% vs. 11.5%). A freeze-all strategy is beneficial in high responders but not in intermediate or low responders, thus refuting the idea that freeze-all cycles are preferable for all patients.

Superovulation alters the expression of endometrial genes critical to tissue remodeling and placentation.

Epidemiologic data suggest that in vitro fertilization (IVF) is associated with an increased risk of disorders of placentation including preeclampsia and fetal growth restriction. Specifically, studies have demonstrated that singleton pregnancies conceived following a fresh embryo transfer are at an increased risk of delivering an infant with low birth weight compared to those conceived following a frozen embryo transfer. The mechanism responsible for this association remains unclear. Procedures utilized in IVF have also been linked with epigenetic changes and gene expression changes in both fetal and maternal tissues. Data suggest that modifications in the maternal endometrium can lead to disordered trophoblast invasion and placentation. This study examines the effect of ovarian stimulation on endometrial gene expression and DNA methylation during the window of implantation to examine potential pathways playing a role in the adverse outcomes associated with IVF. Endometrial biopsies were obtained from oocyte donors and age-matched naturally cycling women 11days following oocyte retrieval in donors or 12days following luteinizing hormone (LH) surge in naturally cycling women. Global gene expression was analyzed via Affymetrix Human Gene 1.1 ST array and confirmed with RT-qPCR. DNA methylation was assessed with the Infinium DNA methylation 450K BeadChip. Analysis of endometrial gene expression from 23 women (11 oocyte donors and 12 controls) demonstrated 165 genes with a greater than twofold change in expression between donors and controls. While there were 785 genes with significant differential methylation in the endometrium of donors when compared with control subjects, none of the genes with altered expression showed significant changes in DNA methylation. Analysis of the differentially expressed genes showed enrichment for genes involved in endometrial remodeling including PLAT, HSPE2, MMP2, and TIMP1. Validation studies using RT-qPCR found a 73% reduction in expression of heparanase 2 (HSPE2) an enzyme associated with both angiogenesis and cell invasion, a greater than twofold increase in tissue-type plasminogen activator (PLAT), a serine protease participating in matrix degradation, and a 70% increase in MMP2, a gelatinase involved in collagen and fibronectin breakdown. Superovulation alters expression of genes critical to endometrial remodeling during early implantation. Such changes could lead to altered trophoblast migration and impaired endovascular invasion. These findings offer a potential mechanism for the adverse perinatal outcomes observed following embryo transfer during fresh IVF cycles.

Effect of Acupuncture vs Sham Acupuncture on Live Births Among Women Undergoing In Vitro Fertilization

Acupuncture is widely used by women undergoing in vitro fertilization (IVF), although the evidence for efficacy is conflicting. To determine the efficacy of acupuncture compared with a sham acupuncture control performed during IVF on live births. A single-blind, parallel-group randomized clinical trial including 848 women undergoing a fresh IVF cycle was conducted at 16 IVF centers in Australia and New Zealand between June 29, 2011, and October 23, 2015, with 10 months of pregnancy follow-up until August 2016. Women received either acupuncture (n = 424) or a sham acupuncture control (n = 424). The first treatment was administered between days 6 to 8 of follicle stimulation, and 2 treatments were administered prior to and following embryo transfer. The sham control used a noninvasive needle placed away from the true acupuncture points. The primary outcome was live birth, defined as the delivery of 1 or more living infants at greater than 20 weeks' gestation or birth weight of at least 400 g. Among 848 randomized women, 24 withdrew consent, 824 were included in the study (mean [SD] age, 35.4 [4.3] years); 371 [45.0%] had undergone more than 2 previous IVF cycles), 607 proceeded to an embryo transfer, and 809 (98.2%) had data available on live birth outcomes. Live births occurred among 74 of 405 women (18.3%) receiving acupuncture compared with 72 of 404 women (17.8%) receiving sham control (risk difference, 0.5% [95% CI, -4.9% to 5.8%]; relative risk, 1.02 [95% CI, 0.76 to 1.38]). Among women undergoing IVF, administration of acupuncture vs sham acupuncture at the time of ovarian stimulation and embryo transfer resulted in no significant difference in live birth rates. These findings do not support the use of acupuncture to improve the rate of live births among women undergoing IVF. anzctr.org.au Identifier: ACTRN12611000226909.

Geographical Variability in the Outcome of Donor egg IVF - Analysis of SART Data on 71,182 Donor egg IVF Cycles

An earlier analysis of abbreviated SART (Society for Reproductive Technology) data for 2007 (n=443) had identified geographical heterogeneity in live birth (LB) rates in the United States resulting from donor egg IVF (In- Vitro Fertilization), and these observations allowed for positing on ecological underpinnings to IVF success. We herein aimed to determine the validity of geographical differences in LB following donor egg IVF through use of a larger study sample of both fresh and frozen embryo transfer donor egg IVF cycles (n=71, 182), after adjusting for a number of variables that are recognized to impact cycle success. Consistent with the earlier observations, geographical location of the IVF clinic emerged as an independent predictor of LB following donor egg IVF; also, highest LB rates with donor egg IVF following both fresh ET and with FET were noted at clinics located in the W compared to centers located in NE of United States (on analyses adjusting for recipient’s age, body mass index (BMI), race, number of embryos transferred (ET), and use of assisted hatching (AH) the likelihood for donor egg IVF related LB for clinics in W compared to the NE:OR 1.28, 95% CI 1.20-1.37 for fresh ET and OR: 1.18, 95% CI: 1.06 -1.30 for FET). This study reaffirms that success of donor egg IVF is susceptible to ecological influences that merit further investigation.

Cycle day, estrogen level, and lead follicle size: analysis of 27,790 in vitro fertilization cycles to determine optimal start criteria for gonadotropin-releasing hormone antagonist

To determine the optimal criteria at which to start GnRH antagonists during controlled ovarian hyperstimulation (COH) for invitro fertilization (IVF). Retrospective clinical cohort. IVF clinics. Women undergoing fresh autologous IVF using GnRH antagonist for ovulation suppression during COH. Measurement of lead follicle size, E2 level, and cycle day of stimulation on day of antagonist initiation. Clinical pregnancy rate (PR). The highest clinical PR was achieved when the antagonist was started when a lead follicle reached 14-15.9mm in size (mean clinical PR 21.3; 95% confidence interval [CI] 19.3, 23.6) on cycle day 6 (mean clinical PR 22.2; 95% CI 17, 28.4), or when the E2 level was between 500 and 599 pg/mL (mean clinical PR 25.4; 95% CI 19.5, 32.4). Starting antagonists when the E2 level was <300 or >1,100 pg/mL reduced the odds of clinical pregnancy by 40% (odds ratio 0.60, 95% CI 0.5, 0.7). Cycle day, E2 level, and follicle size at time of antagonist start are all independent predictors of a clinical pregnancy after IVF. Initiating antagonists when the E2 level is extremely low (<300 pg/mL) or extremely high (>1,100 pg/mL) significantly reduces the odds of pregnancy.

Intracytoplasmic sperm injection use in states with and without insurance coverage mandates for infertility treatment, United States, 2000–2015

To compare indications and trends in intracytoplasmic sperm injection (ICSI) use for invitro fertilization (IVF) cycles among residents of states with and without insurance mandates for IVF coverage. Cross-sectional analysis of the National Assisted Reproductive Technology Surveillance System from 2011 to 2015 for the main outcome and from 2000 to 2015 for trends. IVF cycles performed in U.S. fertility clinics. Fresh IVF cycles. Residency in a state with an insurance mandate for IVF (n = 8 states) versus no mandate (n = 43 states, including DC). ICSI use by insurance coverage mandate status stratified by male-factor infertility diagnosis. During 2000-2015, there were 1,356,377 fresh IVF cycles, of which 25.8% (n = 350,344) were performed for residents of states with an insurance coverage mandate for IVF. ICSI use increased significantly during 2000-2015 in states both with and without a mandate; however, for non-male-factor infertility cycles, the percentage increase in ICSI use was greater among nonmandate states (34.6% in 2000 to 73.9% in 2015) versus mandate states (39.5% in 2000 to 63.5% in 2015). For male-factor infertility cycles, this percentage increase was ∼7.3% regardless of residency in a state with an insurance mandate for IVF. From 2011 to 2015, ICSI use was lower in mandate versus nonmandate states, both for cycles with (91.5% vs. 94.5%), and without (60.3% vs. 70.9%) male-factor infertility. Mandates for IVF coverage were associated with lower ICSI use for non-male-factor infertility cycles.