Factors associated with vitrification-warming survival in 6167 euploid blastocysts.

PURPOSE: To understand the clinical factors associated with embryo survival after vitrification in a cohort of human blastocysts screened by preimplantation genetic testing for aneuploidy (PGT-A). METHODS: Patient demographic, embryo, and cycle characteristics associated with failed euploid blastocyst survival were compared in a cohort of women (n = 6167) who underwent IVF-PGT-A. RESULTS: Compared to those that survived warming, vitrified euploid embryos that failed to survive after warming came from IVF cycles with significantly higher estradiol levels at time of surge (2754.8 ± 1390.2 vs. 2523.1 ± 1190.6 pg/mL, p = 0.03), number of oocytes retrieved (19.6 ± 10.7 vs. 17.5 ± 9.8, p = 0.005), and basal antral follicle count (BAFC) (15.3 ± 8.5 vs. 13.9 ± 7.2, p = 0.05). Euploid embryos were less likely to survive warming if they came from cycles before 2015 (24.6% vs. 13.2%, p < 0.001), were cryopreserved on day 7 versus day 5 or 6 (9.1% vs. 3.0%, p < 0.001), underwent two trophectoderm biopsies (6.9% vs. 2.3%, p < 0.001), had a grade C inner cell mass (15.4% vs. 7.7%, p < 0.001), or were fully hatched (41.1% vs. 12.2%, p < 0.001). In the multivariate model, which controlled for relevant confounders, the association between decreased survival and increased BAFC, year of IVF cycle, double trophectoderm biopsy, and fully hatched blastocysts remained statistically significant. CONCLUSION: Euploid embryos that are fully hatched at time of vitrification, come from patients with high ovarian reserve, or require repeat trophectoderm biopsy are less likely to survive vitrification-warming. Our results provide a framework for reproductive counseling and offer realistic expectations to patients about the number of embryos needed to achieve family building goals.

Infertile patients with inflammatory bowel disease have comparable in vitro fertilization clinical outcomes to the general infertile population.

To assess clinical outcomes of females diagnosed with Inflammatory Bowel Disease (IBD) and infertility, which underwent in vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy. (PGT-A). Retrospective cohort study comparing clinical outcomes of patients with Inflammatory bowel disease who underwent IVF with PGT-A with a subsequent euploid single embryo transfer (SET) against a matched control group. Thirty-eight patients with an IBD diagnosis were compared to 114 controls. There was no significant difference in cycle outcomes among IBD and Control cohorts [implantation rate (71.0% vs. 78.0% (p = .68)], clinical pregnancy rate [50.0% vs. 60.5% (p = .68)], live birth [62.9% vs. 73.0% (p = .06)] multiple pregnancy rate [0% vs. 1.1% (p = .25)] and clinical pregnancy loss rate [10.5% vs. 5.7% (p = .54)]. An IBD diagnosis was not found to significantly modify the odds of implantation [adjusted OR = 0.6 (95% CI -1.2 to 0.8)]. Additionally, the odds of implantation in patients with IBD were not altered by having ulcerative colitis or Crohn's disease diagnosis. (OR = 0.4 95% CI 0.1-1.9). Patients diagnosed with IBD who undergo a SET have clinical outcomes comparable to the general infertile population. Patients and physicians can be reassured that an IBD diagnosis does not impair IVF treatment outcomes.SYNOPSISInfertile patients with inflammatory bowel disease who utilized a single, euploid blastocyst transfer had IVF success rates comparable to the general infertile population.

The correlation between morphology and implantation of euploid human blastocysts.

RESEARCH QUESTION: Does the composite morphology score or a particular developmental component (expansion stage, inner cell mass [ICM] or trophectoderm [TE]) of euploid blastocysts undergoing single frozen embryo transfer (FET) impact ongoing pregnancy/live birth (OP/LB) rates? DESIGN: Retrospective cohort study including a total of 2236 embryos from 1629 patients who underwent single euploid FET between 2012 and 2017. RESULTS: Embryos with an ICM grade of A compared with C had a higher OP/LB rate (55.6% versus 32.3%, P < 0.001). Blastocysts with a TE grade of A or B compared with C had a higher likelihood of OP/LB (A versus C: odds ratio [OR] 1.6, 99% confidence interval [CI] 1.1-2.3, B versus C: OR 1.5, 99% CI 1.1-2.1), and blastocysts with a developmental stage of 4 or 5 compared with 6 had higher odds of OP/LB (4 versus 6: OR 1.6, 99% CI 1.2-2.2, 5 versus 6: OR 1.6, 99% CI 1.2-2.3). CONCLUSIONS: Among euploid embryos, ICM morphology is the best predictor of sustained implantation; however, a composite score may provide additional guidance. While there is a known benefit in genomic screening prior to embryo selection, morphology provides individualized, prognostic information about implantation potential.

Optimal Interval of Time from Operative Hysteroscopy to Embryo Transfer in an In Vitro Fertilization Cycle.

STUDY OBJECTIVE: Data are limited regarding optimal timing between operative hysteroscopy and embryo transfer (ET). This study aimed to assess whether the time interval from operative hysteroscopy to ET affects implantation and clinical pregnancy rates. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Private academic center. PATIENTS: All patients who had operative hysteroscopy followed by a day 5 ET from 2012 to 2017. INTERVENTION: Interval of time from operative hysteroscopy to ET. MEASUREMENTS AND MAIN RESULTS: The interval of time from hysteroscopy to ET was calculated, and linear regression analyses were performed to assess the impact on clinical outcome. A subanalysis of patients who underwent subsequent single, euploid, frozen ET(s) was performed. A total of 318 patients were included. Indications for hysteroscopy included polypectomy (n = 205), myomectomy (n = 36), lysis of adhesions (n = 46), septum resection (n = 19), and retained products of conception (n = 12). The mean interval of time from hysteroscopy to ET was 138.4 ± 162.7 days (range, 20-1390). There was no significant difference in mean interval of time between procedure and subsequent ET when comparing patients who achieved and did not achieve implantation. Patients stratified by interval of time from operative hysteroscopy to ET had similar clinical outcomes. The time interval from hysteroscopy had no impact on odds of implantation (odds ratio [OR], 1.001; 95% confidence interval [CI], .999-1.002; p = .49), ongoing pregnancy (OR, 1.001; 95% CI, .999-1.002; p = .42), or early pregnancy loss (OR, .997; 95% CI, .994-1.000; p = .07) (adjusted for oocyte age, recipient age, endometrial thickness, use of preimplantation genetic testing, use of donor egg, fresh vs frozen ET, ET count). Similar results were observed in the subanalysis restricted to euploid single frozen ETs from autologous cycles. CONCLUSION: The time interval from operative hysteroscopy to subsequent ET does not impact the likelihood of successful clinical outcome. Patients who have undergone operative hysteroscopy do not need to delay fertility treatment.

Blastocyst vitrification, cryostorage and warming does not affect live birth rate, infant birth weight or timing of delivery.

RESEARCH QUESTION: Does vitrification and warming affect live birth rate, infant birth weight and timing of delivery? DESIGN: Retrospective, cohort study comparing outcomes of donor oocyte recipient fresh (n = 25) versus vitrified (n = 86) euploid blastocyst transfers; donor oocyte recipient singleton live births from fresh (n = 100) versus vitrified (n = 102) single embryo transfers (SET); and autologous vitrified euploid SET (n = 1760) (cryostored 21-1671 days). RESULTS: Group 1: fresh and vitrified-warmed blastocysts had similar live birth (OR 1.7; 95% CI 0.5 to 5.9), implantation (OR 0.9; 95% CI 0.2 to 3.9), clinical pregnancy (OR 3.4; 95% CI 0.9 to 13.0) and pregnancy loss (OR 1.2; 95% CI 0.98 to 1.4); group 2: low birth weight (OR 0.44; 95% CI 0.1 to 1.6) and preterm delivery (0.99; 95% CI 0.4 to 2.3) rates were similar in fresh and vitrified-warmed blastocyst transfers; group 3: cryostorage duration did not affect live birth (OR 1.0; 95% CI 1.0 to 1.0), implantation (OR 1.0; 95% CI 0.99 to 1.01), clinical pregnancy (OR 1.0; 95% CI 1.0 to 1.0]), pregnancy loss (OR 0.99; 95% CI 1.0 to 1.0), birth weight (ß = -15.7) or gestational age at delivery (ß = -0.996). CONCLUSIONS: Vitrification and cryostorage (up to 4 years) are safe and effective practices that do not significantly affect clinical outcome after embryo transfer.

The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response.

OBJECTIVE: Controlled ovarian hyperstimulation (COH) promotes multifollicular growth, increasing the chance of obtaining euploid embryos that will successfully implant. Whether aneuploidy is increased from COH with exogenous gonadotropins interfering with natural selection of dominant follicles is a concern. This study evaluates the association between gonadotropin exposure and aneuploidy. METHODS: This is a retrospective cohort study of 828 patients that underwent 1122 IVF cycles involving controlled ovarian stimulation and trophectoderm biopsy for preimplantation genetic screening (PGS), from 2010 to 2015. Polymerase chain reaction (PCR) was used to assess aneuploidy. Kruskal-Wallis tests and logistic regression with generalized estimating equations (GEEs) were used for data analysis. RESULTS: Overall, after controlling for patient age, ovarian reserve, stimulation protocol, days of stimulation, and diagnoses, there was no significant association between cumulative gonadotropin (GND) dose and the odds of aneuploidy (adjusted OR = 1.049, p = 0.232). Similarly, in cycles where patients did not require COH beyond cycle day 12, there was no significant association between cumulative gonadotropin dose and the odds of aneuploidy (adjusted OR = 0.909, p = 0.148). However, in cases where patients were stimulated past cycle day 12, there was a significant increase in the odds of aneuploidy (adjusted OR = 1.20, 95% CI 1.125-1.282, p < 0.0001) with increasing cumulative gonadotropin dose, with a small effect size (Cohen's d = 0.10, 95% CI 0.08-0.12). In this cohort, there was a 16.4% increase in the odds of aneuploidy for each 1000-u increase in cumulative GND exposure (adjusted OR = 1.164, p = 0.002). When the analysis was restricted to low responders (peak estradiol <500 pg/mL or <4 mature follicles achieved; there was no significant association between gonadotropin dose and aneuploidy (adjusted OR = 1.12, 95% CI 0.982-1.28, p = 0.09), regardless of the duration of COH required to reach vaginal oocyte retrieval. CONCLUSION: The degree of exposure to exogenous gonadotropins did not significantly modify the likelihood of aneuploidy in patients with a normal ovarian response to stimulation (not requiring COH beyond cycle day 12). Patients requiring prolonged COH were demonstrated to have elevated odds of aneuploidy with increasing cumulative gonadotropin dose. This finding may reflect an increased tendency towards oocyte and embryonic aneuploidy in patients with a diminished response to gonadotropin stimulation.

In-vitro maturation of germinal vesicle and metaphase I eggs prior to cryopreservation optimizes reproductive potential in patients undergoing fertility preservation.

PURPOSE OF REVIEW: To evaluate current and previous findings related to a timely implementation of in-vitro maturation (IVM) of germinal vesicle, metaphase I and metaphase II oocytes with an optimal cryopreservation to determine whether IVM should be attempted prior to (fresh IVM) or IVM after cryopreservation (postthaw IVM). Mitochondrion, chromatin and spindle formation in both groups were interpreted from referenced studies to establish best management of all oocytes. RECENT FINDINGS: The postthaw survival of germinal vesicle, metaphase I, fresh IVM-metaphase II and control metaphase II oocytes did not differ significantly [83.3% (n=9), 86.7% (n=12), 83% (n=57) and 86% (n=68), respectively]. Overall, combined survival and maturation were significantly higher (P<0.05) in the fresh IVM group at 63.8% (44 of 69) compared with the postthaw IVM group at 33.3% (nine of 27). SUMMARY: Conservation of retrieved immature oocytes after vaginal oocyte retrieval has become a major concern for patients, as they strive to maximize the reproductive viability of all oocytes obtained during treatment. Oocyte cryopreservation is important for patients at risk of ovarian cancer, elective fertility preservation and potentially for ovum donation. The superior maturation rate of germinal vesicle and metaphase I oocytes in the fresh IVM vs. postthaw groups provides strong impetus to mature oocytes to the metaphase II stage prior to cryopreservation.

Association of Myomectomy With Anti-Müllerian Hormone Levels and Ovarian Reserve.

OBJECTIVE: To assess whether open and minimally invasive myomectomy are associated with changes in postoperative ovarian reserve as measured by serum anti-müllerian hormone (AMH) level. METHODS: This prospective cohort study included patients who were undergoing open abdominal myomectomy that used a tourniquet or minimally invasive (robot-assisted or laparoscopic) myomectomy that used vasopressin. Serum AMH levels were collected before the procedure and at 2 weeks, 3 months, and 6 months after surgery. The mean change in AMH level at each postsurgery timepoint was compared with baseline. The effect of surgical route on the change in AMH level at each timepoint was assessed by using multivariable linear regression. A subanalysis evaluated postoperative changes in AMH levels among the open myomectomy and minimally invasive myomectomy groups individually. RESULTS: The study included 111 patients (mean age 37.9±4.7 years), of whom 65 underwent open myomectomy and 46 underwent minimally invasive myomectomy. Eighty-seven patients contributed follow-up data. Serum AMH levels declined significantly at 2 weeks postsurgery (mean change -0.30 ng/mL, 95% CI -0.48 to -0.120 ng/mL, P=.002). No difference was observed at 3 months or 6 months postsurgery. On multiple linear regression, open myomectomy was significantly associated with a decline in AMH level at 2 weeks postsurgery (open myomectomy vs minimally invasive myomectomy: ß=-0.63±0.22 ng/mL, P=.007) but not at 3 months or 6 months. Subanalysis revealed a significant decline in mean serum AMH levels in the open myomectomy group at 2 weeks (mean change -0.46 ng/mL, 95% CI -0.69 to -0.25 ng/mL, P<.001) postsurgery but not at three or 6 months. In the minimally invasive myomectomy group, no significant differences in mean AMH levels were detected between baseline and any postoperative timepoint. CONCLUSION: Myomectomy is associated with a transient decline in AMH levels in the immediate postoperative period, particularly after open surgery in which a tourniquet is used. Anti-müllerian hormone levels returned to baseline by 3 months after surgery, indicating that myomectomy is not associated with a long-term effect on ovarian reserve, even with the use of a tourniquet to decrease blood loss. FUNDING SOURCE: This study was funded in part by a Roche Diagnostics Investigator-Initiated Study Grant.

Endometrial preparation before the transfer of single, vitrified-warmed, euploid blastocysts: does the duration of estradiol treatment influence clinical outcome?

OBJECTIVE: To investigate whether the duration of estrogen administration before euploid embryo transfer affects clinical outcome. DESIGN: Retrospective cohort study. SETTING: Private, academic fertility center. PATIENT(S): Patients (n = 1,439) undergoing autologous freeze-only in vitro fertilization with preimplantation genetic testing (PGT) followed by endometrial preparation with estrogen and progesterone in a frozen, euploid blastocyst transfer cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome was live birth, and secondary outcomes included implantation, clinical pregnancy, early pregnancy loss, live birth, infant birthweight, low birth weight, infant gestational age at delivery, and preterm birth. RESULT(S): The duration of estrogen administration (mean: 17.5 ± 2.9 days; range: 10-36 days) before frozen embryo transfer did not impact implantation (odds ratio [OR] 0.99; 95% confidence interval [CI], 0.95-1.03), clinical pregnancy (OR 0.98; 95% CI, 0.94-1.01), early pregnancy loss (OR 1.03; 95% CI, 0.95-1.12), or live birth (OR 0.99; 95% CI, 0.95-1.03). The duration of estrogen exposure did not affect infant birthweight (in grams) (ß= -10.65 ± 8.91) or the odds of low birth weight (OR 0.87; 95% CI, 0.68-1.13). For every additional day of estrogen administration, we observed a reduction in gestational age at delivery (in weeks) (ß= -0.07 ± 0.03), but the odds of preterm delivery were not affected (OR 1.05; 95% CI, 0.95-1.17). CONCLUSION(S): Variation in the duration of estradiol supplementation before progesterone initiation does not impact frozen, euploid blastocyst transfer outcome. The duration of estrogen administration was inversely correlated with gestational age at delivery, but this did not translate into an increase in preterm delivery. Further studies are required on the downstream effects of endometrial preparation on the placental-endometrium interface.

Effect of oocyte donation on pregnancy outcomes in in vitro fertilization twin gestations.

OBJECTIVE: To estimate the effect of oocyte donation on pregnancy outcomes in patients with twin pregnancies conceived via IVF. DESIGN: Retrospective cohort study. SETTING: Patients with IVF twin pregnancies delivered by one maternal-fetal medicine practice from 2005 to 2013. PATIENT(S): Fifty-six patients with IVF twin pregnancies who had oocyte donation and 56 age-matched controls with IVF twin pregnancies who used autologous oocytes. We excluded women aged >50 years because there were no age-matched controls aged >50 years using autologous oocytes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gestational hypertension, pre-eclampsia. RESULT(S): The baseline characteristics were similar between the groups, including maternal age, race, parity, chorionicity, and comorbidities. The mean (±SD) age was 43.0 ± 6.0 vs. 41.9 ± 1.7 years. There were no differences in outcomes between the groups in regard to preterm birth, birth weight, or gestational diabetes. There was a greater incidence of gestational hypertension (32.1% vs. 13.0%) and pre-eclampsia (28.3% vs. 13.0%) in the group that underwent IVF with donor oocytes. CONCLUSION(S): In patients who conceive twin pregnancies using IVF, oocyte donation increases the risk of gestational hypertension and pre-eclampsia. However, this did not translate into increased rates of preterm birth or low birth weight. Patients who require oocyte donation should be carefully counseled regarding the increased risk for pre-eclampsia and gestational hypertension but should be reassured that oocyte donation does not seem to lead to other adverse outcomes.

Oxidative stress and antioxidants for idiopathic oligoasthenoteratospermia: Is it justified?

Oxidative stress contributes to defective spermatogenesis and the poor quality of sperm associated with idiopathic male factor infertility. The aim of this study was to review the current literature on the effects of various types of antioxidant supplements in patients to improve fertilization and pregnancy rates in subfertile males with idiopathic oligoasthenoteratozoospermia (iOAT). Review of recent publications through PubMed and the Cochrane database. Oxidative stress is implicated in impaired spermatogenesis leading to the poor semen parameters and increased DNA damage and apoptosis in iOAT. Strategies to modulate the level of oxidative stress within the male reproductive tract include the use of oral antioxidant compounds to reinforce the body's defence against oxidative damage. In our evaluation, carnitines were considered the most established pharmacotherapeutic agent to treat iOAT, as evidence and data concerning carnitine supplementation have been shown to be most consistent and relevant to the population of interest. Other therapies, such as combined vitamin E and C therapy, are still considered controversial as vitamin C can act as a pro-oxidant in certain instances and the results of randomized controlled trials have failed to show significant benefit to sperm parameters and pregnancy rates. There is a need for further investigation with randomized controlled studies to confirm the efficacy and safety of antioxidant supplementation in the medical treatment of idiopathic male infertility as well as the need to determine the dosage required to improve semen parameters, fertilization rates and pregnancy outcomes in iOAT.

The role of antioxidant therapy in the treatment of male infertility.

Oxidative stress contributes to defective spermatogenesis leading to male factor infertility. The aim of this study was to review the current literature on the effects of various antioxidants to improve fertilisation and pregnancy rates. The sources of literature were Pubmed and the Cochrane data base. Reviewing the current literature revealed that Carnitines and vitamin C and E have been clearly shown to be effective by many well-conducted studies and may be considered as a first line treatment. The efficacy of antioxidants, such as glutathione, selenium and coenzyme Q10 has been demonstrated by few, but well-performed studies, and may be considered second line treatment. There is, however, a need for further investigation with randomised controlled studies to confirm the efficacy and safety of antioxidant supplementation in the medical treatment of idiopathic male infertility as well as the need to determine the ideal dose of each compound to improve semen parameters, fertilisation rates and pregnancy outcomes.

Lipid peroxidation and antioxidant status in preeclampsia: a systematic review.

BACKGROUND: Preeclampsia is characterized by increased lipid peroxidation and diminished antioxidant capacity; however, there is no consensus as to the extent of these conditions. OBJECTIVE: To assess the association of lipid peroxidation and antioxidant status with preeclampsia quantitatively using meta-analysis. DESIGN: Systematic review and meta-analysis. SEARCH STRATEGY: Studies were identified by performing an extensive search using BIOSIS (1986-2007), EMBASE (1986-2007), Medline (1986-2007), and the Cochrane database. DATA ANALYSIS: Standardized mean differences (SMD) with 95% confidence intervals (CI) were used in the meta-analysis and sources of heterogeneity were examined. MAIN RESULTS: In the included studies, the overall SMD was a 1.21 nmol/mL increase in serum malondialdehyde in preeclampsia cases compared to controls (95% CI: 0.76, 1.66). Overall, total serum thiobarbituric acid-reactive substances SMD were 1.62 nmol/mL greater in cases than in controls (95% CI: 0.27, 2.96). The overall estimate SMD for serum vitamin E was 1.12 nmol/mL less in cases than controls (95% CI: -1.77, -0.48) and vitamin C SMD overall estimate was -0.53 (95%CI: -1.03, -0.02), significantly lower in cases compared with controls. The overall SMD for erythrocyte superoxide dismutase was -2.37 (95% CI: -4.76, 0.03), a marginally significant decrease in cases versus controls. CONCLUSIONS: Established preeclampsia is associated with increased concentrations of oxidative stress markers including lipid peroxidation products, and a reduction in antioxidant concentrations. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this educational activity, the participant should be better able to describe the pattern of oxidative stress markers associated with preeclampsia, and interpret the available literature as it relates to oxidative stress and preeclampsia.

Redox considerations in female reproductive function and assisted reproduction: from molecular mechanisms to health implications.

Physiological levels of reactive oxygen species (ROS) play an important regulatory role through various signaling transduction pathways in folliculogenesis, oocyte maturation, endometrial cycle, luteolysis, implantation, embryogenesis, and pregnancy. Persistent and elevated generation of ROS leads to a disturbance of redox potential that in turn causes oxidative stress (OS). Our literature review captures the role of ROS in modulating a range of physiological functions and pathological processes affecting the female reproductive life span and even thereafter (i.e., menopause). The role of OS in female reproduction is becoming increasingly important, as recent evidence suggest that it plays a part in conditions such as polycystic ovarian disease, endometriosis, spontaneous abortions, preeclampsia, hydatidiform mole, embryopathies, preterm labor, and intrauterine growth retardation. OS has been implicated in different reproductive scenarios and is detrimental to both natural and assisted fertility. Many extrinsic and intrinsic conditions exist in assisted reproduction settings that can be tailored to reduce the toxic effects of ROS. Laboratory personnel should avoid procedures that are known to be deleterious, especially when safer procedures that can prevent OS are available. Although antioxidants such as folate, zinc, and thiols may help enhance fertility, the available data are contentious and must be evaluated in controlled studies with larger populations.