The impact of microfluidics sperm processing on blastocyst euploidy rates compared with density gradient centrifugation: a sibling oocyte double-blinded prospective randomized clinical trial.

OBJECTIVE: To compare the euploidy rates among blastocysts created from sibling oocytes injected with sperm and processed using microfluidics or density gradient centrifugation. DESIGN: Sibling oocyte randomized controlled trial. SETTING: Single university-affiliated infertility practice. PATIENTS: A total of 106 patients aged 18-42 years undergoing fresh in vitro fertilization treatment cycles with preimplantation genetic testing between January 2021 and April 2022 contributed 1,442 mature oocytes, which were injected with sperm and processed using microfluidics or density gradient centrifugation. INTERVENTION(S): The sperm sample is divided and processed using a microfluidics device and density gradient centrifugation for injection into sibling oocytes. MAIN OUTCOME MEASURE(S): The primary outcome was the embryo euploidy rate. Secondary outcomes included fertilization, high-quality blastulation, and ongoing pregnancy rates. RESULT(S): The blastocyst euploidy rate per mature oocyte was not significantly different in the study group compared with the control group (22.9% vs. 20.5%). The blastocyst euploidy rate per biopsied embryo was also similar between the 2 groups (53.0% vs. 45.7%). However, the fertilization rate per mature oocyte injected was found to be significantly higher in the study group compared with the control group (76.0% vs. 69.9%). The high-quality blastulation rate per mature oocyte injected was similar between the 2 groups, as was the total number of embryos frozen. There were no differences in the number of participants with no blastocysts for biopsy or the number of participants with no euploid embryos between the 2 groups. Among the male factor infertility and recurrent pregnancy loss subgroups, there were no differences in euploidy rates, fertilization rates, blastulation rates, or total numbers of blastocysts frozen, although the study was underpowered to detect these differences. Seventy-seven patients underwent frozen embryo transfer; there were no significant differences in pregnancy outcomes between the 2 groups. CONCLUSION(S): Microfluidics processing did not improve embryo euploidy rates compared with density gradient centrifugation in this sibling oocyte study, although fertilization rates were significantly higher. CLINICAL TRIAL REGISTRATION NUMBER: NCT04744025.

Impact of trophectoderm biopsy on obstetric and perinatal outcomes following frozen-thawed embryo transfer cycles.

STUDY QUESTION: Does trophectoderm biopsy for preimplantation genetic testing (PGT) increase the risk of obstetric or perinatal complications in frozen-thawed embryo transfer (FET) cycles? SUMMARY ANSWER: Trophectoderm biopsy may increase the risk of hypertensive disorders of pregnancy (HDP) in pregnancies following FET cycles. WHAT IS KNOWN ALREADY: Trophectoderm biopsy has replaced blastomere biopsy as the standard of care to procure cells for PGT analysis. Recently, there has been concern that trophectoderm biopsy may adversely impact obstetric and perinatal outcomes. Previous studies examining this question are limited by use of inappropriate control groups, small sample size or reporting on data that no longer reflects current IVF practice. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study conducted at a single university-affiliated fertility center. A total of 756 patients who underwent FET with transfer of previously vitrified blastocysts that had either trophectoderm biopsy or were unbiopsied and resulted in a singleton live birth between 2013 and 2019 were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Obstetric and perinatal outcomes for patients aged 20-44 years who underwent FET with transfer of previously vitrified blastocysts that were either biopsied (n = 241) or unbiopsied (n = 515) were analyzed. Primary outcome was odds of placentation disorders including HDP and rate of fetal growth restriction (FGR). Binary logistic regression was performed to control for potential covariates. MAIN RESULTS AND THE ROLE OF CHANCE: The biopsy group was significantly older, had fewer anovulatory patients, was more often nulliparous and had fewer embryos transferred compared to the unbiopsied group. After controlling for potential covariates, the probability of developing HDP was significantly higher in the biopsy group compared with unbiopsied group (adjusted odds ratio (aOR) 1.943, 95% CI 1.072-3.521; P = 0.029).There was no significant difference between groups in the probability of placenta previa or placenta accreta. There was also no significant difference in the rate of FGR (aOR 1.397; 95% CI, 0.815-2.395; P = 0.224) or the proportion of low (aOR 0.603; 95% CI, 0.336-1.084; P = 0.091) or very low (aOR 2.948; 95% CI, 0.613-14.177; P = 0.177) birthweight infants comparing biopsied to unbiopsied groups. LIMITATIONS, REASON FOR CAUTION: This was a retrospective study performed at a single fertility center, which may limit the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: Trophectoderm biopsy may increase the risk of HDP in FET cycles, however, a prospective multicenter randomized trial should be performed to confirm these findings. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NA.

The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35 h later for the prevention of OHSS.

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian stimulation. The use of gonadotropin releasing hormone (GnRH) agonist for the trigger of oocyte maturation is effective in the prevention of OHSS although it may result in a lower pregnancy rate. The use of adjuvant low dose human chorionic gonadotropin (hCG) at the time of trigger or at the time of oocyte retrieval may improve pregnancy rates. The goal of this dual trigger study is to evaluate the safety and efficacy of the use of low dose hCG administered at the time of GnRH agonist trigger or 35 h later as well as the potential impact on pregnancy rates. The population will consist of 82 women undergoing IVF treatment who are at risk of developing OHSS. This study will be a single center prospective randomized double-blind placebo controlled trial. The randomization schedule will be administered by the Investigational Drug Services of the University. After controlled ovarian stimulation, induction of oocyte maturation will be achieved using a GnRH agonist and patients will be randomized to receive either low dose hCG 1000 IU at the time of trigger and placebo at oocyte retrieval (Study group) or placebo at the time of trigger and hCG 1500 IU at the time of oocyte retrieval (Control group). The main outcomes will be live birth rates and incidence of OHSS. Two ancillary studies will include a quality of life survey and serum assessment of independent corpus luteum function.

Ovulation rate and cycle characteristics in a subsequent clomiphene citrate cycle after stair-step protocol.

OBJECTIVE: To determine the ovulation rate after ovulation induction with clomiphene citrate (CC) in women who had previously been ovulatory after a stair-step (CC-SS) ovulation induction. DESIGN: Retrospective cohort. SETTING: University-based tertiary fertility center. PATIENT(S): 61 anovulatory patients <40 years of age with polycystic ovary syndrome who underwent ovulation induction with a CC-SS protocol and a subsequent CC cycle. INTERVENTION(S): Ovulation induction with CC. MAIN OUTCOME MEASURE(S): Ovulation rates and cycle characteristics. RESULT(S): Of 61 patients who underwent a subsequent CC cycle, 15 (25%) failed to ovulate at the previously ovulatory dose. Of those 15 patients, 13 (86.7%) ovulated after an increase in dose. The total number of follicles ≥15 mm (2.8 ± 1.2 vs. 1.6 ± 0.7) and peak estradiol (E2) levels (604 ± 272 pg/mL vs. 447 ± 218 pg/mL) were statistically significantly higher in the CC-SS cycle compared with the subsequent CC cycle, respectively. The endometrial lining was statistically significantly thinner in the CC-SS than the CC cycle (7.8 ± 1.8 vs. 9.2 ± 2.7, respectively). CONCLUSION(S): The majority of patients who ovulate after a CC-SS protocol will ovulate after taking the previously ovulatory CC dose in a subsequent cycle. Those who do not ovulate will likely ovulate with a further increase in CC dose.

Selection of first in vitro fertilization cycle stimulation protocol for good prognosis patients: gonadotropin releasing hormone antagonist versus agonist protocols.

OBJECTIVE: The objective of this study was to compare outcome parameters in patients anticipated to have a good response to stimulation based upon baseline characteristics using either a gonadotropin releasing hormone (GnRH) agonist or antagonist protocol in their first in vitro fertilization (IVF) cycle. STUDY DESIGN: A retrospective chart review of all first-time IVF cycles performed during the time period 2005 through 2007 in an academic teaching center. Patients <40 years of age with a normal baseline follicle stimulating hormone (<10 mIU/mL) and normal antral follicle counts (> or = 3 in each ovary) were included. All patients studied were undergoing their first IVF cycle. The main outcome measures were clinical pregnancy and live birth rates. RESULTS: Included in the study were 755 patients undergoing a GnRH agonist protocol and 378 patients undergoing a GnRH antagonist cycle. Implantation rates (39.4% vs. 39.5%), cancellation rates (22.4% vs. 19.2%), clinical pregnancy rates (43.6% vs. 48.6%) and live birth rates (34.9% vs. 40.1%) were similar between GnRH antagonist and GnRH agonist protocol groups, respectively. CONCLUSION: Clinical pregnancy and live birth rates are similar in good responders utilizing either a GnRH agonist or antagonist during their first cycle of IVF.

A randomized trial of microdose leuprolide acetate protocol versus luteal phase ganirelix protocol in predicted poor responders.

We performed a randomized trial to compare IVF outcomes in 54 poor responder patients undergoing a microdose leuprolide acetate (LA) protocol or a GnRH antagonist protocol incorporating a luteal phase E(2) patch and GnRH antagonist in the preceding menstrual cycle. Cancellation rates, number of oocytes retrieved, clinical pregnancy rates (PR), and ongoing PRs were similar between the two groups.

Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting.

Ninety-four women undergoing IVF with peak E2 level>4000 pg/mL received leuprolide acetate (LA) trigger (LA trigger group) or had gonadotropins withheld for one or more days (coasting group) followed by hCG trigger, unless cycle cancellation occurred. There were no cases of ovarian hyperstimulation syndrome in either group, and the LA trigger group had significantly more oocytes retrieved (26.9+/-9.5 vs. 17.7+/-9.3) P<0.001, more normally fertilized oocytes (15.0+/-7.8 vs. 10.3+/-6.3) P=0.01, and higher clinical and ongoing pregnancy rates than the coasting group (52.5% vs. 27.2%; 49.2% vs. 24.2%, P=0.02 for both comparisons, respectively).

Comparison of luteal estradiol patch and gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation versus microdose gonadotropin-releasing hormone agonist protocol for patients with a history of poor in vitro fertilization outcomes.

OBJECTIVE: To compare IVF outcomes in poor-responder patients undergoing stimulation after luteal phase E(2) patch/GnRH antagonist (LPG) protocol versus microdose GnRH agonist protocol. DESIGN: Retrospective analysis. SETTING: University-based IVF center. PATIENT(S): Forty-five women undergoing ovarian stimulation for IVF using the LPG protocol were compared with 76 women stimulated with the microdose GnRH agonist protocol from May 2005 to April 2006. MAIN OUTCOME MEASURE(S): Cancellation rate, number of oocytes retrieved, and clinical pregnancy rates. RESULT(S): The mean number of oocytes (9.1 +/- 4.1 vs. 8.9 +/- 4.3) and mature oocytes (6.7 +/- 3.5 vs. 6.8 +/- 3.1) retrieved were similar, as were the fertilization rates (70.0% +/- 24.2% vs. 69.9% +/- 21.5%) and the number of embryos transferred (2.5 +/- 1.1 vs. 2.7 +/- 1.3). The cancellation rate was not significantly different between the groups (13/45, 28.9% vs. 23/76, 30.3%). Likewise, there were no significant differences among the implantation rate (15.0% vs. 12.5%), clinical pregnancy rate (43.3% vs. 45.1%), and ongoing pregnancy rate per transfer (33.3% vs. 26.0%) between both groups. CONCLUSION(S): This study demonstrates that the use of an E(2) patch and a GnRH antagonist during the preceding luteal phase in patients with a history of failed cycles can provide similar IVF outcomes when compared with the microdose GnRH agonist protocol.

Prevention of recurrent adnexal torsion.

OBJECTIVE: To report a case of adnexal torsion after in vitro fertilization (IVF) with two subsequent episodes of contralateral adnexal torsion and a novel approach for reducing the risk of recurrence. DESIGN: Case report. SETTING: University-based IVF program. PATIENT(S): A 32-year-old woman who conceived with IVF and experienced sequential bilateral adnexal torsion. Left adnexal torsion was diagnosed with laparoscopic detorsion performed 2 days after embryo transfer. At 7 weeks' gestation, right adnexal torsion occurred and was managed with laparoscopic detorsion. Subsequently, right adnexal torsion recurred at 10 weeks' gestation, and laparoscopic detorsion with shortening of the uteroovarian ligament was performed. INTERVENTION(S): Gonadotropin ovulation induction, IVF, and laparoscopic detorsion of both right and left adnexa with shortening of the right uteroovarian ligament. MAIN OUTCOME MEASURE(S): Preservation of adnexa after torsion and successful pregnancy. RESULT(S): Successful pregnancy and birth; resolution of torsion, prevention of recurrence with viable bilateral adnexa after detorsion and shortening of the utero-ovarian ligament with novel use of laparoscopic Endoloop. CONCLUSION(S): This is a unique case of multiple episodes of adnexal torsion following IVF with a new form of treatment using the laparoscopic Endoloop. Management of the infertility patient should be conservative and warrants ovarian preservation whenever possible. Multiple sequential episodes of adnexal torsion during a single pregnancy are a rare complication of IVF. Shortening of the utero-ovarian ligament is an alternative to oophoropexy to prevent recurrence.

Ruptured ectopic pregnancy with contralateral adnexal torsion after spontaneous conception.

OBJECTIVE: To describe a case of ruptured ectopic pregnancy and contralateral adnexal torsion after spontaneous conception. DESIGN: Case report. SETTING: Tertiary university medical center. PATIENT(S): A 23-year-old multiparous female with severe bilateral pelvic pain and a positive pregnancy test. INTERVENTION(S): Operative laparoscopy with detorsion of left adnexa, drainage of left ovarian hemorrhagic corpus luteum cyst, right salpingectomy, and dilation and curettage. MAIN OUTCOME MEASURE(S): Laparoscopy revealed a 5 cm hemorrhagic corpus luteum cyst of the left ovary, torsion of the left ovary and fallopian tube, and a ruptured right ampullary ectopic pregnancy. RESULT(S): Normal perfusion of left ovary and fallopian tube after detorsion, resolution of left ovarian hemorrhagic corpus luteum cyst, patent left fallopian tube with chromopertubation, and successful removal of ectopic pregnancy. CONCLUSION(S): This is a unique case of adnexal torsion and contralateral ectopic pregnancy occurring after spontaneous conception.

Meiotic arrest in human oocytes is maintained by a Gs signaling pathway.

In mammalian oocytes, the maintenance of meiotic prophase I arrest prior to the surge of LH that stimulates meiotic maturation depends on a high level of cAMP within the oocyte. In mouse and rat, the cAMP is generated in the oocyte, and this requires the activity of a constitutively active, Gs-linked receptor, GPR3 or GPR12, respectively. To examine if human oocyte meiotic arrest depends on a similar pathway, we used RT-PCR and Western blotting to look at whether human oocytes express the same components for maintaining arrest as rodent oocytes. RNA encoding GPR3, but not GPR12, was expressed. RNA encoding adenylate cyclase type 3, which is the major adenylate cyclase required for maintaining meiotic arrest in the mouse oocyte, was also expressed, as was Galphas protein. To determine if this pathway is functional in the human oocyte, we examined the effect of injecting a function-blocking antibody against Galphas on meiotic resumption. This antibody stimulated meiotic resumption of human oocytes that were maintained at the prophase I stage using a phosphodiesterase inhibitor. These results demonstrate that human oocytes maintain meiotic arrest prior to the LH surge using a signaling pathway similar to that of rodent oocytes.

The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study.

OBJECTIVE: To determine whether the use of luteal phase vaginal E(2) supplementation improves clinical pregnancy rates in patients undergoing IVF treatment. DESIGN: Prospective randomized controlled trial. SETTING: University-based tertiary fertility center. PATIENT(S): One hundred sixty-six patients undergoing their first cycle of IVF treatment. INTERVENTION(S): Patients underwent three different protocols for controlled ovarian hyperstimulation for IVF treatment with long GnRH agonist suppression, use of GnRH antagonist, or a microdose GnRH agonist protocol. Luteal phase support was in the form of IM P. Patients randomized into the study group (n = 84) received E(2) supplementation in the form of vaginal estrace 2 mg twice a day starting on the day of ET. Patients randomized to the control group (n = 82) received no E(2) supplementation. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): There were no significant differences in the implantation (56/210 [26.7%] vs. 64/203 [31.5%]), clinical pregnancy (42/84 [50%] vs. 52/82 [63.4%]), and ongoing pregnancy rates (40/84 [47.6%] vs. 46/82 [56.1%]) between the study and control groups, respectively. In the subgroup of patients who used the long GnRH agonist suppression protocol, there was a lower clinical pregnancy rate in the study group compared with the control group (27/55 [49.1%] vs. 42/59 [71.2%]). There were, however, no differences in clinical pregnancy rates between the two groups in patients who used either the GnRH antagonist or microdose GnRH agonist protocols. CONCLUSION(S): The addition of vaginal E(2) supplementation to routine P supplementation for luteal support does not improve the probability of conception after IVF treatment.

The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study.

OBJECTIVE: To determine whether there are any differences in the incidence of ovarian hyperstimulation syndrome (OHSS) and implantation rates in high-risk patients undergoing IVF using a protocol consisting of GnRH agonist trigger after cotreatment with GnRH antagonist or hCG trigger after dual pituitary suppression protocol. DESIGN: Prospective randomized controlled trial. SETTING: University-based tertiary fertility center. PATIENT(S): Sixty-six patients under 40 years of age with polycystic ovarian syndrome, polycystic ovarian morphology, or previous high response undergoing IVF. INTERVENTION(S): Patients were randomized to an ovarian stimulation protocol consisting of either GnRH agonist trigger after cotreatment with GnRH antagonist (study group) or hCG trigger after dual pituitary suppression with a GnRH agonist (control group). Both groups received luteal phase and early pregnancy supplementation with IM progesterone (P), and patients in the study group also received E(2) patches and their doses were adjusted according to the serum levels. MAIN OUTCOME MEASURE(S): Incidence of OHSS and implantation rate. RESULT(S): None of the patients in the study group developed any form of OHSS compared with 31% (10/32) of the patients in the control group. There were no significant differences in the implantation (22/61 [36.0%] vs. 20/64 [31.0%]), clinical pregnancy (17/30 [56.7%] vs. 15/29 [51.7%]), and ongoing pregnancy rates (16/30 [53.3%] vs. 14/29 [48.3%]) between the study and control groups, respectively. CONCLUSION(S): The use of a protocol consisting of GnRH agonist trigger after GnRH antagonist cotreatment combined with adequate luteal phase and early pregnancy E(2) and P supplementation reduces the risk of OHSS in high-risk patients undergoing IVF without affecting implantation rate.

Effects of gonadotropin-releasing hormone agonists and antagonists on luteal function.

PURPOSE OF REVIEW: This review addresses the effects of gonadotropin-releasing hormone agonists and antagonists on various aspects of the luteal phase. RECENT FINDINGS: Recent studies have shown that use of both gonadotropin-releasing hormone agonists and antagonists during in-vitro fertilization cycles leads to alterations in the hormonal profiles of the luteal phase as well as changes in endometrial histology. Gonadotropin-releasing hormone agonists are effective in triggering final oocyte maturation and reducing the incidence of ovarian hyperstimulation syndrome. Ongoing pregnancy rates are excellent after gonadotropin-releasing hormone agonist trigger when luteal phase and early pregnancy supplementation with estradiol and progesterone is provided. Gonadotropin-releasing hormone agonists have recently been used for luteal phase support in in-vitro fertilization cycles. SUMMARY: Although gonadotropin-releasing hormone agonists and antagonists are clinically useful, they may have adverse effects on luteal function. Luteal phase supplementation significantly improves clinical outcomes in in-vitro fertilization cycles because it may correct some of these detrimental effects. Use of gonadotropin-releasing hormone agonist to induce oocyte maturation is beneficial to patients who are at increased risk for ovarian hyperstimulation syndrome. The key factor in achieving favorable ongoing pregnancy rates with use of gonadotropin-releasing hormone agonist to induce oocyte maturation appears to be adequate luteal phase support.

Factors associated with increased charges for hysterectomy.

OBJECTIVE: To evaluate factors associated with increased hospital charges for hysterectomy with specific attention to differences based on surgical approach. METHODS: We performed a retrospective cohort study of 686 patients who underwent hysterectomy between January 1997 and September 1997 using medical chart review and hospital financial information. Demographic information, surgical approach (abdominal, vaginal, or laparoscopic), and surgical and postoperative factors were extracted from the medical record. Hospital charges were obtained from the hospital billing database. Relationships between charges and various clinical and demographic variables were examined using chi(2), Fisher exact test, t tests, or analysis of variance, where appropriate. Logistic regression was used to estimate odds ratios while controlling for important confounding variables. RESULTS: In our logistic regression model, blood loss greater than 1,000 mL (odds ratio [OR] 11.8, 95% confidence interval [CI] 4.2-33.2) and operative time 105 minutes or more (OR 14.2, CI 5.8-34.5) were strongly associated with higher charges for hysterectomy. Other factors associated with higher charges included: postoperative fever (OR 2.2, CI 1.1-4.5), increasing length of hospitalization (OR 5.3, CI 3.7-7.7), the use of prophylactic antibiotics (OR 3.0, CI 1.3-6.6), and the laparoscopic surgical approach compared with vaginal hysterectomy (OR 2.7, CI 1.0-7.0). CONCLUSION: Surgical factors such as operative time and blood loss were strongly associated with increased hospital charges for hysterectomy.

Prophylactic antibiotic administration prior to hysterectomy: a quality improvement initiative.

OBJECTIVE: To determine whether institution of a preoperative antibiotic policy could increase the use of prophylactic antibiotics prior to hysterectomy. STUDY DESIGN: A retrospective cohort study of 400 women who underwent abdominal, vaginal or laparoscopic hysterectomy for benign indications at Women and Infants Hospital was performed. Rates and timing of prophylactic preoperative antibiotic administration were determined, as were the rates of postoperative febrile morbidity. These data were compared to data collected in a medical record review of 686 hysterectomies performed prior to institution of the antibiotic policy. RESULTS: Prior to the institution of the antibiotic policy, 50% of patients (342/686, 95% CI 46.0, 53.7) received prophylactic preoperative antibiotics. After introduction of the antibiotic policy, 91.2% (95% CI 88.0, 93.8) of patients received prophylactic preoperative antibiotics. Approximately 66% of the antibiotics were administered within the 60 minutes preceding the surgical incision. Postoperative febrile morbidity was noted in 14% of patients prior to the antibiotic policy as compared to 11% of patients after the policy was instituted. Abdominal surgical approach was found to be a clinically and statistically significant risk factor for febrile morbidity (OR = 7.0; 95% CI 2.3, 20.9). CONCLUSION: Rates of prophylactic preoperative antibiotic administration significantly increased after institution of a hospital policy advocating routine antibiotic prophylaxis prior to hysterectomy. Additional steps must be taken to ensure more routine and appropriately timed administration of antibiotics prior to hysterectomy and to continuously monitor the use of prophylactic antibiotics.