Length of estradiol exposure >100 pg/ml in the follicular phase affects pregnancy outcomes in natural frozen embryo transfer cycles.

STUDY QUESTION: Do the length of follicular phase estradiol exposure and the total length of the follicular phase affect pregnancy and live birth outcomes in natural frozen embryo transfer (FET) cycles? SUMMARY ANSWER: An estradiol level >100 pg/ml for ≤4 days including the LH surge day is associated with worse pregnancy and live birth outcomes; however, the total length of the follicular phase is not associated with pregnancy and live birth outcomes. WHAT IS KNOWN ALREADY: An estradiol level that increases above 100 pg/ml and continues to increase is indicative of the selection and development of a dominant follicle. In programmed FET cycles, a limited duration of follicular phase estradiol of <9 days results in worse pregnancy rates, but a prolonged exposure to follicular phase estradiol for up to 4 weeks does not affect pregnancy outcomes. It is unknown how follicular phase characteristics affect pregnancy outcomes in natural FET cycles. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included infertile patients in an academic hospital setting who underwent their first natural frozen autologous Day-5 embryo transfer cycle in our IVF clinic between 01 January 2013 and 31 December 2018. Donor oocyte and gestational carrier cycles were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcomes of this study were pregnancy and live birth rates. Patients were stratified into two groups based on the cohorts' median number of days from the estradiol level of >100 pg/ml before the LH surge: Group 1 (≤4 days; n = 1052 patients) and Group 2 (>4 days; n = 839 patients). Additionally, patients were stratified into two groups based on the cohorts' median cycle day of LH surge: Group 1 (follicular length ≤15 days; n = 1287 patients) and Group 2 (follicular length >15 days; n = 1071 patients). A subgroup analysis of preimplantation genetic testing for aneuploidies (PGT-A) embryo transfer cycles was performed. Logistic regression analysis, adjusted a priori for patient age, number of embryos transferred, and use of PGT-A, was used to estimate the odds ratio (OR) with a 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: In the length of elevated estradiol analysis, the pregnancy rate per embryo transfer was statistically significantly lower in patients with an elevated estradiol to surge of ≤4 days (65.6%) compared to patients with an elevated estradiol to surge of >4 days (70.9%; OR 1.30 (95% CI 1.06-1.58)). The live birth rate per embryo transfer was also statistically significantly lower in patients with an elevated estradiol to surge of ≤4 days (46.6%) compared to patients with an elevated estradiol to surge of >4 days (52.0%; OR 1.23 (95% CI 1.02-1.48)). In the follicular phase length analysis, the pregnancy rate per embryo transfer was similar between patients with a follicular length of ≤15 days (65.4%) and patients with a follicular length of >15 days (69.0%; OR 1.12 (95% CI 0.94-1.33)): the live birth rate was also similar between groups (45.5% vs 51.5%, respectively; OR 1.14 (95% CI 0.97-1.35)). In all analyses, once a pregnancy was achieved, the length of the follicular phase or the length of elevated oestradiol >100 pg/ml no longer affected the pregnancy outcomes. LIMITATIONS, REASONS FOR CAUTION: The retrospective design of this study is subject to possible selection bias in regard to which patients at our clinic were recommended to undergo a natural FET compared to a fresh embryo transfer or programmed FET. To decrease the heterogeneity of our study population, we only included patients who had blastocyst embryo transfers; therefore, it is unknown whether similar results would be observed in patients with cleavage-stage embryo transfers. The retrospective nature of the study design did not allow randomized to a specific ovarian stimulation or ovulation trigger protocol. However, all patients were managed with the standardized protocols at a single center, which strengthens the external validity of our results when compared to a study that only evaluates one specific stimulation protocol. WIDER IMPLICATIONS OF THE FINDINGS: Our observations provide cycle-level characteristics that can be applied during a natural FET cycle to help optimize embryo transfer success rates. Physicians should consider the parameter of number of days that oestradiol is >100 pg/ml prior to the LH surge when determining whether to proceed with embryo transfer in a natural cycle. This cycle-specific characteristic may also help to provide an explanation for some failed transfer cycles. Importantly, our findings should not be used to determine whether to recommend a natural or a programmed FET cycle for a patient, but rather, to identify natural FET cycles that are not optimal to proceed with embryo transfer. STUDY FUNDING/COMPETING INTEREST(S): No financial support, funding, or services were obtained for this study. The authors do not report any potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Risk factors and human chorionic gonadotropin trends in patients with ruptured tubal ectopic pregnancies despite methotrexate treatment.

This retrospective cohort study investigates the risk factors and beta-human chorionic gonadotropin (ß-hCG) trends in patients with ruptured tubal ectopic pregnancies (EPs) despite methotrexate (MTX) treatment. All patients receiving MTX for sonographically confirmed tubal EPs at our fertility center between 2004 and 2014 were included. Baseline demographics and ß-hCG trends of patients with EP rupture after MTX were compared to patients with resolved EPs after MTX. One-hundred-thirty-seven patients with EPs were treated with MTX during the study duration; 27 experienced EP rupture and 110 EP resolution. There was no difference in the baseline demographics or ß-hCG levels on the day of MTX between the groups. Patients with ruptured EPs after MTX had higher ß-hCG levels on day-4 (1223.9 ± 243.5 vs. 1111.2 ± 179.7 mIU/mL; p < .001) and day-7 (1156.9 ± 206.2 vs. 872.4 ± 690.2 mIU/mL; p < .001). The odds of EP rupture compared to EP resolution was 6.2 (95% CI 2.1-19.1), 13.7 (95% CI 4.8-38.9), and 3.0 (95% CI 1.2-7.2) times higher when the change in ß-hCG levels was <5% between day-7 vs. day of MTX, day-7 vs. day-4, and day-4 vs. day of MTX, respectively. Our results demonstrate that ruptured tubal EPs despite MTX have <5% change in ß-hCG levels between the day of MTX and day-4 or day-7 after MTX.

Cyst aspiration or GnRH antagonist administration for ovarian cysts detected at the start of fresh in vitro fertilization cycles.

The primary objective of this study is to investigate the effect of transvaginal ultrasonogram (TVUS)-guided cyst aspiration or gonadotropin releasing hormone antagonist (GnRH-ant) administration for the management of solitary ovarian cysts detected at the start of in vitro fertilization (IVF) cycles on the outcomes of the same cycles. This is a single-center, retrospective, cohort study of patients who had TVUS-guided cyst aspiration or GnRH-ant treatment for ovarian cysts detected at the start of IVF during a 5-year period. Four hundred and three patients met inclusion criteria: 41 (10.2%) underwent cyst aspiration and 362 (89.2%) were treated with GnRH-ant. There was no difference in the demographics or baseline IVF cycle characteristics of the two groups. Patients treated with GnRH-ant had a longer duration of ovarian stimulation (10.8 ± 3.45 days versus 9.05 ± 4.06 days, p = 0.003) and required higher gonadotropin doses (3887.7 ± 1097.8 IU versus 3293.7 ± 990.5 IU; p = 0.01) compared with the cyst aspiration group. There was no difference in the clinical pregnancy (43.9% versus 41.4%), spontaneous miscarriage (9.76% versus 8.01%) and live birth (34.1% versus 33.4%) rates between the groups. Our findings suggest that cyst aspiration is comparable to GnRH-ant administration for the management of solitary ovarian cysts detected at the start of IVF cycles.

5-millimeter Trocar-site Hernias After Laparoscopy Requiring Surgical Repair.

Trocar-site hernias are rare complications of laparoscopic surgery. Although trocar-site hernias occur more often at >10-mm sites, hernias can still develop at 5-mm sites after laparoscopy and can lead to serious complications. The primary objective of this review is to summarize the current medical literature pertaining to the clinical presentation and predisposing risk factors of trocar-site hernias at 5-mm sites after laparoscopy. A total of 295 publications were identified, 17 (5.76%) of which met the inclusion criteria. Twenty-seven patients with trocar-site hernias were identified after laparoscopic cases. The median age (interquartile range) for all adult patients with trocar-site hernias was 63 years (interquartile range, 39.5-66.5 years). Eight of the 18 patients (44.4%) undergoing gynecologic laparoscopy were parous although details of parity were not reported in most publications. Simple manual reduction or laparoscopic reduction with fascial closure (21 patients [84%]) was used more often compared with exploratory laparotomy (4 patients [16%], p < .001) to manage trocar-site hernias. There was no statistical difference in the location of trocar-site hernias (i.e., umbilical [14 patients, 56%] vs nonumbilical/lateral [11 patients, 44%], p = .12). Findings of this review suggest that increased operative times and excessive manipulation can extend 5-mm fascial incisions, thereby increasing the risk of trocar-site hernias. Parous women older than 60 years may have unrecognized fascial defects, which confer a higher risk of trocar-site hernias after laparoscopic surgery, even in the absence of incision manipulation or prolonged surgical duration. Such patients may benefit from closure of 5-mm fascial incisions although prospective data are required to validate the overall generalizability of this management strategy.

Clinical pregnancy resulting from intracytoplasmic sperm injection of prematurely ovulated oocytes retrieved from the posterior cul-de-sac.

OBJECTIVE: To report a clinical pregnancy resulting from intracytoplasmic sperm injection of prematurely ovulated oocytes retrieved from the posterior cul-de-sac. DESIGN: Case report. SETTING: Academic center. PATIENTS: A 40-year-old nulligravid woman underwent ovarian stimulation for in vitro fertilization (IVF). Daily injections of gonadotropin-releasing hormone antagonist were initiated on cycle day 8. A 10,000 IU dose of human chorionic gonadotropin was administered on cycle day 15 to trigger follicular maturation. The estradiol and luteinizing hormone levels on the trigger day were 1528 pg/mL and 2.4 mIU/mL, respectively. The patient underwent oocyte retrieval 35 hours after the trigger. Transvaginal sonography at the time of the retrieval revealed a large pocket of free fluid in the posterior cul-de-sac. Only 3 follicles measuring 10-12 mm were noted in both ovaries. No lead follicles were visualized. INTERVENTIONS: Aspiration of free fluid from the posterior cul-de-sac. MAIN OUTCOME MEASURES: Clinical pregnancy. RESULTS: The fluid in the posterior cul-de-sac was aspirated, and 3 mature oocytes were retrieved. Aspiration of the smaller ovarian follicles measuring 10-12 mm did not yield oocytes. All mature oocytes retrieved from the posterior cul-de-sac were fertilized with intracytoplasmic sperm injection. Three cleavage-stage embryos were transferred 3 days later. A single intrauterine pregnancy with cardiac activity was confirmed at a gestational age of 7 weeks. CONCLUSIONS: In the setting of premature ovulation, aspiration of free fluid from the posterior cul-de-sac can result in the retrieval of mature oocytes, which may result in clinical pregnancies.

Combined transvaginal and transabdominal oocyte retrieval in a patient with an ectopic ovary and unicornuate uterus.

OBJECTIVE: To report the utility of combined transvaginal and transabdominal oocyte retrieval in a patient with an ectopic ovary and unicornuate uterus. DESIGN: Video case report with demonstration of oocyte retrieval technique. SETTING(S): University-affiliated fertility center. PATIENT(S): A 35-year-old woman, gravida 0, with a 6-month history of infertility who presented to our center for fertility evaluation. Hysterosalpingography revealed a left unicornuate uterus and patent left fallopian tube magnetic resonance imaging and laparoscopy showed a right ectopic ovary located in the upper abdomen. Her partner was a 36-year-old male with isolated teratozoospermia. The couple did not conceive with intrauterine insemination. INTERVENTION(S): Ovarian stimulation for in vitro fertilization (IVF). Transvaginal retrieval of oocytes from the right ovary was not deemed possible due the anatomic location of the ovary, intervening blood vessels, and limited mobility of the ovary. Institutional review board approval was not required for this case report as per our institution's policy; patient consent was obtained for publication of the case. MAIN OUTCOME MEASURE(S): Transabdominal retrieval of oocytes from the right ovary and transvaginal retrieval of oocytes from the left ovary. RESULT(S): The couple underwent two IVF cycles. Nine oocytes were retrieved during the first IVF cycle: seven transabdominal (right ovary) and two transvaginal (left ovary). All oocytes were mature, and five blastocysts were cryopreserved. Eight oocytes were retrieved during the second IVF cycle, of which five oocytes were retrieved transabdominally from the right ovary, and three oocytes were retrieved transvaginally from the left ovary. All oocytes were mature, and four blastocysts were cryopreserved. A single thawed embryo was transferred in the natural menstrual cycle, which resulted in the live birth of a full-term baby boy weighing 2,410 grams. CONCLUSION(S): The current case highlights the safety and feasibility of combined transvaginal and transabdominal oocyte retrieval in patients with an ectopic ovary located in the upper abdomen.

Optimal lead follicle size for human chorionic gonadotropin trigger in clomiphene citrate and intrauterine insemination cycles: an analysis of 1,676 treatment cycles.

OBJECTIVE: To identify the optimal lead follicle size for hCG trigger in clomiphene citrate (CC)-intrauterine insemination (IUI) cycles. DESIGN: Retrospective cohort study. SETTING: University-affiliated center. PATIENT(S): Patients <40 years of age with ovulatory dysfunction or unexplained infertility undergoing their first CC-IUI cycle. INTERVENTION(S): Ovulation induction, hCG trigger, and IUI. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR) was the primary outcome and was plotted against lead follicle size in increments of 1 mm. Odds ratios with 95% confidence intervals for associations between lead follicle size and CPR were calculated from a multivariable logistic regression model. A receiver operating characteristic (ROC) curve was generated for CPR as a function of lead follicle size. RESULT(S): 1,676 cycles were included. The overall CPR was 13.8% (232/1,676). There was no difference in baseline demographics or ovulation induction parameters of patients who did or did not conceive. The odds of clinical pregnancy were 2.3 and 2.2 times higher with lead follicle sizes of 21.1-22.0 mm and >22.0 mm, respectively, compared with the referent category of 19.1-20.0 mm. Lead follicle size was an independent predictor of CPR, even after accounting for confounders. A lead follicle size of 22.1 mm corresponded to a sensitivity and specificity of 80.1% and 90.4% for clinical pregnancy, respectively, with an area under the ROC curve of 0.89. CONCLUSION(S): hCG administration at a lead follicle size of 21.1-22.0 mm is associated with higher odds of clinical pregnancy in patients undergoing their first CC-IUI cycles for ovulatory dysfunction or unexplained infertility.

Does the time interval between hysteroscopic polypectomy and start of in vitro fertilization affect outcomes?

OBJECTIVE: To investigate whether the time interval between hysteroscopic polypectomy and the start of IVF-ET cycles affect IVF cycle outcomes. DESIGN: Retrospective cohort. SETTING: Academic center. PATIENT(S): All patients diagnosed with endometrial polyps undergoing hysteroscopic polypectomy before fresh IVF-ET. INTERVENTION(S): Hysteroscopic polypectomy. MAIN OUTCOME MEASURE(S): Patients were divided into three groups based on the time interval between hysteroscopic polypectomy and the start of a fresh IVF-ET cycle. Group 1 consisted of patients who underwent IVF-ET after their next menses, group 2 after two or three menstrual cycles, and group 3 after more than three menstrual cycles. Demographics, baseline IVF characteristics, controlled ovarian stimulation response, and pregnancy outcomes after ET were compared among the groups. RESULT(S): A total of 487 patients met inclusion criteria: 241 in group 1 (49.5%), 172 in group 2 (35.3%), and 74 in group 3 (15.2%). There were no differences in the baseline characteristics of the three groups. Ovarian stimulation outcomes, specifically total stimulation days, total gonadotropins administered, and number of oocytes retrieved, were similar between groups. There were no differences in the mean number of embryos transferred. The overall pregnancy outcomes were similar for groups 1, 2, and 3: implantation rate (42.4%, 41.2%, and 42.1%, respectively), clinical pregnancy rate (48.5%, 48.3%, and 48.6%), spontaneous miscarriage rate (4.56%, 4.65%, and 4.05%), and live birth rate (44.0, 43.6%, and 44.6%). CONCLUSION(S): Because waiting for two or more menstrual cycles after hysteroscopic polypectomy does not necessarily yield superior outcomes, patients can undergo ovarian stimulation after their next menses without affecting IVF-ET outcomes.

Role of acupuncture in the treatment of female infertility.

OBJECTIVE: To review existing scientific rationale and clinical data in the utilization of acupuncture in the treatment of female infertility. DESIGN: A MEDLINE computer search was performed to identify relevant articles. RESULTS: Although the understanding of acupuncture is based on ancient medical theory, studies have suggested that certain effects of acupuncture are mediated through endogenous opioid peptides in the central nervous system, particularly beta-endorphin. Because these neuropeptides influence gonadotropin secretion through their action on GnRH, it is logical to hypothesize that acupuncture may impact on the menstrual cycle through these neuropeptides. Although studies of adequate design, sample size, and appropriate control on the use of acupuncture on ovulation induction are lacking, there is only one prospective randomized controlled study examining the efficacy of acupuncture in patients undergoing IVF. Besides its central effect, the sympathoinhibitory effects of acupuncture may impact on uterine blood flow. CONCLUSION: Although the definitive role of acupuncture in the treatment of female infertility is yet to be established, its potential impact centrally on the hypothalamic-pituitary-ovarian axis and peripherally on the uterus needs to be systemically examined. Prospective randomized controlled studies are needed to evaluate the efficacy of acupuncture in female fertility treatment.

Relationship between maternal age and aneuploidy in in vitro fertilization pregnancy loss.

OBJECTIVE: To determine the fetal loss rate after documented fetal cardiac activity (7-week sonogram) and to evaluate the chromosomal makeup of these losses in IVF pregnancies. DESIGN: Retrospective analysis. SETTING: University-based IVF center. PATIENT(S): Two thousand fourteen consecutive IVF pregnancies with documented fetal cardiac activity. MAIN OUTCOME MEASURE(S): Miscarriage rates and karyotypes of pregnancy losses were analyzed. RESULT(S): The overall pregnancy loss rate after demonstrated fetal cardiac activity was 11.6% (233/2014). A highly significant increase in fetal loss with advancing maternal age was observed (<30 years = 5.3% vs. 31-34 years = 7.6% vs. 35-39 years = 12.8% vs. > or =40 years = 22.2%). Patients with a multiple gestation were more likely to deliver a live infant, compared with those with a singleton detected at a 7-week sonogram. Of the 233 losses in the study period, cytogenetic analyses were obtained for 74 (31.8%). Three specimens were nondiagnostic. Fifty-two patients had abnormal karyotypes (71.2% [52/71]). Eighty-two percent of the pregnancy losses in women aged > or =40 years were associated with chromosomally abnormal fetuses, compared with 65% of the losses in women aged <40 years (odds ratio, 3.35; 95% confidence interval, 0.96-11.97). CONCLUSION(S): Pregnancy loss after documentation of fetal cardiac activity is >10%. This loss is significantly increased with advancing maternal age. The major underlying cause of these losses seems to be chromosomal aneuploidy.

Ultrasound-guided trial transfer may be beneficial in preparation for an IVF cycle.

BACKGROUND: The objective of this study is to determine if ultrasound-guided trial transfer (UTT) in the office in preparation for an IVF cycle can be utilized as an alternative and/or adjunct to ultrasound-guided embryo transfer (UGET). METHODS: Patients planning to undergo an IVF cycle at an academic centre were included. Each patient underwent an UTT in the office by the same practitioner. The difference in length (DL), if any, was measured from the perceived top of the uterine cavity (catheter tip) to the actual cavity apex as visualized by ultrasound. RESULTS: Of the 64 patients enrolled, 19 patients (29.7%) had a measurable DL, of which 14 (21.9%) had a DL exists 0.5 cm, and nine (14.1%) had a DL exists 1.0 cm. Significant differences were noted between patients when comparing DL to previous pregnancy status and the total cavity depth (sounding depth + DL) (P < 0.05). CONCLUSION: UTT in the office setting appears to be beneficial in preparation for an IVF cycle with embryo transfer.