The influence of obesity on incidence of complications in patients hospitalized with ovarian hyperstimulation syndrome.

OBJECTIVE: To study the impact of body habitus on risk of complications resulting from ovarian hyperstimulation syndrome (OHSS) in hospitalized patients. METHODS: This is a retrospective observational study examining the National Inpatient Sample between January 2012 and September 2015. Patients were women < 50 years of age diagnosed with OHSS, classified as non-obese, class I-II obesity, or class III obesity. Intervention included multinomial logistic regression to identify factors associated with obesity and binary logistic regression for independent risk factors for complications. Main outcome measures were incidence of (i) any or (ii) multiple complication(s). RESULTS: Of 2745 women hospitalized with OHSS, 2440 (88.9%) were non-obese, 155 (5.6%) had class I-II obesity, and 150 (5.5%) had class III obesity. Obese women (either class I-II or III) had a higher degree of comorbidity, had lower incomes, and were less likely to have private insurance than non-obese women (all P < 0.001). Obese women had lower rates of OHSS-related complications than non-obese women (any complication: non-obese 65.2%, class I-II 54.8%, and class III 46.7%, P < 0.001; and multiple complications: non-obese 38.5%, class I-II 32.3%, and class III 20.0%, P < 0.001). In the multivariable model, obesity remained independently associated with a decreased risk of complications (class I-II odds ratio 0.57, 95% confidence interval 0.39-0.83, P = 0.003; class III odds ratio 0.30, 95% confidence interval 0.20-0.44, P < 0.001). Obese women were also less likely to require paracentesis (non-obese 32.8%, class I-II 9.7%, and class III 13.3%, P < 0.001). CONCLUSION: Our study suggests that obesity is associated with decreased OHSS-related complication rates in hospitalized patients.

Developmental potential of immature human oocytes aspirated after controlled ovarian stimulation.

PURPOSE: Intracytoplasmic sperm injection (ICSI) for initially immature oocytes that mature in vitro is controversial and practice varies widely. While it may increase the number of usable embryos, it may also be time-intensive and potentially low-yield. This study sought to elucidate which patients may benefit from ICSI of initially immature oocytes that matured in vitro. METHODS: A retrospective study comparing fertilization, cleavage, blastulation, and embryo usage rates between sibling initially immature and mature oocytes that underwent ICSI between 2015 and 2019 was performed. Outcomes of initially immature oocytes were stratified by initial maturation stage, timing of progression to metaphase II (MII) in vitro, percentage of mature oocytes in the cycle, and female age. RESULTS: Ten thousand eight hundred seventeen oocytes from 889 cycles were included. Of 3137 (29.0%) initially immature oocytes, 418 (13.3%) reached MII later on the day of retrieval (day 0) and 1493 (47.6%) on day 1. Overall, embryos originating from initially immature oocytes had lower cleavage and blastulation rates compared to those from initially mature oocytes (P<0.05, all groups). However, embryos from oocytes that matured later on day 0 comprised a unique subset that had clinically similar cleavage (75% vs 80%, RR 0.93, P=0.047) and blastulation rates (41% vs 50%, RR 0.81, P=0.024) compared to initially mature oocytes. Women with low percentages of mature oocytes in the cycle overall and women ≥40 in cleavage cycles derived the highest relative benefit from the use of immature oocytes. CONCLUSION: ICSI of immature oocytes, particularly those that mature later on the day of retrieval, may improve numbers of usable embryos. This study supports routine reassessment of immature oocytes for progression to MII and ICSI on day 0. An additional reassessment on day 1 may also be of use in older women or those with low percentage of mature oocytes.

What is the optimal timing of intracytoplasmic sperm injection (ICSI) after EGG retrieval? A randomized controlled trial.

PURPOSE: To determine if oocyte denudation and ICSI at 36.5 versus 39 h post HCG and/or Lupron trigger (2.5 h versus 5 h post-oocyte retrieval) influences fertilization and blastulation rates in good prognosis couples METHODS: We performed a prospective, randomized controlled trial of 12 patients undergoing IVF with ICSI at an academic fertility center, resulting in 206 MII oocytes analyzed. At time of retrieval, patients with more than 10 oocytes retrieved had their oocytes randomized into two groups-one group for oocyte denudation and ICSI at 36.5 h post HCG and/or Lupron trigger and the other group for these procedures at 39 h post HCG and/or Lupron trigger (2.5 and 5 h after oocyte retrieval). Primary outcomes were fertilization and blastulation rates. RESULTS: No difference was observed in fertilization rate, total blastulation rate, or day of blastulation based on timing of denudation and ICSI (all p > 0.05). Multiple regression analyses for fertilization and blastulation controlling for age and BMI revealed no difference in fertilization based on time of ICSI (p = 0.38, 0.71, respectively). A conditional logistic regression to account for multiple oocytes derived from each patient also found no difference in fertilization or blastulation based on timing of ICSI, even when controlling for age and BMI (p = 0.47, 0.59, respectively). CONCLUSION(S): In good prognosis couples, we observed no difference in fertilization or blastulation rates based on timing of ICSI within the currently accepted 2- to 6-h window post-retrieval based on a 34-h trigger. The oocyte appears to have a physiological tolerance for fertilization during this window of time, and variability in the timing of ICSI during this window is unlikely to have an impact on cycle outcome.

A validated model for predicting live birth after embryo transfer.

Accurately predicting the probability of live birth and multiple gestations is important for determining a safe number of embryos to transfer after in vitro fertilization. We developed a model that can be fit to individual clinic data for predicting singleton, twin, and total live birth rates after human embryo transfer. The predicted and observed rates of singleton and twin deliveries were compared in a tenfold cross-validation study using data from a single clinic. The model presented accounts for patient age, embryo stage (cleavage or blastocyst), type of transfer cycle (fresh or frozen) and uterine/universal factors. The standardized errors for rates of singleton and twin deliveries were normally distributed and the mean errors were not significantly different from zero (all p > 0.05). The live birth rates per embryo varied from as high as 43% for fresh blastocysts in the 35-year-old age group to as low as 1% for frozen cleavage stage embryos in the 43-year-old age group. This quantitative model or a simplified version can be used for clinics to generate and analyze their own data to guide the number of embryos to transfer to limit the risk of multiple gestations.

Advanced paternal age and the risk of spontaneous abortion: an analysis of the combined 2011-2013 and 2013-2015 National Survey of Family Growth.

BACKGROUND: Maternal and paternal age at first birth are increasing across the global population. Spontaneous abortion, one of the most common abnormal pregnancy outcomes, is known to occur more frequently with increasing maternal age. However, the relationship of advanced paternal age and spontaneous abortion is poorly understood, and previous results have yielded conflicting results. OBJECTIVE: To examine the influence of paternal age on the risk of spontaneous abortion among singleton pregnancies conceived without assisted reproductive technologies. MATERIALS AND METHODS: This was a retrospective, case-control study using combined pregnancy data from the Centers for Disease Control and Prevention's 2011-2013 and 2013-2015 National Survey of Family Growth. Spontaneous, singleton pregnancy data from women aged 15-45 years were analyzed. Ongoing pregnancies, induced abortions, ectopic pregnancies, preterm births, and intrauterine fetal deaths were excluded. Bivariate associations of pregnancy outcome (spontaneous abortion at <20 weeks and ≤12 weeks vs. live birth at ≥37 weeks) and paternal age were determined, along with those of maternal age and selected demographic and pregnancy characteristics. Significant associations were included in a multivariable logistic regression, which accounted for multiple pregnancies derived from the same respondent. RESULTS: A total of 12,710 pregnancies from 6979 women were analyzed, consisting of 2300 (18.2%) spontaneous abortions and 10,410 (81.8%) term live births. Median maternal and paternal ages were 25 and 28 years, respectively. After adjusting for maternal age, race/ethnicity, socioeconomic status, marital status, and pregnancy intention, pregnancies resulting in spontaneous abortions had 2.05 (95% confidence interval, 1.06-2.20) times the odds of being from a father aged 50 years or older, vs. 25-29 years of age. These relationships remained significant when defining SABs at ≤12 weeks (adjusted odds ratio, 2.30; 95% confidence interval, 1.17-4.52). CONCLUSION: Paternal age may increase the odds of spontaneous abortion, independent of selected factors, including demographics, pregnancy intention, and maternal age. This association was robust across several gestational age-based definitions of spontaneous abortion, even after adjustment.

Pushing the limits of detection: investigation of cell-free DNA for aneuploidy screening in embryos.

OBJECTIVE: To determine the accuracy of cell-free DNA (cfDNA) in spent embryo medium (SEM) for ploidy and sex detection at the cleavage and blastocyst stages. To determine if assisted hatching (AH) and morphologic grade influence cfDNA concentration and accuracy. DESIGN: Prospective cohort. SETTING: Academic fertility center. PATIENT(S): Nine patients undergoing IVF; 41 donated two-pronuclei embryos and 20 embryos from patients undergoing preimplantation genetic testing for aneuploidy (PGT-A). INTERVENTIONS(S): In a donated embryo arm, SEM was collected on days 3 and 5, with one-half of the embryos undergoing AH before and one-half after. In a clinical arm, SEM was collected on day 5 before trophectoderm (TE) biopsy. Samples underwent PGT-A with the use of next-generation sequencing. cfDNA results were compared with corresponding whole embryos and TE biopsies. MAIN OUTCOME MEASURE(S): Concordance rates, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for ploidy and sex detection with the use of cfDNA. RESULT(S): Of 141 samples, cfDNA was amplified in 39% and 80.4% of days 3 and 5 SEM, respectively. Concordances for ploidy and sex, respectively, were 56.3% and 81.3% between day 3 cfDNA and whole embryos, and 65% and 70% between day 5 cfDNA and TE biopsies. Day 5 cfDNA sensitivity and specificity for aneuploidy were 0.8 and 0.61, respectively. PPV and NPV were 0.47 and 0.88, respectively. Timing of AH and morphology did not influence cfDNA concentration or accuracy. CONCLUSION(S): cfDNA is detectable on days 3 and 5, but more accurate on day 5. Although our data suggest moderate concordance rates, PGT-A with the use of cfDNA must be further optimized before clinical implementation.

Blastulation timing is associated with differential mitochondrial content in euploid embryos.

PURPOSE: Preimplantation genetic screening (PGS) and assessment of mitochondrial content (MC) are current methods for selection of the best embryos for transfer. Studies suggest that time-lapse morphokinetics (TLM) may also be helpful for selecting embryos more likely to implant. In our study, we sought to examine the relationship between TLM parameters and MC to determine if they could be used adjunctively in embryo selection. We also examined the relationship between MC with ploidy and blastulation. METHODS: Cryopreserved human embryos at the zygote stage were thawed and cultured in a time-lapse system. Blastomere and trophectoderm biopsies were performed on days 3 and 6. Biopsied cells and all whole embryos from day 6 were analyzed for MC (ratio of mitochondrial to nuclear DNA) and ploidy using next-generation sequencing. RESULTS: In embryos, MC per cell declined between day 3 and day 6. While early cleavage parameters did not predict MC, embryos with longer blastulation timing had higher MC on day 6. Day 6 MC was lower in euploid vs. aneuploid embryos and lower in blastocysts vs. arrested embryos. CONCLUSIONS: A lower MC at the blastocyst stage was associated with euploid status and blastocyst formation, indicating better embryo quality compared to those with a higher MC. Higher MC in aneuploid and arrested embryos may be explained by slower cell division or degradation of genomic DNA over time. Blastulation timing may be helpful for selection of higher quality embryos. Combining blastulation timing and MC along with morphologic grading and euploid status may offer a new direction in embryo selection.

Clomiphene Stair-Step Protocol for Women With Polycystic Ovary Syndrome.

OBJECTIVE: To compare time to ovulation, ovulation rates, and side effect profile of traditional and the stair-step protocol for ovulation induction using clomiphene citrate in women with polycystic ovary syndrome (PCOS). METHODS: We performed a retrospective study of women seeking care for infertility with a diagnosis of PCOS at a university-based infertility clinic from July 2012 to July 2014. We included patients who were resistant to the initial starting dose of 50 mg clomiphene. The primary outcome was time to ovulation. Secondary outcomes included ovulation rates, clinical pregnancy rates, and mild and moderate-to-severe side effects based on dose. For the traditional protocol, higher doses of clomiphene were used each subsequent month if no ovulation occurred. For the stair-step protocol, higher doses of clomiphene were given 7 days after the last dose if no dominant follicles were seen on ultrasonography. Our study had 80% power to detect a 20% difference in ovulation. RESULTS: One hundred nine patients were included in the analysis with 66 (60.6%) in the traditional and 43 (39.4%) in the stair-step protocol. Age and body mass index were similar between groups. The time to ovulation was decreased in the stair-step protocol group compared with the traditional protocol group (23.1±0.9 days vs 47.5±6.3 days). Ovulation rates were increased in the stair-step group compared with the traditional group at 150 mg (16 [37%] vs 8 [12%], P=.004) and at 200 mg (9 [21%] vs 3 [5%], P=.01). Pregnancy rates were similar between groups once ovulation was achieved (12 [18.1%] vs 7 [16.3%], P=.08). The stair-step protocol had an increased incidence of mild side effects (vasomotor flushes, headaches, gastrointestinal disturbance, mastalgia, changes in mood; 18 [41%] vs 8 [12%]), but there was no difference in the incidence of severe side effects (headaches, visual disturbances). CONCLUSION: For women with PCOS, the stair-step clomiphene protocol is associated with decreased time to ovulation and increased ovulation rates at higher doses when compared with the traditional protocol.

A comparison of live birth rates and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos.

PURPOSE: Prior studies suggest that pregnancy outcomes after autologous oocyte cryopreservation are similar to fresh in vitro fertilization (IVF) cycles. It is unknown whether there are differences in pregnancy and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos. METHODS: This is a retrospective cohort study comparing pregnancy and perinatal outcomes between oocyte and embryo cryopreservation at a university-based fertility center. We included 42 patients and 68 embryo transfers in patients who underwent embryo transfer after elective oocyte preservation (frozen oocyte-derived embryo transfer (FOET)) from 2005 to 2015. We compared this group to 286 patients and 446 cycles in women undergoing cryopreserved embryo transfer (frozen embryo transfer (FET)) from 2012 to 2015. RESULTS: Five hundred fourteen transfer cycles were included in our analysis. The mean age was lower in the FOET vs FET group (34.3 vs 36.0 years), but there were no differences in ovarian reserve markers. Thawed oocytes had lower survival than embryos (79.1 vs 90.1%); however, fertilization rates were similar (76.2 vs 72.8%). In the FOET vs FET groups, clinical pregnancies were 26.5 and 30%, and live birth rates were 25 and 25.1%. Miscarriages were higher in the FET group, 8.1 vs 1.5%. There were no differences in perinatal outcomes between the two groups. The mean gestational age at delivery was 39.1 vs 38.6 weeks, mean birth weight 3284.2 vs 3161.1 gms, preterm gestation rate 5.9 vs 13.4%, and multiple gestation rate 5.9 vs 11.6%. CONCLUSIONS: In our study, live birth rates and perinatal outcomes were not significantly different in patients after oocyte and embryo cryopreservation.

The dilemma of counseling patients about poor prognosis: live birth after IVF with autologous oocytes in a 43-year-old woman with FSH levels above 30 mIU/mL.

Providing reasonable expectations to patients with diminished ovarian reserve prior to attempting pregnancy through in vitro fertilization (IVF) is one of the most challenging aspects of fertility care. In some instances, advice from the clinician to pursue more effective treatment, such as donor oocytes, may not be acceptable to the patient. In this case report, a patient is presented who represents a poor prognosis candidate for IVF treatment. She was 43 years old with six prior failed IVF cycles and repetitive basal FSH values above 30 mIU/mL. Presented are the challenges in patient counseling and decision making. In her seventh IVF cycle, which she was strongly counseled against pursuing, the patient experienced the desired outcome of live birth. Increasing reports are emerging of live birth using autologous oocytes among women of advanced reproductive age. These instances, as well as the case of our patient, raise issues commonly encountered in patient counseling in poor prognosis patients. This discussion should include an emphasis on patient goals as well as an acknowledgement that no test for ovarian reserve has a 100% positive predictive value.

Embryo transfer techniques: an American Society for Reproductive Medicine survey of current Society for Assisted Reproductive Technology practices.

OBJECTIVE: To better understand practice patterns and opportunities for standardization of ET. DESIGN: Cross-sectional survey. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): An anonymous 82-question survey was emailed to the medical directors of 286 Society for Assisted Reproductive Technology member IVF practices. A follow-up survey composed of three questions specific to ET technique was emailed to the same medical directors. Descriptive statistics of the results were compiled. MAIN OUTCOME MEASURE(S): The survey assessed policies, protocols, restrictions, and specifics pertinent to the technique of ET. RESULT(S): There were 117 (41%) responses; 32% practice in academic settings and 68% in private practice. Responders were experienced clinicians, half of whom had performed <10 procedures during training. Ninety-eight percent of practices allowed all practitioners to perform ET; half did not follow a standardized ET technique. Multiple steps in the ET process were identified as "highly conserved;" others demonstrated discordance. ET technique is divided among [1] trial transfer followed immediately with ET (40%); [2] afterload transfer (30%); and [3] direct transfer without prior trial or afterload (27%). Embryos are discharged in the upper (66%) and middle thirds (29%) of the endometrial cavity and not closer than 1-1.5 cm from fundus (87%). Details of each step were reported and allowed the development of a "common" practice ET procedure. CONCLUSION(S): ET training and practices vary widely. Improved training and standardization based on outcomes data and best practices are warranted. A common practice procedure is suggested for validation by a systematic literature review.

Low-dose human chorionic gonadotropin alone can complete follicle maturity: successful application to modified natural cycle in vitro fertilization.

OBJECTIVE: To investigate the feasibility of utilizing low-dose hCG alone to complete follicle maturity in a natural cycle, without the need for antecedent exogenous FSH stimulation. DESIGN: Case series. SETTING: Academic fertility program. PATIENT(S): Normally ovulatory women with infertility thought to be predominantly due to male factor. INTERVENTION(S): Modified natural IVF cycles were conducted as follows: natural ovulatory cycles were monitored with serial ultrasound examinations and serum E2 determinations. When the lead follicle reached preovulatory status according to cycle day, ultrasound, and E2 levels, 0.25 mg of the GnRH antagonist ganirelix acetate was administered along with 200 IU of hCG. These medications were repeated daily for 2 to 3 days with further serial monitoring. A trigger dose of 10,000 IU of hCG was followed by follicle aspiration, IVF, and ET in a standard manner. MAIN OUTCOME MEASURE(S): Follicle maturity, live births, documentation of the feasibility of this new approach. RESULT(S): In all cases, E2 levels rose and the dominant follicle continued to increase in size in response to low-dose hCG after GnRH antagonist administration. Follicle aspiration yielded one or more mature oocytes. In vitro fertilization and ET resulted in live births. CONCLUSION(S): Low-dose hCG can be used to complete follicle maturity in a natural cycle without the need for antecedent exogenous FSH stimulation. This finding may have strong clinical utility in modified natural cycle IVF.

Influence of vitamin D levels on in vitro fertilization outcomes in donor-recipient cycles.

OBJECTIVE: To elucidate the role of vitamin D in reproduction by examining the relationship between recipient vitamin D levels and pregnancy rates in donor-recipient IVF cycles. DESIGN: Retrospective cohort study. SETTING: Academic tertiary care center. PATIENT(S): Ninety-nine recipients of egg donation at University of Southern California Fertility. INTERVENTION(S): Serum was collected from egg donor recipients before ET and was tested for vitamin D levels [25(OH)D]. MAIN OUTCOME MEASURE(S): Clinical pregnancy as defined by sonographic presence of a heartbeat at 7-8 weeks of gestation. RESULT(S): In a diverse population of 99 recipients (53% Caucasian, 20% Asian, 16% Hispanic, 7% African American), adjusted clinical pregnancy rates were lower among vitamin D-deficient recipients than among vitamin D-replete recipients (37% vs. 78%). Live-birth rates were 31% among vitamin D-deficient recipients, compared with 59% among vitamin D-replete recipients. There were no differences in adjusted clinical pregnancy and live-birth rates among recipients who were vitamin D deficient [25(OH)D<20 ng/mL] vs. among those who were vitamin D insufficient [20 ng/mL ≤ 25(OH)D<30 ng/mL]. CONCLUSION(S): Nonreplete vitamin D status [25(OH)D<30 ng/mL] was associated with lower pregnancy rates in recipients of egg donation. Since the oocyte donor-recipient model is able to separate the impact of vitamin D on oocyte vs. endometrium, these data suggest that the effects of vitamin D may be mediated through the endometrium.

Egg banking in the United States: current status of commercially available cryopreserved oocytes.

OBJECTIVE: To estimate the current availability of donor cryopreserved oocytes and to describe the emerging phenomenon of commercial egg banks (CEBs) in the United States. DESIGN: Cross-sectional survey of CEBs. SETTING: E-mail, telephone, and fax survey of all CEB scientific directors, conducted April 2012. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number and location of CEBs in the United States, years in existence, number of donors, number of available oocytes, level of donor anonymity, donor screening, cost of oocytes to recipients, freezing/thawing technique, pregnancy statistics. RESULT(S): Seven CEBs were identified and surveyed (response rate: 100%). The CEBs used three distinct operational models, had been in existence for a median of 2 years (range: 1 to 8 years), with a median 21.5 (range: 6 to 100) donors and 120 (range: 20 to 1,000) currently available oocytes. The median recommended minimum number of eggs to obtain was six (range: four to seven), at an estimated mean cost per oocyte of $2,225 (range: $1,500 to $2,500). An estimated 3,130 oocytes from 294 donors are currently stored for future use. Of these CEBs, 6 (86%) of 7 use vitrification as cryopreservation method. To date, 8,780 frozen donor oocytes from CEBs have been used for in vitro fertilization, resulting in 602 pregnancies. Pregnancy rates per oocyte, available for 5 (71%) of 7 CEBs, were 532 (7.5%) of 7,080 for CEBs using vitrification and 70 (10%) of 700 for the single CEB using slow freezing as cryopreservation method. CONCLUSION(S): Frozen donor eggs are currently widely available in the United States. Three different operational models are currently used, resulting in more than 600 pregnancies from oocytes obtained at CEBs. The majority of CEBs use vitrification as cryopreservation technique.

The outcome of intracytoplasmic sperm injection using occasional spermatozoa in the ejaculate of men with spermatogenic failure.

PURPOSE: Men with spermatogenic failure so profound that they are considered as having nonobstructive azoospermia occasionally have spermatozoa in the ejaculate. We compared intracytoplasmic sperm injection outcomes following the injection of ejaculated or surgically retrieved spermatozoa from these men. MATERIALS AND METHODS: A study was performed of intracytoplasmic sperm injection cycles with no spermatozoa on initial semen analysis and 100 or fewer following centrifugation (cryptozoospermia). Only 16 couples that underwent intracytoplasmic sperm injection cycles with ejaculated spermatozoa and cycles with testicular spermatozoa were included. RESULTS: Initial analysis was done to compare outcomes between the 2 semen origins. There was no difference in the rate of normal or abnormal fertilization between the 2 groups. The rate of clinical pregnancies seemed to favor testicular spermatozoa (47.4% vs 20.8%), although results were not significant. When a comparison was performed between the first testicular cycle and the ejaculated cycle closest in time to the cycle with testicular spermatozoa, a higher rate of normal fertilization with testicular spermatozoa was observed (60.9% vs 48.5%, p <0.05). Also, in this comparison a clear trend toward a higher percent of clinical pregnancies and deliveries in the testicular group was observed (50.0% vs 14.3%). CONCLUSIONS: Transit through the male genital tract did not enhance the ability of ejaculated spermatozoa to achieve fertilization with intracytoplasmic sperm injection compared to that of testicular spermatozoa in men with severely impaired production. In ejaculated samples a lower number of spermatozoa available resulted in an impaired chance of achieving pregnancy. Using testicular spermatozoa may be a reasonable alternative for couples in whom multiple attempts at intracytoplasmic sperm injection have failed using ejaculated sperm from men with cryptozoospermia.