Assisted gamete treatment to pinpoint acquired meiotic maturity and overcome oocyte activation deficiency contributed by both gametes.

Objective: To treat couples with total fertilization failure (TFF) based on a combined oocyte- and sperm-related oocyte activation deficiency by optimizing oocyte response to chemical activation with calcium ionophore. Design: Case report. Setting: Tertiary Hospital. Patients: Two couples with a history of TFF after intracytoplasmic sperm injection intracytoplasmic sperm injection (ICSI). Interventions: To overcome oocyte-related oocyte activation deficiency (OAD), extended in vivo/in vitro oocyte maturation was performed to enhance ooplasmic maturity; to address sperm-related OAD, assisted gamete treatment (AGT) was performed to trigger oocyte activation. Main outcome measures: Treatment cycle outcomes for the 2 couples undergoing ICSI with extended oocyte maturation (EOM) and AGT. Results: We identified 2 couples with TFF after ICSI because of a combined factor of OAD confirmed by phospholipase C zeta expression and genomic assessment. Initial AGT treatment alone failed to enhance fertilization, suggesting superimposed oocyte dysmaturity prohibiting oocytes from responding to chemical stimuli. To address this complex form of OAD, in couple 1, 27 oocytes out of 34 retrieved presented normal metaphase II spindles after EOM; ICSI with AGT yielded a fertilization rate of 63.0% (17/27). All 17 zygotes were cryopreserved initially. Two embryos were thawed and transferred, yielding a monochorionic diamniotic twin pregnancy. Couple 2 underwent 3 ICSI cycles with EOM and AGT; 91.4% (32/35) of oocytes displayed normal metaphase II spindle and achieved an overall fertilization rate of 43.8% (14/32). A total of 12 blastocysts were cryopreserved. A single 46XY blastocyst was thawed and transferred, resulting in a singleton pregnancy. Conclusions: Our study has demonstrated the usefulness of EOM by targeting spindle presence to enhance chemical responses to AGT.

Three-dimensional sperm surface reconstruction: a novel approach to assessing sperm morphology.

OBJECTIVE: To create a rapid, inexpensive, efficient, and reproducible real-time three-dimensional (3-D) analysis of viable spermatozoa. Previous studies have demonstrated that abnormal semen profiles are associated with a modest increase in the frequency of sperm chromosomal abnormalities, and that sperm with aberrations in the shape and contours of the head may be carriers of chromatinic defects. Although high-power magnification and enhanced video-generated magnification have been suggested, these techniques are inherently limited by the clarity of the image, the time required for the analysis, and the risk of variable head-positioning during imaging. DESIGN: In vitro experiment. SETTING: University-affiliated infertility research laboratory. PATIENT(S): Anonymous sperm donors. INTERVENTION(S): Individual motile sperm were identified, analyzed at ×600 magnification, and a 10-second digital video was obtained. MAIN OUTCOME MEASURE(S): Image-tracking software captured serial photographs of sperm from recorded videos. Images were automatically extracted from each video frame using enhanced correlation coefficient maximization; the general shape of the sperm was extracted via space-carving. The reconstructed image was rotated to permit viewing from any direction, and the final image was rendered through interpolation. RESULT(S): This technique yielded images that enable noninvasive, 3-D, real-time, in vitro assessment of sperm surface morphology. CONCLUSION(S): This proof-of-principle demonstrates that by keeping spermatozoa in a fluid environment, a 3-D sperm-surface reconstruction can be created. This technique can be automated, requires minimal computing power, and utilizes equipment already available in most embryology laboratories.

Predictive biomarkers of preterm delivery in women with ongoing IVF pregnancies.

In vitro fertilization (IVF) pregnancies potentially have a higher rate of preterm delivery (PTD) than do spontaneously conceived gestations, and differences persist following adjustment for multiple gestation, maternal age, and parity. The reasons for this increased susceptibility to PTD remain incompletely elucidated. To identify potential biomarkers predictive of PTD in IVF subjects, we performed a retrospective analysis of multiple markers in sera obtained during early gestation that have been suggested to be associated with peri-implantation events. Sera from 35 women with a preterm birth and 68 women with a term delivery, obtained between 9 and 11 days after embryo transfer, were tested blindly for concentrations of interleukin (IL)-1ß, IL-6, IL-13, IL-17, human epididymal protein 4 (HE4), secretory leukocyte protease inhibitor (SLPI), insulin-like growth factor (IGF)-I, IGF-II, IGF binding protein (BP)-1, and interferon-γ. Concentrations of HE4 (p=0.001) and IL-13 (p=0.029) were reduced, and levels of IGF-II (p=0.023) and SLPI (p=0.043) were increased, in women who subsequently delivered preterm. By receiver operator curve analysis, the combination of HE4 and IL-13 levels best predicted the outcome preterm birth. The association between deficiencies in circulating HE4 and IL-13 levels during early pregnancy and subsequent PTD suggest that factors contributing to sub-optimal embryo implantation influence length of gestation in women undergoing IVF.

Impact of elevated peak serum estradiol levels during controlled ovarian hyperstimulation on the birth weight of term singletons from fresh IVF-ET cycles.

PURPOSE: To investigate the impact of elevated serum estradiol (E2) levels on the day of hCG trigger on the birth weight of term singletons after fresh In Vitro Fertilization (IVF)-Embryo Transfer (ET) cycles. METHODS: Retrospective cohort study of all patients initiating fresh IVF-ET cycles resulting in live births between January 2004 and February 2013. The incidence of low birthweight (LBW) term singletons in patients with E2 levels on day of hCG trigger above or below the 95 % cutoff for E2 values in our clinic (3,069.2 pg/mL) was estimated. Multiple gestations and vanishing twin pregnancies were excluded. RESULTS: Two thousand nine hundred thirty-nine singleton live births were identified for inclusion. One hundred forty seven (5 %) and 2792 (95 %) live singleton births occurred in patients with peak E2 levels above and below 3,069.2 pg/mL, respectively. The overall incidence of term LBW was 5.4 % in the >3,069.2 pg/mL group compared to 2.4 % in the ≤3,069.2 pg/mL group (P = .038). An E2 level >3,069.2 pg/mL on the day of hCG administration was associated with increased odds of LBW term singletons (OR = 2.29; 95 % CI = 1.03-5.11). The increased odds remained unchanged when adjusting for maternal age (aOR = 2.29; 95 % CI = 1.02-5.14; P = .037), gestational age at delivery (aOR = 2.04; 95 % CI = 1.22-3.98; P = .025), and day 3 versus blastocyst transfer (aOR = 2.5; 95 % CI = 1.11-5.64; P = .023). CONCLUSIONS: Peak E2 level >3,069.2 pg/mL is associated with increased odds of LBW term singletons after fresh IVF-ET cycles. Conservative stimulation protocols aiming not to exceed an E2 level of 3,000 pg/mL may be advantageous for placentation and fetal growth if a fresh transfer is planned.

Value of antimüllerian hormone as a prognostic indicator of in vitro fertilization outcome.

OBJECTIVE: To determine the predictive attributes of antimüllerian hormone (AMH) in terms of oocyte yield, cycle cancellation, and pregnancy outcomes. DESIGN: Retrospective cohort. SETTING: Academic center. PATIENT(S): All patients initiating IVF at the Weill-Cornell Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine from April 2010 through January 2013. INTERVENTION(S): In vitro fertilization without preimplantation genetic testing. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved, cycle cancellation, clinical and ongoing pregnancy, implantation, and miscarriage rates. RESULT(S): Antimüllerian hormone was positively correlated with number of eggs retrieved. Number of oocytes retrieved increased with increasing AMH within each age group and diminished slightly within AMH groupings as age increased. Overall, AMH was significantly correlated with risk of cycle cancellation, with an area under the curve (AUC) of 0.74. Patients with undetectable AMH had a 13.3-fold increased risk of cancellation as compared with patients with an AMH >2.0 ng/mL. Antimüllerian hormone had an AUC of 0.83 for prediction of three or fewer oocytes; undetectable AMH exhibited sensitivity and specificity of 21.1% and 98.2%, respectively, for three or fewer oocytes retrieved. Antimüllerian hormone was less predictive of pregnancy, with AUCs ranging from 0.55 to 0.65. Even with undetectable AMH, 23.5% of patients <40 years old achieved live birth after transfer. CONCLUSION(S): Antimüllerian hormone is a fairly robust metric for the prediction of cancellation and how many oocytes may be retrieved after stimulation but is a relatively poor test for prediction of pregnancy after any given treatment cycle. Patients with extremely low levels of AMH still can achieve reasonable treatment outcomes and should not be precluded from attempting IVF solely on the basis of an AMH value.

In vitro fertilization for Orthodox Jewish couples: antagonist cycle modifications allowing for mikveh attendance before oocyte retrieval.

OBJECTIVE: To describe a novel method of altering conventional gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles, thereby allowing for the observance of ritual Jewish practices, and to investigate the impact of these cycle modifications on IVF outcomes. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): Orthodox Jewish couples undergoing GnRH antagonist IVF cycles at The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College from January 1, 2007, to November 1, 2011, in whom cycle starts were delayed using GnRH antagonists and estradiol patches. INTERVENTION(S): GnRH antagonist administration on cycle days 2, 3, and 4, as well as estradiol patch application on cycle days 2, 4, and 6. MAIN OUTCOME MEASURE(S): Days of stimulation, total cycle length, implantation, clinical pregnancy, and live-birth rate were compared for 42 Orthodox Jewish couples undergoing a "mikveh patching protocol" versus 42 control patients matched for age, diagnosis, and IVF cycle characteristics. RESULT(S): The protocol modifications successfully ensured the ability to visit the mikveh before retrieval by extending total cycle length by 3.85 days on average, with no decrement in implantation (43.2% vs. 39.3%), clinical pregnancy (57.1% vs. 59.5%), or live-birth rates (50.0% vs. 54.8%) as compared with controls. CONCLUSION(S): GnRH antagonist cycles can be successfully modified to allow for IVF that remains consistent with the observance of Orthodox Jewish practices.

Fertility preservation using controlled ovarian hyperstimulation and oocyte cryopreservation in a premenarcheal female with myelodysplastic syndrome.

OBJECTIVE: To report the first case of fertility preservation in a premenarcheal female by use of controlled ovarian hyperstimulation and oocyte cryopreservation. DESIGN: Case report. SETTING: Reproductive endocrinology and infertility unit of a tertiary care university-based medical center. PATIENT(S): A 13-year-old premenarcheal female with Tanner stage 3 breast development and Tanner stage 1 pubic hair diagnosed with myelodysplastic syndrome, referred by her medical oncologist for fertility preservation before undergoing a potentially sterilizing antineoplastic therapy. INTERVENTION(S): Evaluation of ovarian reserve, ovarian stimulation, transvaginal oocyte aspiration, in vitro maturation of immature oocytes, and oocyte cryopreservation. MAIN OUTCOME MEASURE(S): Cryopreservation of mature oocytes. RESULT(S): Successful controlled ovarian hyperstimulation allowed for the cryopreservation of 18 mature oocytes before the patient's gonadotoxic treatment. The oocyte retrieval and cryopreservation did not delay the patient's planned chemotherapy. CONCLUSION(S): Ovarian stimulation and oocyte cryopreservation can be successfully performed in premenarcheal/peripubertal patients, thus providing a viable alternative to ovarian tissue freezing for fertility preservation in the pediatric population.

Intracytoplasmic sperm injection (ICSI) using cryopreserved sperm from men with malignant neoplasm yields high pregnancy rates.

OBJECTIVE: To investigate the efficacy of IVF-intracytoplasmic sperm injection (ICSI) in patients who cryobanked semen before cancer treatment. DESIGN: Retrospective consecutive study. SETTING: University-based IVF unit. PATIENT(S): One hundred eighteen couples undergoing IVF-ICSI using pretreatment frozen sperm. INTERVENTION(S): Treatment follow-up. MAIN OUTCOME MEASURE(S): Semen parameters and clinical pregnancy rates. RESULT(S): One hundred eighteen couples underwent 169 IVF cycles using pretreatment cryopreserved sperm; the average sperm count was 66.5 x 10(6)/mL, and the average motility was 45.6%. Post-thaw sperm average density was 40.9 x 10(6)/mL with 14.2% motility. The clinical pregnancy rate was 56.8% per retrieval; 96 pregnancies were achieved, resulting in 126 children born and 11 spontaneous abortions. Patients with prostate cancer had the worst semen parameters before sperm banking and the lowest clinical pregnancy rates. CONCLUSION(S): IVF-ICSI is the recommended treatment for most couples with cryopreserved sperm for male cancer. High pregnancy and delivery rates after IVF-ICSI using cryopreserved sperm from patients with cancer should encourage all reproductive-age males to cryobank semen immediately after diagnosis; physicians should discuss this and advise freezing multiple samples before treatment.

Obesity and in vitro fertilization: negative influences on outcome.

OBJECTIVE: To determine the influence of body mass index (BMI) on in vitro fertilization (IVF) outcome by studying a large cohort of good-prognosis IVF patients. STUDY DESIGN: This was a retrospective study at a university-based IVF center evaluating 920 good-prognosis patients (< 40 years, all with normal ovarian reserve) undergoing luteal leuprolide down-regulation and gonadotropin stimulation for IVF and evaluating IVF outcome, including response to stimulation, cancellation rates and pregnancy outcome based on obesity status. RESULTS: One hundred forty-eight (16.09%) patients were classified as obese (BMI > 27). Obese patients were more likely to undergo cancellation (14.9% vs. 9.1%, p = 0.03) when compared to nonobese patients. There was no difference in the amount of gonadotropins required. Obese patients had fewer oocytes retrieved and lower peak estradiol levels than did nonobese patients. In spite of the lower response, the clinical pregnancy rates per retrieval were no different (56.4% for both groups). CONCLUSION: Obese patients undergoing IVF are more likely to undergo cancellation. If cancellation does not occur, obesity confers a risk of a lower stimulation response. Despite this, the clinical pregnancy rates (per retrieval) were no different in obese patients and nonobese patients.

Ovarian hyperstimulation syndrome: strategies for prevention.

Ovarian hyperstimulation syndrome (OHSS) is a serious, iatrogenic complication of ovarian stimulation. The following report is a review of traditional and new strategies to prevent the development of OHSS. Techniques such as reducing the ovarian stimulus, coasting and cryopreservation are discussed. Other more investigative strategies are also summarized, including follicular aspiration, in-vitro maturation of immature oocytes, the use of gonadotrophin-releasing hormone (GnRH) agonists to trigger ovulation and the use of volume expanders such as hydroxyethyl starch. In addition, a review of the internal experience with OHSS at the authors' institution is described. All these preventative approaches are based on current understanding of the physiologic mechanisms involved in the pathogenesis of OHSS.