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To understand the impact of sperm speed as they swim against the flow on fertilization rates, we created conditions similar to the female reproductive tract (FRT) on a microfluidic platform for sperm selection. Selected sperm were evaluated based on early development of fertilized embryos. Bovine and human spermatozoa were selected at various fluid flow rates within the device. We found that the speed of bovine spermatozoa increases as the flow rate increases and that the amount of DNA fragmentation index is lowered by increasing the flow rate. Bovine spermatozoa selected by our platform at low (150 μL h -1 , shear rate 3 s -1 ), medium (250 μL h -1 , shear rate 5 s -1 ), and high flow rates (350 μL h -1 , shear rate 7 s -1 ) were used for fertilization and compared to sperm sorted by centrifugation. The samples collected at the highest flow rate resulted in the formation of 23% more blastocysts compared to the control. While selecting for higher quality sperm by increasing the flow rate does result in lower sperm yield, quality improvement and yield may be balanced by better embryonic development.

Objective: To determine if increasing paternal age has an adverse effect on pregnancy outcomes in paired donor egg recipients who received oocytes from the same donor in the same stimulation cycle., Design: Retrospective cohort study., Setting: Reproductive Medicine Center., Patient(s): The study included 154 recipients who received oocytes from a split donor oocyte cycle and received sperm from men in discrepant age groups (group A: <45 years old; group B: ≥45 years old)., Intervention(s): None., Main Outcome Measure(s): Implantation rate, pregnancy loss rate, pregnancy rate, and live birth rate., Result(s): The median paternal age was 41 years old for group A and 48 years old for group B. The pregnancy rate was 81% in group A compared with 69% in group B. The live birth rate was 65% in group A compared with 53% in group B. The rate of pregnancy loss was 19% in group A and 23% in group B. The implantation rate was 69% in group A compared with 66% in group B. The adjusted odds of pregnancy were found to be 65% lower for patients in the older partner age group (95% confidence interval [CI], 0.13, 0.95). The adjusted odds of live birth rate (odds ratio [OR], 0.45; 95% CI, 0.20, 1.00), implantation rate (OR, 0.91; 95% CI, 0.43, 1.92), and rate of pregnancy loss (OR, 1.5; 95% CI, 0.5, 4.5) favored the younger partner age group; however, these results were not statistically significant., Conclusion(s): In this model that controlled for oocyte quality to the greatest degree possible by using paired recipients from the same donor from the same stimulation cycle, we found that increased paternal age had a negative effect on pregnancy rates., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of this article is to gather 9 thought leaders and their team members to present their ideas about the future of in vitro fertilization and the andrology laboratory. Although we have seen much progress and innovation in the laboratory over the years, there is still much to come, and this article looks at what these leaders think will be important in the future development of technology and processes in the laboratory., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The in vitro fertilization and andrology laboratories are at the center of assisted reproductive technologies and the place where technicians and embryologists manipulate gametes and preimplantation-stage embryos with the goal of achieving the best embryo for transfer. Through the years, these laboratories have seen developments in technique, technology, and testing. The goal of this Views and Interviews series is to bring together the thought leaders in the field and envision what the laboratories will look like in the next 10 years., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Research Question: Do women of racial minorities aged 40 years or older have similar reproductive and obstetric outcomes as white women undergoing IVF?, Design: A retrospective cohort study conducted at a single academic university-affiliated centre. The study population included women aged 40 years or older undergoing their first IVF cycle with fresh cleavage-stage embryo transfer stratified by racial minority status: minority (black or Asian) versus white. Clinical intrauterine pregnancy and live birth rate were the primary outcomes. Preterm delivery (<37 weeks) and small for gestational age were the secondary outcomes. Odds ratios with 95% confidence intervals were estimated. P < 0.05 was considered to be statistically significant., Results: A total of 2050 cycles in women over the age of 40 years were analysed, 561 (27.4%) of which were undertaken by minority women and 1489 (72.6%) by white women. Minority women were 30% less likely to achieve a pregnancy compared with their white (non-Hispanic) counterparts (adjusted OR 0.68, CI 0.54 to 0.87). Once pregnant, however, the odds of live birth were similar (adjusted OR 1.23, CI 0.91 to 1.67). Minority women were significantly more likely to have lower gestational ages at time of delivery (38.5 versus 39.2 weeks, P = 0.009) and were more likely to have extreme preterm birth delivery 24-28 weeks (5.5 versus 1.0%, P = 0.021)., Conclusion: Minority women of advanced reproductive age are less likely to achieve a pregnancy compared with white (non-Hispanic) women. Once pregnancy is achieved, however, live birth rates are similar albeit with minority women experiencing higher rates of preterm delivery., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: This study sought to identify the initiation of placental hormonal production as defined by the production of endogenous estradiol (E2) and progesterone (P4) in a cohort of patients undergoing programmed endometrial preparation cycles with single embryo transfers resulting in live-born singletons., Methods: In this retrospective cohort study, patients undergoing either programmed frozen-thawed embryo transfer (FET) with autologous oocytes or donor egg recipient (DER) cycles with fresh embryos were screened for inclusion. Only patients who underwent a single embryo transfer, had a single gestational sac, and a resultant live-born singleton were included. All patients were treated with E2 patches and intramuscular progesterone injections. Main outcome measures were serial E2 and P4, with median values calculated for cycle days 28 (baseline), or 4w0d gestational age (GA), through 60, or 8w4d GA. The baseline cycle day (CD) 28 median value was compared to each daily median cycle day value using the Wilcoxon signed rank test., Results: A total of 696 patients, 569 using autologous oocytes in programmed FET cycles and 127 using fresh donor oocytes, from 4/2013 to 4/2019 met inclusion criteria. Serum E2 and P4 levels stayed consistent initially and then began to increase daily. Compared to baseline CD 28 E2 (415 pg/mL), the serum E2 was significantly elevated at 542 pg/mL (P < 0.001) beginning on CD 36 (5w1d GA). With respect to baseline CD 28 P4 (28.1 ng/mL), beginning on CD 48 (6w6d GA), the serum P4 was significantly elevated at 31.6 ng/mL (P < 0.001)., Conclusion: These results demonstrate that endogenous placental estradiol and progesterone production may occur by CD 36 and CD 48, respectively, earlier than traditionally thought.

Research Question: What is the impact of low body mass index (BMI) on live birth rates and obstetric outcomes in infertile women treated with IVF and fresh embryo transfer?, Design: This was a retrospective cohort study of infertile patients in an academic hospital setting who underwent their first oocyte retrieval with planned autologous fresh embryo transfer between 1 January 2012 and 31 December 2018. The primary study outcome was live birth rate. Secondary outcomes were IVF treatment and delivery outcomes. Underweight patients were stratified into a significantly underweight group (body mass index [BMI] <17.5 kg/m 2 ) and a mildly underweight group (BMI 17.5-18.49 kg/m 2 ), and were compared with a normal-weight group (BMI 18.5-24.9 kg/m 2 )., Results: A total of 5229 patients were included (significantly underweight, 76; mildly underweight, 231; normal weight, 4922), resulting in 4798 embryo transfers. After oocyte retrieval, there were no significant differences between groups for total oocytes, mature oocyte yield and number of supernumerary blastocysts cryopreserved. Among women who had an embryo transfer, there were no significant differences in the live birth rates in significantly (31.0%, odds ratio [OR] 0.67, confidence interval [0.95, CI] 0.40-1.13) and mildly (37.7%, OR 0.95, CI 0.73-1.33) underweight patients compared with normal-weight patients (35.9%). Additionally, there were no statistically significant increased risks of preterm delivery, Caesarean delivery or a low birthweight (<2500 g) neonate., Conclusions: Mildly and significantly underweight infertile women have similar pregnancy and live birth rates to normal-weight patients after IVF treatment. In addition, underweight patients do not have an increased risk of preterm delivery (<37 weeks), Caesarean delivery or a low birthweight neonate., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: Assess the effect of class III (body mass index [BMI, kg/m 2 ] 40-49.9) and class IV obesity (≥ 50) on clinical pregnancy and live birth outcomes after first oocyte retrieval and fresh embryo transfer cycle., Design: Cohort study SETTING: Academic center PATIENTS: Patients undergoing their first oocyte retrieval with planned fresh embryo transfer in our clinic between 01/01/2012 and 12/31/2018. Patients were stratified by BMI: 18.5-24.9 (n = 4913), 25-29.9 (n = 1566) 30-34.9 (n = 559), 35-39.9 (n = 218), and ≥ 40 (n = 114)., Intervention: None MAIN OUTCOME MEASURE: Live birth rate RESULTS: Following embryo transfer, there were no differences in pregnancy rates across all BMI groups (p value, linear trend = 0.86). However among pregnant patients, as BMI increased, a significant trend of a decreased live birth rate was observed (p value, test for linear trend = 0.004). Additionally, as BMI increased, a significant trend of an increased miscarriage rate was observed (p value, linear trend = < 0.001). Compared to the normal-weight cohort, women with a BMI ≥ 40 had a significantly higher rate of cancelled fresh transfers after retrieval (18.4% vs. 8.2%, OR 2.51; 95%CI 1.55-4.08). Among singleton deliveries, a significant trend of an increased c-section rate was identified as the BMI increased (p value, linear trend = <0.001)., Conclusion: Overall, patients with a BMI > 40 have worse IVF treatment outcomes compared to normal-weight patients. After embryo transfer, their pregnancy rate is comparable to normal-weight women; however, their miscarriage rate is higher, leading to a lower live birth rate for pregnant women in this population. Patients with a BMI > 40 have a c-section rate that is 50% higher than normal-weight patients.

Study Question: Do women ≥40 years old without a male partner who utilize donor sperm have the same reproductive outcomes as those who utilize their partner's sperm?, Summary Answer: After controlling for relevant confounders, women ≥40 years old using donor sperm for IVF have significantly higher odds of having a live birth compared to those utilizing their partner's sperm., What Is Known Already: Women who are unpartnered or in same-sex relationships are by definition not infertile, but may choose to conceive using donor sperm. It is not known how IVF outcomes are affected with the use of donor sperm compared to women utilizing their partner's sperm, particularly at very advanced maternal ages., Study Design, Size, Duration: This is a retrospective cohort study conducted at a university-affiliated center of women undergoing IVF with fresh embryo transfer between 2008 and 2018., Participants/materials, Setting, Methods: Patients were divided into two groups based on the ejaculated sperm source utilized: donor or partner sperm. Live birth rate was the primary outcome. Pregnancy rate was the secondary outcome. Multivariable logistic regression was performed and adjusted for age, the developmental stage of the embryo, and the number of embryos transferred. Unadjusted odds ratio (OR) and adjusted OR (aOR) with 95% CI for pregnancy and live birth were estimated. Statistical significance was denoted by P < 0.05., Main Results and the Role of Chance: A total of 3910 cycles in women ≥40 years old were analyzed, of which 307 utilized donor sperm and 3603 utilized their partner's sperm to conceive. In the univariate analysis, patients utilizing donor sperm were found to have similar pregnancy rates as those utilizing partner sperm (41.0 vs 39.8%, OR: 0.95, 95% CI: 0.75-1.20). After adjusting for age, the number of embryos transferred and the developmental stage of the embryos, the model estimates did not vary (aOR: 1.22, 95% CI: 0.95-1.56). Similarly, the univariate analysis for live birth did not demonstrate a difference between groups (19.2 vs 17.8%, OR: 0.91, 95% CI: 0.67-1.22). However, after a similar adjustment was made for confounders, the use of donor sperm was associated with statistically significant increased odds of live birth (aOR: 1.38, 95% CI: 1.01-1.88)., Limitations, Reasons for Caution: As with any retrospective study, the potential for residual confounding exists, despite attempts to control for this with regression modeling., Wider Implications of the Findings: Women ≥40 years old who are unpartnered or in same-sex relationships can be counseled that their odds of a live birth are slightly better than women in heterosexual relationships utilizing their partner's sperm. These findings serve to further refine and individualize counseling on the expected IVF outcomes for women in this population., Study Funding/competing Interest(s): No funding was sought for this study. The authors declare no competing interests., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Artificial intelligence (AI) systems have been proposed for reproductive medicine since 1997. Although AI is the main driver of emergent technologies in reproduction, such as robotics, Big Data, and internet of things, it will continue to be the engine for technological innovation for the foreseeable future. What does the future of AI research look like?, (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Embryo evaluation and selection embody the aggregate manifestation of the entire in vitro fertilization (IVF) process. It aims to choose the "best" embryos from the larger cohort of fertilized oocytes, the majority of which will be determined to be not viable either as a result of abnormal development or due to chromosomal imbalances. Indeed, it is generally acknowledged that even after embryo selection based on morphology, time-lapse microscopic photography, or embryo biopsy with preimplantation genetic testing, implantation rates in the human are difficult to predict. Our pursuit of enhancing embryo evaluation and selection, as well as increasing live birth rates, will require the adoption of novel technologies. Recently, several artificial intelligence (AI)-based methods have emerged as objective, standardized, and efficient tools for evaluating human embryos. Moreover, AI-based methods can be implemented for other clinical aspects of IVF, such as assessing patient reproductive potential and individualizing gonadotropin stimulation protocols. As AI has the capability to analyze "big" data, the ultimate goal will be to apply AI tools to the analysis of all embryological, clinical, and genetic data in an effort to provide patient-tailored treatments. In this chapter, we present an overview of existing AI technologies in reproductive medicine and envision their potential future applications in the field., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Question: Will a delay in initiating IVF treatment affect pregnancy outcomes in infertile women with diminished ovarian reserve?, Summary Answer: A delay in IVF treatment up to 180 days does not affect the live birth rate for women with diminished ovarian reserve when compared to women who initiate IVF treatment within 90 days of presentation., What Is Known Already: In clinical practice, treatment delays can occur due to medical, logistical or financial reasons. Over a period of years, a gradual decline in ovarian reserve occurs which can result in declining outcomes in response to IVF treatment over time. There is disagreement among reproductive endocrinologists about whether delaying IVF treatment for a few months can negatively affect patient outcomes., Study Design, Size, Duration: A retrospective cohort study of infertile patients in an academic hospital setting with diminished ovarian reserve who started an IVF cycle within 180 days of their initial consultation and underwent an oocyte retrieval with planned fresh embryo transfer between 1 January 2012 and 31 December 2018., Participants/materials, Setting, Methods: Diminished ovarian reserve was defined as an anti-Müllerian hormone (AMH) <1.1 ng/ml. In total, 1790 patients met inclusion criteria (1115 immediate and 675 delayed treatment). Each patient had one included cycle and no subsequent data from additional frozen embryo transfer cycles were included. Since all cycle outcomes evaluated were from fresh embryo transfers, no genetically tested embryos were included. Patients were grouped by whether their cycle started 1-90 days after presentation (immediate) or 91-180 days (delayed). The primary outcome was live birth (≥24 weeks of gestation). A subgroup analysis of more severe forms of diminished ovarian reserve was performed to evaluate outcomes for patients with an AMH <0.5 and for patients >40 years old with an AMH <1.1 ng/ml (Bologna criteria for diminished ovarian reserve). Logistic regression analysis, adjusted a priori for patient age, was used to estimate the odds ratio (OR) with a 95% CI. All pregnancy outcomes were additionally adjusted for the number of embryos transferred., Main Results and the Role of Chance: The mean ± SD number of days from presentation to IVF start was 50.5 ± 21.9 (immediate) and 128.8 ± 25.9 (delayed). After embryo transfer, the live birth rate was similar between groups (immediate: 23.9%; delayed: 25.6%; OR 1.08, 95% CI 0.85-1.38). Additionally, a similar live birth rate was observed in a subgroup analysis of patients with an AMH <0.5 ng/ml (immediate: 18.8%; delayed: 19.1%; OR 0.99, 95% CI 0.65-1.51) and in patients >40 years old with an AMH <1.1 ng/ml (immediate: 12.3%; delayed: 14.7%; OR 1.21, 95% CI 0.77-1.91)., Limitations, Reasons for Caution: There is the potential for selection bias with regard to the patients who started their IVF cycle within 90 days compared to 91-180 days after initial consultation. In addition, we did not include patients who were seen for initial evaluation but did not progress to IVF treatment with oocyte retrieval; therefore, our results should only be applied to patients with diminished ovarian reserve who complete an IVF cycle. Finally, since we excluded patients who started their IVF cycle greater than 180 days from their first visit, it is not known how such a delay in treatment affects pregnancy outcomes in IVF cycles., Wider Implications of the Findings: A delay in initiating IVF treatment in patients with diminished ovarian reserve up to 180 days from the initial visit does not affect pregnancy outcomes. This observation remains true for patients who are in the high-risk categories for poor response to ovarian stimulation. Providers and patients should be reassured that when a short-term treatment delay is deemed necessary for medical, logistic or financial reasons, treatment outcomes will not be affected., 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: Not applicable., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To determine whether luteal support with intramuscular injection of human chorionic gonadotropin 1 day post-LH surge in natural cycle frozen embryo transfer (nFETs) increases ongoing pregnancy rates (OPR)., Methods: Retrospective cohort study of women who underwent natural cycle FET with transfer of a single day-5 or - 6 euploid blastocyst between January 2017 and December 2018 at an academic medical center were divided into two groups based on whether they received hCG 1 day post-LH surge. Patients with uterine factor infertility were excluded., Results: A total of 529 nFET cycles were included. The OPR was significantly higher in the treatment group than in the non-treatment group when controlling for potential confounders such as embryo morphology (69.9% versus 57.4%, p = 0.0119, aOR1.724, 95% CI 1.13-2.65). There were no significant differences observed in the rates of first trimester loss (aOR 1.05, 95% CI 0.032-2.96) or biochemical pregnancy (aOR 0.79, 95% CI 0.31-1.76). Odds ratios were adjusted for patient's age, body mass index, peak endometrial thickness, gravidity, and parity., Conclusion: The current data suggest that the hCG booster given to patients within 1 day post-LH surge results in improved cycle outcomes compared to patients who do not receive the booster.

The past decade has witnessed a rapid increase in the number of frozen-thawed embryo transfer (FET) cycles. Several factors have contributed to the increase in FET cycles, including improvement in culture media, vitrification, and an increase in preimplantation genetic testing of embryos. However, the accelerated trend in FET cycles also suggests that FET may be preferred over fresh embryo transfer. The current review explores the factors that have influenced this practice shift toward preferential FET and why this shift may be premature.

Background: Age-related decline in reproductive potential is mainly due to the increased incidence of aneuploidy. Furthermore, 2 recent studies have shown that euploid embryos of older women may have a lower implantation potential compared to those of younger women, suggesting that aging might compromise embryos beyond their ploidy status. However, the inherent limitations of these studies preclude solid conclusions., Objective: The aim of this study was to determine whether maternal age at retrieval affects the implantation potential of euploid blastocysts., Materials and Methods: This is a retrospective cohort study that was conducted at an academic medical center. Patients who underwent frozen-thawed euploid embryo transfers (FET) between 2013 and 2016 were included. Cycles were divided into the following 5 age groups: <35, 35-37, 38-40, 41-42, and >42 years of age. Blastocysts were assessed before biopsy and assigned the following morphological grades: excellent (3-6AA), good (3-6AB, 3-6BA), average (2-6BB), and poor (3-6BC, 3-6CB, 3-6CC). The main outcome measures were implantation (IR) and live birth (LBR) rates. Both χ 2 and Fisher exact tests were used to compare categorical variables. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and controlled for confounders., Results: A total of 785 FET cycles (870 blastocysts) were included. Excellent-quality blastocysts were associated with a significantly higher LBR compared with good-quality (78.8% vs 63.8%), average-quality (78.8% vs 54.2%), and poor-quality (78.8% vs 28.3%) counterparts. Poor-quality embryos yielded a higher spontaneous abortion (SAB) rate compared with average-, good-, and excellent-quality blastocysts (25.0%, 9.0%, 6.9%, and 2.4%, respectively). Embryos biopsied on day 5 had a significantly higher LBR compared with those biopsied on day 6 (60.0% vs 46.6%). The 5 age groups (<35, 35-37, 38-40, 41-42, and >42 years) had comparable IRs (56.5%, 52.9%, 55.4%, 59.1%, and 71.4%, respectively), LBRs (55.1%, 51.3%, 53.5%, 52.4%, and 61.9%, respectively), and SAB rates (8.8%, 7.9%, 8.3%, 14.3, and 13.3%, respectively). Older women had fewer euploid embryos, but they were of comparable morphology and developed at a similar rate to the blastocyst stage as compared to those of younger women., Conclusion: Maternal age at retrieval influences the number of euploid embryos; however, contrary to previously published studies, it does not affect their implantation potential. The morphodynamic characteristics of embryos, as reflected by blastocyst morphology and speed of development, are critical for selecting among euploid embryos., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

In commemoration of 40 years of in vitro fertilization (IVF), herein we describe the early evolution of the first IVF program at the Eastern Virginia Medical School in Norfolk, Virginia. The birth of the first American IVF baby was the result of the work of many investigators, both in experimental animal models and in humans, heavily relying on the experience of Robert Edwards and Patrick Steptoe in Great Britain. Although their first IVF baby was the result of the retrieval of a single oocyte in the natural cycle, duplicating their methods was not successful in Norfolk. It turns out that the achievement of the first pregnancy in the United States was associated with introducing ovarian stimulation with gonadotropins, establishing the appropriate timing for egg retrieval after hCG administration, retrieving multiple mature oocytes, determining the ideal time for in vitro insemination, and optimizing embryo culture media., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine IVF outcomes in women 45 years and older using autologous oocytes., Methods: This is a retrospective cohort study reviewing all IVF cycles in women ≥ 45 years old from January 1995 to June 2015 that were conducted at one academic medical center. One thousand seventy-eight fresh, autologous IVF cycles met inclusion criteria. PGD/S, natural IVF, and donor egg cycles were excluded. Outcomes were analyzed for the different age groups (age 45, n = 773; age 46, n = 221; age 47, n = 57; age 48, n = 22; age 49, n = 5). Primary outcome measures included IVF cycle characteristics, total pregnancy loss, clinical pregnancy, and live birth rates, and were stratified according to patient age., Results: Mean age of patients in the study cohort was 45.4 ± 0.72. 11.7% of patients did not start due to an elevated FSH or cyst and 28.5% of patients were canceled prior to oocyte retrieval. The overall pregnancy rate per transfer was 18.7% (117/626), of which 82.1% ended in a pregnancy loss. The overall clinical pregnancy and live birth rates per transfer were 9.6 and 3.4%, respectively, which did not differ between age groups. Per cycle start women aged 45 had significantly higher positive pregnancy rates compared to women aged 46 and 47 (14.1 vs. 8.6 vs. 5.9%, p = 0.04). For women 45 years old, the live birth rate was 2.9% per cycle start and was 4.4% per embryo transfer. Of the 21 live births, 20 were in women aged 45 and one live birth was in a 46-year-old woman. There were no live births in any patient with ≤ 4 oocytes retrieved., Conclusion: Autologous IVF in women aged 45 with acceptable ovarian reserve is not futile; however, it does carry very low prognosis. Patients aged 46 and older should be counseled appropriately that a live birth seems highly unlikely.

Intracytoplasmic sperm injection (ICSI) has often been heralded as a ground-breaking technique that has transformed the treatment of couples with infertility. By injecting a single spermatozoon into the cytoplasm of the oocyte, ICSI bypasses the zona pellucida and increases the chances of fertilization and subsequent embryo development, independent of semen parameters. Ever since the first live births using ICSI were reported in 1992, ICSI has become the mainstay of treating male factor infertility as well as overcoming fertilization failure associated with conventional in vitro insemination. Today, ICSI is utilized in nearly 66% of all assisted reproductive treatments worldwide and has resulted in the birth of millions of babies. The primary goal of this review is to provide historical perspectives about the pioneering of ICSI. We begin by highlighting the scientific work of early investigators who elucidated the mechanisms central to mammalian fertilization. Furthermore, we briefly discuss how these findings contributed to the development of IVF for the treatment of infertility. We then emphasize the shortcomings of IVF in treating severe forms of male factor infertility and enumerate the micromanipulation techniques that were developed to circumvent these shortcomings. Finally, we indicate how the inadequacies of these micromanipulation techniques lead to the inception, application and popularity of ICSI., (© 2017 Society for Reproduction and Fertility.)

Among infertile couples, 25% involve both male and female factors, while male factor alone accounts for another 25% due to oligo-, astheno-, teratozoospermia, a combination of the three, or even a complete absence of sperm cells in the ejaculate and can lead to a poor prognosis even with the help of assisted reproductive technology (ART). Intracytoplasmic sperm injection (ICSI) has been with us now for a quarter of a century and in spite of the controversy generated since its inception, it remains in the forefront of the techniques utilized in ART. The development of ICSI in 1992 has drastically decreased the impact of male factor, resulting in millions of pregnancies worldwide for couples who, without ICSI, would have had little chance of having their own biological child. This review focuses on the state of the art of ICSI regarding utility of bioassays that evaluate male factor infertility beyond the standard semen analysis and describes the current application and advances in regard to ICSI, particularly the genetic and epigenetic characteristics of spermatozoa and their impact on reproductive outcome., (© 2017 Society for Reproduction and Fertility.)

Over the past four decades we have witnessed great progress and increasing pregnancy success rates with in vitro fertilization. However, this apparent success has been accompanied by the burden of multiple pregnancies. While efforts to reduce the number of embryos transferred have had a salutary impact on the incidence of high order multiple pregnancies, twin gestations have not diminished significantly. Thus, the search for a marker of embryo quality with the goal of selecting the single best embryo for transfer continues to be the major challenge facing our field. The four contributions in this Views and Reviews present several contemporary approaches, both invasive and non-invasive, for evaluating embryo viability. Each group makes the case that recent techniques, including time-lapse microscopy, biomechanical markers for oocytes and embryos, novel non-invasive methods of evaluating embryo metabolism and function as well as measurement of mitochondrial DNA, will allow the identification of the single best embryo for transfer. They describe several promising markers of embryo viability, although the goal of finding the "holy grail" of embryo selection has not yet been realized., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the association between ABO blood type and live-birth outcomes in patients undergoing IVF with day 5 single-embryo transfer (SET)., Design: Retrospective cohort study., Setting: University-affiliated center., Patient(s): Normal responders, <40 years old, undergoing their first IVF cycle with fresh SET., Intervention(s): None., Main Outcome Measure(s): Live-birth rate was the primary outcome. Secondary outcomes were birth weight and gestational age at delivery. Univariate and multivariable logistic regression was used to examine the association between blood type and live birth, while controlling for confounders. Odds ratios (OR) with 95% confidence intervals (CI) for live birth were estimated., Result(s): A total of 2,329 patients were included. The mean age of the study cohort was 34.6 ± 4.78 years. The distribution of blood types was as follows: A = 897 (38.5%); B = 397 (17.0%); AB = 120 (5.2%); and, O = 1,915 (39.3%) patients. There was no difference in the baseline demographics, ovarian stimulation, or embryo quality parameters between the blood types. The unadjusted ORs for live birth when comparing blood type A (referent) with blood types B, AB, and O were 0.96 (95% CI, 0.6-1.7), 0.72 (95% CI, 0.4-1.2), and 0.96 (95% CI. 0.6-1.7), respectively. The adjusted ORs for live birth remained not significant when comparing blood type A to blood types B, AB, and O individually. No difference in birth weight or gestational age at delivery was noted among the four blood types., Conclusion(s): Our findings suggest that ABO blood type is not associated with live-birth rate, birth weight, or gestational age at delivery in patients undergoing IVF with day 5 SET., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Question: Is supraphysiologic estradiol (E2) an independent predictor of low birth weight (LBW) in singletons born after fresh IVF-embryo transfer (ET) cycles?, Summary Answer: Our results suggest that E2 > 2500 pg/ml is an independent predictor for LBW in full-term singletons born to normal responder patients undergoing fresh IVF-ET cycles., What Is Known Already: The pathogenesis of LBW in IVF singletons remains unknown. However, recent studies have suggested that the hyperestrogenic milieu generated during ovarian stimulation may create a sub-optimal peri-implantation environment, leading to placental dysfunction, and therefore, LBW., Study Design, Size, Duration: Retrospective cohort study of normal responder patients, <40 years old, undergoing fresh IVF-ET cycles resulting in live singleton births between January 2005 and June 2014., Participants/materials, Setting, Methods: A total of 6419 patients had live births after fresh IVF-ET during the study period, of which 2348 (36.6%) patients were excluded due to multiple gestation, vanishing twins or incomplete records. Perinatal outcomes recorded for all patients included birth weight, gestational age (GA) at delivery, mode of delivery and gender. Term birth, preterm birth (PTB) and LBW incidence proportions were plotted against E2 level on the day of trigger. The term LBW incidence proportion (i.e. singletons born at GA ≥ 37 weeks with birth weight <2500 g) was considered the primary outcome of interest., Main Results and the Role of Chance: A total of 4071 patients with live singleton births were included. The median age, BMI, E2 level and birth weight for the study cohort was 36 (33-39) years, 22.3 (20.4-25.0) kg/m2, 1554 (1112.7-2179) pg/ml and 3289 (2920-3628) g, respectively. The incidence proportion of LBW rose from 6.4% (E2 2001-2500 pg/ml) to 20.7% (E2 3501-4000 pg/ml), without a corresponding rise in the incidence proportion of PTB. The odds of term LBW with E2 > 2500 pg/ml were 6.1-7.9 times higher compared to the referent E2 group. Multivariable logistic regression analysis revealed that E2 was an independent predictor for term LBW, even after adjusting for age, BMI, race, parity, infertility diagnosis, duration of ovarian stimulation, gonadotropin dosage and method of insemination (adjusted odds ratio 10.8, 95% CI 9.2-12.5). Receiver operating characteristic analysis generated an AUC estimate of 0.85 for E2 level as a predictor of LBW., Limitations Reasons for Caution: The current study did not include analyses of hypertensive disorders of pregnancy or placental abnormalities. Furthermore, all patients were normal responders and of normal BMI, possibly limiting the overall generalizability of the study. Finally, as with any retrospective study, prospective data are required to validate the role of E2 in predicting LBW., Wider Implications of the Findings: Our results emphasize the importance of minimizing the supraphysiologic elevations of E2 levels during ovarian stimulation in fresh IVF-ET cycles. This, in turn, can optimize the early peri-implantation environment and mitigate adverse perinatal outcomes such as LBW., Study Funding/competing Interest(s): Dr Paul J. Christos was partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (UL1-TR000457-06)., Trial Registration Number: N/A., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Purpose: The purpose of this study was to investigate the utility of a combined GnRH-agonist (GnRH-a) and human chorionic gonadotropin (hCG) trigger in improving ICSI cycle outcomes in patients with poor fertilization history after standard hCG trigger in prior ICSI cycles., Methods: Retrospective cohort study. Patients with a fertilization rate of <20% in at least two prior ICSI cycles who subsequently underwent another ICSI cycle with hCG trigger were compared to those who underwent another ICSI cycle with a combined GnRH-a and hCG trigger. Oocyte maturity, fertilization, clinical pregnancy, and live birth rates were compared. A multiple linear regression model was used to explore the association between combined GnRH-a and hCG trigger (vs hCG trigger alone) and fertilization rate., Results: A total of 427 patients with mean age of 37.3 ± 1.94 years and mean baseline fertilization rate of 17.9 ± 2.03% were included, of which 318 (74.5%) and 109 (25.5%) patients underwent a subsequent ICSI cycle with hCG and combined GnRH-a and hCG trigger, respectively. The baseline parameters of the male and female partner were similar. The mean fertilization rate in the combined trigger group was 16.4% (95% CI: 7.58-25.2%) higher than the hCG trigger group, even after adjustment for confounders. Patients in the combined trigger group had higher oocyte maturity (82.1 vs 69.8%), higher clinical pregnancy (27.5 vs 5.67%), and higher live birth rates (20.2 vs 3.46%) compared to the hCG trigger group., Conclusions: Combined GnRH-a and hCG trigger in ICSI cycles increase oocyte maturity, fertilization, clinical pregnancy, and live birth rates in patients with a history of poor fertilization after standard hCG trigger alone.

Study Objective: To investigate whether the ovarian response and pregnancy outcomes of patients undergoing in vitro fertilization (IVF) after salpingectomy are affected by the underlying indication for salpingectomy., Design: Retrospective cohort study (Canadian Task Force classification II-3)., Setting: University-affiliated fertility center., Patients: All patients age <37 years undergoing IVF within 12 months of laparoscopic salpingectomy. The underlying indication for laparoscopic salpingectomy in the study cohort was tubal ectopic pregnancy, unilateral or bilateral hydrosalpinx, or other reason (hematosalpinx or pyosalpinx), as confirmed by histopathology., Interventions: IVF and embryo transfer (ET)., Measurements and Main Results: Surgical characteristics, demographics, ovarian stimulation parameters, total oocytes retrieved, fertilization rates, implantation rates, and clinical pregnancy rates were compared among the salpingectomy groups. Age- and time-matched patients undergoing their first IVF-ET cycle for male factor infertility, with no previous history of laparoscopy, served as controls., Results: Of the 996 patients who underwent a laparoscopic procedure during the study period, 136 patients underwent unilateral salpingectomy for the following indications: 39 for ectopic pregnancy, 81 for unilateral hydrosalpinx, and 16 for other indications. Among these 136 patients, 29 in the ectopic pregnancy group, 75 in the unilateral hydrosalpinx group, and 10 in the "other" group underwent subsequent IVF-ET. Thirty-one patients underwent both bilateral salpingectomy and subsequent IVF-ET. There was no difference in the antral follicle counts before and after salpingectomy in all groups. There was a statistically significant difference in the mean duration of ovarian stimulation in the salpingectomy groups: ectopic pregnancy, 10.9 ± 2.15 days; unilateral hydrosalpinx, 9.56 ± 1.95 days; bilateral hydrosalpinx, 9.51 ± 2.01 days; "other", 9.89 ± 2.20 days; control, 9.76 ± 1.99 days. Similar trends were noted for total gonadotropins administered when comparing the ectopic pregnancy group (3375.9 ± 931.0 IU) with the remaining groups (unilateral hydrosalpinx, 2841.3 ± 1160.9 IU; bilateral hydrosalpinx, 2519.3 ± 1004.7 IU; "other", 2808.6 ± 990.1 IU; control, 2726.1 ± 1129.8 IU). There were no significant differences in the total number of oocytes retrieved, fertilization rate, implantation rate, or clinical pregnancy rate in the salpingectomy groups compared with controls., Conclusion: Although our findings indicate that patients undergoing IVF after salpingectomy for an ectopic pregnancy have a statistically significantly longer duration of stimulation and require higher gonadotropin doses compared with patients undergoing IVF after salpingectomy for other indications, these differences are of limited clinical significance, given that the total number of oocytes retrieved, implantation rate, and clinical pregnancy rate among the different salpingectomy groups are comparable to those in controls., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether blastocyst grading can predict pregnancy outcomes in the frozen-thawed embryo transfer (FET) of euploid blastocysts., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): Women who underwent FET of euploid embryo(s) between January 2013 and December 2015, with blastocysts were divided into four groups based on their morphologic grading before cryopreservation: excellent (≥3AA), good (3-6AB, 3-6BA, 1-2AA), average (3-6BB, 3-6AC, 3-6CA, 1-2AB, 1-2BA), and poor (1-6BC, 1-6CB, 1-6CC, 1-2BB)., Intervention(s): FET., Main Outcomes Measure(s): Ongoing pregnancy rate (OPR)., Result(s): A total of 417 FET cycles (477 embryos) were included. Excellent-quality embryos (n = 38) yielded a statistically significantly higher OPR than poor-quality embryos (n = 106) (84.2% vs. 35.8%; adjusted odds ratio 11.0; 95% confidence interval, 3.8-32.1) and average-quality embryos (n = 197) (84.2% vs. 55.8%; adjusted odds ratio 4.8; 95% confidence interval, 1.7-13.3). Good-quality embryos (n = 76) were associated with a statistically significantly higher OPR than poor-quality embryos (61.8% vs. 35.8%). These odds ratios were adjusted for patient's age, body mass index, number of transferred embryos, type of frozen cycle, peak endometrial thickness, day of trophectoderm biopsy (5 or 6), and total number of euploid embryos for each patient. An inner cell mass grade of A yielded a statistically significantly higher OPR than ICM grade C (76.2% vs. 13.5%) or grade B (76.2% vs. 53.6%) after controlling for all confounders., Conclusion(s): Contrary to prior published studies, the current data suggest that blastocyst morphologic grading and particularly inner cell mass grade is a useful predictor of OPR per euploid embryo. Morphologic grading should be used to help in the selection among euploid blastocysts., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the impact of prolonged ovarian stimulation on pregnancy outcomes in IVF cycles with fresh day 3 ET., Design: Retrospective cohort study., Setting: University-affiliated center., Patient(s): All patients initiating their first IVF cycle with fresh day 3 ET. Prolonged ovarian stimulation was defined as a duration of more than two standard deviations (95th percentile) for the study cohort (i.e., >13 days)., Intervention(s): None., Main Outcome Measure(s): Live birth rate was considered the primary outcome and was compared between patients undergoing ovarian stimulation for ≤13 days and >13 days. Odds ratios (OR) with 95% confidence intervals (CI) for all pregnancy outcomes after day 3 ET were calculated. The OR for live birth was adjusted using logistic regression., Result(s): A total of 6,410 and 339 patients underwent ovarian stimulation for ≤13 days and >13 days, respectively. There were no differences in the demographics or mean number of day 3 embryos transferred between the two groups. Ovarian stimulation ≤13 days was associated with increased odds of clinical pregnancy (OR 2.15, 95% CI 1.19-3.89) and live birth (OR 2.35, 95% CI 1.25-4.43). The increased odds for live birth in the ≤13-day group remained unchanged after logistic regression. Patients with clinical pregnancies in the >13-day group were younger (34.6 ± 4.91 years) compared with those who did not conceive (38.2 ± 4.72 years)., Conclusion(s): Our findings suggest that ovarian stimulation ≤13 days is associated with increased odds of clinical pregnancy and live birth. In patients undergoing ovarian stimulation >13 days, younger age is associated with live birth., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Although the majority of singleton births after in vitro fertilization (IVF) are uncomplicated, studies have suggested that IVF pregnancies may be independently associated with low birth weight (LBW), preterm birth (PTB), and perinatal mortality. These outcomes complicate multiple gestations as expected, but have also been reported in singletons. A multiple embryo implantation model allows for assessment of the early in utero environment, and therefore, assessment of any maternal constraints on developing fetuses. We question whether adverse perinatal outcomes associated with assisted reproductive techniques (ART) occur as a result of maternal physiologic adaptations., Patients and Methods: This is a retrospective, single center study of ART cycles, specifically intracytoplasmic sperm injection (ICSI) cycles during a 16-year period. For each positive pregnancy test 9-11 days after embryo transfer, an ultrasonogram was performed at 7 weeks of gestation to record the number of implanted fetal poles with cardiac activity. Controlled ovarian stimulation (COS), hCG trigger, oocyte retrieval and sperm injection were performed as per our standard protocols. First trimester implantation sites that resulted in live births were defined as "true" to distinguish them from those that spontaneously reduced called "virtual." Birth outcomes analyzed included birth weight and gestational age at delivery., Results: A total of 17,415 cycles were analyzed. The average maternal age was 36.9 (±5.0) years. An overall fertilization rate of 73.4% generated approximately 48,708 good quality cleavage-stage embryos. In most patients (92.8%), an average of 3 embryos were transferred. The clinical pregnancy rate was 39.2% (n = 6,281). The overall occurrence of multiple gestations was 38.2% (n = 2,608) consisting of 2,038 twin, 511 triplet, and 59 quadruplet pregnancies. Of these multiple gestations, 18.6% of twin, 54.2% of triplet and 76.3% of quadruplet gestations spontaneously reduced. Failure of the implanted embryo to progress was not related to maternal age. Singleton newborns resulting from multiple implantation sites had lower birth weights (P<0.01) and shorter gestational ages (P<0.01) than those from a single implanted embryo. The number of embryos transferred did not affect the gestational length of singleton newborns. Although the birth weights of singletons from multiple implantation sites (virtual singletons) were lower than true singletons, the birth weight of virtual singletons were comparable to the birth weights of true twin, triplet, and quadruplet live births. Multiple logistic regression revealed that virtual singletons were an independent risk factor for PTB (odds ratio: 4.55, 95% CI 2.23-9.29) and LBW (odds ratio: 3.61, 95% CI 1.78-7.32), even after controlling for the number of oocytes, stimulation protocol type, sperm source, total gonadotropins administered, age, embryo quality, and day of embryo transfer., Conclusions: Our study highlights that embryonic implantation sites during early gestation set the growth profile of each embryo, dictating later growth patterns. Specifically, spontaneous reduction of an embryo after multiple embryo implantations can confer greater perinatal risk in the form of LBW and PTB to the surviving fetus. Our findings suggest that maternal constraints or physiologic adaptations maybe one of the mechanisms mediating adverse perinatal outcomes when multiple embryo implantation occurs., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the effect of ovarian stimulation on endometrial receptivity by comparing singleton pregnancy and perinatal outcomes following fresh or frozen-thawed blastocyst transfers., Methods: A retrospective cohort study enrolled patients undergoing fresh or frozen-thawed blastocyst transfers that resulted in live deliveries between January 1, 2010 and September 30, 2013 at a single academic center. Implantation, clinical pregnancy, spontaneous abortion, and live delivery rates were calculated. The incidence of term delivery, preterm delivery, low birth weight, term low birth weight, and very low birth weight were also recorded. To detect a 10% difference in the implantation rate, a minimum sample size of at least 415 transfer cycles in each group was estimated., Results: The study included data from 918 fresh and 1273 frozen-thawed cycles. Patients in both groups were of similar age and there was no difference in the grading of blastocysts. No differences were observed in the implantation (37.3% vs 37.7%), clinical pregnancy (50.2% vs 49.4%), spontaneous abortion (7.3% vs 9.3%), and live delivery (42.9% vs 40.6%) rates of the two groups. A sub-analysis of all live singleton and twin deliveries revealed no difference in perinatal outcomes between the two techniques., Conclusions: The present study demonstrated equivalent singleton pregnancy and perinatal outcomes when comparing frozen-thawed and fresh blastocyst transfer procedures., (Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To compare IVF outcomes between women undergoing frozen transfers of blastocysts verified as euploid by preimplantation genetic screening (PGS) with patients undergoing fresh nonbiopsied blastocyst transfers., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): All patients undergoing IVF-PGS cycles between January 2010 and November 2014 were included (n = 274). Patients were compared with a control group consisting of all fresh blastocyst transfers that occurred during the same period (n = 863)., Intervention(s): Patients underwent IVF-PGS with 24-chromosome screening. Patients with euploid embryos had transfer of one to two embryos in a subsequent frozen ET cycle., Main Outcome Measure(s): Implantation, clinical intrauterine gestation (CIG), miscarriage, biochemical pregnancy (BC), and live birth (LB) rates were compared., Result(s): Odds ratios (ORs) were estimated for outcomes in women undergoing PGS versus controls. Among patients ≤37 years old, there were no differences in CIG and LB rates for single (adjusted ORs [aORs], 1.20 [95 %confidence interval {CI}, 0.66-2.21]; 1.21 [95% CI, 0.66-2.2]) and double ETs (aORs, 1.09 [95% CI, 0.54-2.18]; 0.87 [95% CI, 0.44-1.7]). BC and miscarriage rates were also similar. For patients >37 years old, CIG and LB rates were increased for single (aORs, 3.86 [95% CI, 1.25-11.9]; 8.2 [95% CI, 2.28-29.5]) and double ETs (aORs, 9.91 [95% CI, 2.0-49.6]; 8.67 [95% CI, 2.08-36.2]) with no difference in BC and miscarriage rates. A per-retrieval analysis of the >37 group failed to demonstrate any difference in CIG or LB rates., Conclusion(s): Among patients ≤37, IVF-PGS does not improve CIG, LB, and miscarriage rates. IVF-PGS in women >37 improved CIG and LB rates. However, per cycle, the PGS advantage in this age group does not persist., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2016. Published by Elsevier Inc.)

Study Objective: To investigate the trends in liver function tests (LFTs), renal function tests (RFTs), and complete blood count (CBC) between day 1 and day 7 after single- or double-dose methotrexate (MTX) treatment for sonographically confirmed ectopic pregnancies., Design: Single center, retrospective chart review (Canadian Task Force classification II-3)., Setting: University-affiliated center., Patients: All patients with a sonographically confirmed ectopic pregnancy after fresh in vitro fertilization-embryo transfer cycles between January 2004 and June 2013 treated with MTX were included., Interventions: Single- or double-dose MTX treatment., Measurements and Main Results: LFTs, specifically alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, and total bilirubin levels, were measured on day of MTX administration (baseline) and 7 days later (day 7). Similar measurements of RFTs (blood urea nitrogen [BUN] and creatinine) and CBC (white blood cell [WBC] and platelets) were also performed. The change in LFTs, RFTs, and CBC (Δ) between baseline and day 7 was calculated for both single- and double-dose MTX protocols. Furthermore, the change in LFTs, RFTs, and CBC (Δ baseline vs day 7) for single- and double-dose MTX protocols were compared. Complete data was available for 107 patients: 89 (83.2%) and 18 (16.8%) patients received single- and double-dose MTX treatment, respectively. For either single- or double-dose treatment, no significant difference was found between baseline and day 7 ALT, AST, albumin, total bilirubin, BUN, creatinine, WBC, or platelet levels after MTX treatment. A comparison of post-treatment changes in LFTs, RFTs, and CBC (Δ baseline vs day 7) also showed no difference between single- and double-dose protocols., Conclusion: Our study suggests that repeating LFTs, RFTs, or CBC on day 7 after single- or double-dose MTX treatment for sonographically confirmed ectopic pregnancies may not be necessary in patients with normal baseline testing on day 1., (Copyright © 2015. Published by Elsevier Inc.)

Objective: To investigate whether interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1RA) serum levels in the early luteal phase differ in IVF cycles that result in an ectopic pregnancy (EP) when compared with other outcomes., Design: Retrospective cohort., Setting: Not applicable., Patient(s): A total of 307 women whose serum samples were available, with the following IVF outcomes: 103 live births, 80 negative pregnancy tests, 52 biochemical pregnancies, 47 EPs, and 25 miscarriages., Intervention(s): Serum samples were obtained on cycle days 24 and 28 (cycle day 14 = day of egg retrieval). Levels of IL-1β and IL-1RA were determined by quantitative ELISA performed by blinded personnel., Main Outcome Measure(s): IL-1β and IL-1RA levels, IL-1β-to-IL-1RA ratio versus cycle outcome., Result(s): The IL-1β levels were predictive of an EP. At cycle days 24 and 28 the mean IL-1β levels were higher in patients with an EP (127.1 pg/mL and 166.9 pg/mL, respectively) than in women with any other IVF outcome (15.8-55.3 pg/mL and 14.8-75.5 pg/mL, respectively). At cycle day 24 the IL-1β-to-IL-1RA ratio was 0.18 in the ectopic group versus 0.01-0.09 in the other groups., Conclusion(s): Elevated IL-1β levels and IL-1β-to-IL-1RA ratio as early as 4 days before the first pregnancy test are associated with an EP. If confirmed by prospective studies, clinical application of these findings could potentially improve EP detection., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify risk factors for a suboptimal response to gonadotropin-releasing hormone (GnRH) agonist trigger in in vitro fertilization (IVF) cycles., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): All 424 patients undergoing fresh IVF cycles (n = 500) between August 2007 and June 2013 in whom a GnRH agonist was used as all or part of the ovulation trigger., Intervention(s): GnRH-antagonist-based IVF cycles triggered with leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin., Main Outcome Measure(s): Suboptimal response to GnRH-agonist trigger, as defined by a serum luteinizing hormone (LH) level <15 mIU/mL on the morning after trigger., Result(s): The rate of suboptimal response to the GnRH-agonist trigger was 5.2%. Patients with a suboptimal hormone response had lower follicle-stimulating hormone (<0.1 vs. 3.48) and LH (<0.1 vs. 2.51) levels on day 2 of the cycle start, lower LH (0.109 vs. 0.596) on the day of trigger, and required longer stimulation and more gonadotropins than those with an adequate response. Suboptimal responders were also more likely to have irregular menses and be on long-term oral contraception. Patients with an undetectable LH on the day of trigger had a 25% chance of a suboptimal LH surge. In our study cohort, limiting the use of the GnRH-agonist trigger alone to patients with a trigger day LH ≥0.5 would have reduced the rate of suboptimal response from 5.2% to 0.2%., Conclusion(s): Long-term hormonal contraception use is an independent risk factor for suboptimal response to GnRH-agonist trigger. Patients with very low endogenous serum LH levels on the day of LH trigger are at increased risk for a suboptimal GnRH-agonist trigger response. Understanding the at-risk phenotype and using trigger day LH as a marker for increased risk of suboptimal GnRH-agonist trigger response can be helpful for individualizing treatment and selecting a safe and efficacious trigger medication for patients undergoing IVF., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of methotrexate (MTX) or salpingectomy for ectopic pregnancy on the outcomes of subsequent in vitro fertilization (IVF)-embryo transfer (ET) cycles., Design: Retrospective cohort study (Canadian Task Force Classification II-3)., Setting: Academic center., Patients: All patients undergoing fresh IVF-ET between January 2004 and July 2013 after treatment of an ectopic pregnancy with MTX or salpingectomy in the preceding IVF-ET cycle were analyzed for potential inclusion., Intervention: MTX or laparoscopic salpingectomy for an ectopic pregnancy followed by a subsequent IVF-ET cycle., Measurements and Main Results: A total of 144 patients with sonographically confirmed ectopic pregnancies were identified during the study period. Of these, 107 (74.3%) patients were treated with MTX and 37 (25.7%) were treated with laparoscopic salpingectomy. Eighty-eight patients (82.2%) in the MTX group and 22 patients (59.4%) patients in the salpingectomy group underwent a subsequent IVF-ET cycle. There were no significant differences in demographic data or baseline cycle characteristics between the 2 groups. No difference was observed in basal follicle-stimulating hormone (FSH) level before and after MTX or salpingectomy treatment. Indicators of ovarian responsiveness, including total days of stimulation, total dosage of gonadotropins, and number of mature oocytes before and after either treatment, were comparable in the 2 groups. The number of doses of MTX (1 vs > 1) did not correlate with changes in ovarian response. The pregnancy outcomes, specifically live birth, were equivalent in the 2 groups. Comparing post-MTX cycles and post-salpingectomy cycles, patients in the latter group required higher doses of gonadotropins (+705 IU vs +221.5 IU; p < .01), although the number of mature oocytes remained similar in the 2 groups., Conclusion: Treatment of ectopic pregnancies with MTX or salpingectomy might not adversely affect ovarian reserve, ovarian responsiveness, or subsequent IVF cycle outcomes. However, in our study cohort, patients treated with MTX, those s treated with laparoscopic salpingectomy required higher gonadotropin doses in a subsequent cycle to attain the same number of mature oocytes., (Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF., Design: Phase 3 randomized, double-blind, noninferiority trial., Setting: Multicenter trial., Patient(s): A total of 1,390 women aged 35-42 years., Intervention(s): A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3., Main Outcome Measure(s): Vital pregnancy rate (PR), number of oocytes, and live birth rate., Result(s): Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups., Conclusion(s): Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated., Clinical Trial Registration Number: NCT01144416., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether endometrial biopsy timing affects implantation rates and pregnancy outcomes in patients undergoing in vitro fertilization (IVF) with autologous endometrial coculture (AECC)., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): All patients with a history of at least one failed IVF cycle who underwent an IVF-AECC cycle at our center from May 2004 to November 2013 were included., Intervention(s): Patients underwent luteal-phase endometrial biopsy in preparation for IVF. Biopsy samples were used for IVF in either the subsequent menstrual cycle or a future cycle. Embryos were cultured in AECC media and transferred on day 3., Main Outcome Measure(s): A total of 2,533 cycles of 1,719 patients who underwent an IVF-AECC cycle were identified. Cycles were stratified by endometrial biopsy timing. Clinical outcomes, including implantation, pregnancy, and live birth rates, were analyzed and compared between the two groups., Result(s): A total of 1,416 coculture biopsies were performed in the menstrual cycle before IVF and 1,117 were performed more than one cycle before IVF. The two groups were similar in age, body mass index, number of mature oocytes retrieved, and best embryo grade. There were no significant differences in implantation, clinical pregnancy, or live birth rates, with adjusted relative risks of 1.02 (95% confidence interval [CI] 0.92-1.13), 1.02 (95% CI 0.91-1.14), and 0.99 (95% CI 0.86-1.16), respectively., Conclusion(s): Coculture biopsy in the cycle preceding IVF does not increase implantation, clinical pregnancy, or live birth rates compared with biopsies performed more than one cycle before IVF. Previously demonstrated improvements in embryo quality and pregnancy outcomes in patients undergoing IVF with AECC are probably not attributable to biopsy-induced endometrial injury., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Objective: To investigate the impact of newly diagnosed endometrial polyps during controlled ovarian hyperstimulation (COH) on the outcomes of fresh in vitro fertilization (IVF)-embryo transfer (ET) cycles., Design: A retrospective cohort study (Canadian Task Force classification II-3)., Setting: An academic center., Patients: All patients initiating IVF cycles at the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine during a 1-year period. Patients were stratified into 2 groups based on the presence or absence of newly diagnosed endometrial polyps during COH., Interventions: IVF with fresh ET., Measurements and Main Results: Two thousand nine hundred ninety-three patients were identified: 60 in the polyp group and 2933 in the nonpolyp group. The overall positive pregnancy, clinical pregnancy, spontaneous miscarriage, and live birth rates were similar between the groups. The biochemical pregnancy rate was 18.3% in the polyp group compared with 9.6% in the nonpolyp group (p = .01). This represented a 2-fold increased odds of biochemical pregnancy in the polyp group (odds ratio = 2.12; 95% confidence interval, 1.09-4.12) compared with the nonpolyp group., Conclusion: Newly diagnosed endometrial polyps during COH is associated with an increased biochemical pregnancy rate but ultimately does not adversely impact clinical pregnancy or live birth rates after fresh IVF-ET., (Copyright © 2015. Published by Elsevier Inc.)

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.

In general, standardized in vitro fertilization (IVF) protocols and practice regimens can be applied with success for most patients. Such approaches, however, may not be effective for some women who do not "fit the mold" and for whom highly individualized treatments are more suitable. In this article, we outline our personal experience and treatment approaches for these challenging patients., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To determine the number of cleavage-stage embryos that can be safely transferred in women ≥43 years old., Design: Retrospective cohort., Setting: Academic medical center., Patient(s): All patients ≥43 years old undergoing transfer of five or more cleavage-stage embryos during the period from January 2004 through April 2012., Intervention(s): In vitro fertilization., Main Outcome Measure(s): A total of 567 cycles in 464 patients aged 43-45 years, whose IVF cycles were characterized by transfer of five to eight cleavage-stage embryos were identified. Clinical outcomes and risk of multiples were analyzed, stratifying by age and number of embryos transferred., Result(s): Live birth rates per transfer were 14.4%, 9.4%, and 1.3% for women aged 43, 44, and 45 years, respectively. In 43-year-old women, 2.9% (2/69) of pregnancies were triplet gestations (one selective reduction and one spontaneous reduction). Twin birth rate was 16.3%, 6.7%, and 0 (of all live births) for ages 43, 44, and 45 years, respectively. There was no higher order multiple births. Women aged 43 and 44 years having five or more embryos transferred experienced higher clinical pregnancy rates (PRs) than those patients receiving a transfer of three or four embryos. Clinical outcomes for patients undergoing transfer with six or more embryos were not better than those undergoing transfer with five embryos., Conclusion(s): Transferring five or more day 3 embryos may be a safe option for patients ≥43 years of age, as it is associated with an overall low rate of multiple gestations. Having more than five embryos available for transfer on day 5 is associated with improved IVF outcomes. Whether this benefit is from the additional embryo(s) for transfer or the inherently better prognosis of such patients remains to be determined., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify risk factors for breakthrough LH surge despite GnRH antagonist (GnRH-ant) suppression in IVF cycles., Design: Case-control study., Setting: Academic medical center., Patient(s): All patients undergoing IVF from August 2004 through July 2012 in whom GnRH-ant pituitary suppression (0.25 mg/d) was used in a flexible protocol., Intervention(s): GnRH-ant-based IVF., Main Outcome Measure(s): Breakthrough LH surges as evidenced by an increase in LH (minimum 2.5-fold increase from baseline above a threshold of 17 mIU/mL) associated with a decrease in E2, and free fluid on ultrasound., Result(s): Breakthrough LH surges despite GnRH-ant administration occurred in 37 (0.34%) of the 10,809 antagonist cycles during the study period. Compared with all patients remaining suppressed, patients with breakthrough surges were significantly older and had significantly increased FSH and decreased antral follicle counts. Compared with age-matched controls (allocation ratio, 1:50), significant differences in ovarian reserve remained evident., Conclusion(s): The occurrence of a breakthrough LH surge despite GnRH-ant treatment is a reassuringly rare event. However, patients with diminished ovarian reserve are at risk for this outcome despite GnRH-ant down-regulation. Further studies are needed to determine whether these patients can be prospectively identified and whether they may benefit from higher doses of GnRH-ant., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2014. Published by Elsevier Inc.)

Assisted reproductive technologies (ART) encompass fertility treatments, which involve manipulations of both oocyte and sperm in vitro. This chapter provides a brief overview of ART, including indications for treatment, ovarian reserve testing, selection of controlled ovarian hyperstimulation (COH) protocols, laboratory techniques of ART including in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI), embryo transfer techniques, and luteal phase support. This chapter also discusses potential complications of ART, namely ovarian hyperstimulation syndrome (OHSS) and multiple gestations, and the perinatal outcomes of ART.

Early follow-up studies of IVF children showed that the frequency of birth anomalies resembled those arising with natural conception. More detailed analyses confirmed these findings, reinforcing the concept of the preimplantation period as teratologically "safe." The use of intracytoplasmic sperm injection (ICSI) to achieve fertilization introduced another variable.ICSI's safety has often been criticized because the fertilizing spermatozoon neither binds to the zona pellucida nor fuses with oolemma. Bypassing these physiologic steps together with the arbitrary selection of the spermatozoon has been reason for concern. Thus far, ICSI offspring undergoing adolescence and beyond has provided sufficient information to reassure these qualms. In fact, the health of the offspring generated through ICSI, once taken into consideration the gestational order, the age and the genetic makeup of the couples are generally reassuring.

Since the establishment of in vitro fertilization, it became evident that almost half of the couples failed to achieve fertilization and this phenomenon was attributed to a male gamete dysfunction. The adoption of assisted fertilization techniques particularly ICSI has been able to alleviate male factor infertility by granting the consistent ability of a viable spermatozoon to activate an oocyte. Single sperm injection, by pinpointing the beginning of fertilization, has been an invaluable tool in clarifying the different aspects of early fertilization and syngamy. However, even with ICSI some couples fail to fertilize due to ooplasmic dysmaturity in relation to the achieved nuclear maturation marked by the extrusion of the first polar body. More uncommon are cases where the spermatozoa partially or completely lack the specific oocyte activating factor. In this work, we review the most relevant aspects of fertilization and its failure through assisted reproductive technologies. Attempts at diagnosing and treating clinical fertilization failure are described., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this chapter we elaborate on the intricacies of employing GnRH antagonists for prevention of the endogenous luteinizing hormone surge during IVF. Several practical aspects of implementing a GnRH antagonist-based stimulation protocol are described; selection of the correct dose, choosing when to start the antagonist, programming of cycle starts, selection of the appropriate gonadotropins, and triggering of final oocyte maturation are elucidated.