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Private equity investment in fertility clinics has rapidly increased and is leading to unprecedented changes in the field of reproductive endocrinology and infertility (REI). The goal of this paper was to review private equity's current integration in REI and discuss both benefits and challenges of investor involvement. We found that at least 25% of fellowship programs and medical schools were affiliated with private practice fertility clinics, not free-standing academic clinics. Approximately half of medical schools and nearly all REI fellowship programs that were affiliated with private practices were also backed by private investors. Research participation remains robust in private equity-affiliated REI clinics. With the changing infrastructure, we discuss the potential influence on trainee experience and research while also acknowledging the unique advantages that investor involvement may offer., Competing Interests: F.L.S. has nothing to disclose. E.Y.A. has nothing to disclose. H.S.T. has nothing to disclose. D.B.S. manages investment funds that invest in the IVF industry, with ownership in Cooper Companies Inc, CryoPort Inc, Hamilton Thorne Ltd, INVO Bioscience Inc, Jinxin Fertility Group Ltd, Monash IVF Group Ltd, Progyny Inc, Virtus Health Ltd, Vitrolife AB, Celmatix Inc, MedAnswers, Oova, and TMRW Life Sciences. V.A.K. is a medical policy consultant for eviCore Healthcare and Cigna Healthcare., (© 2023 The Authors.)

In recent years, there has been rapid increase in the availability of elective sex selection via genetic testing of preimplantation embryos created through in vitro fertilization. We explore the standing of this ethically controversial practice in the context of a changing legal landscape after the Dobbs v Jackson Women's Health decision by the US Supreme Court., (© 2023 The Author(s).)

Increased demand for in vitro fertilization (IVF) due to socio-demographic trends, and supply facilitated by new technologies, converged to transform the way a substantial proportion of humans reproduce. The purpose of this article is to describe the societal and demographic trends driving increased worldwide demand for IVF, as well as to provide an overview of emerging technologies that promise to greatly expand IVF utilization and lower its cost., (© 2021. The Author(s).)

Objective: The aim: Identification, verification and analysis of clinically effective risks of limb amputation as a basis for the formation of risk-oriented treatment and diagnostic tactics in victims with limb injuries due to modern hostilities., Patients and Methods: Materials and methods: This research is based on a study of 1,072 cases of limb damage due to modern hostilities in eastern Ukraine in 2014-2020. All injuries were gunshot (bullet and mine injuries). According to the concept of Clinical Risk Management, Clinical Result Risk was chosen for evaluation and analysis. Risk factors - epidemiological and anatomical signs of damage., Results: Results: Quantitative indicators of the clinical effective risk of limb loss are generally small and range from minimal to significant values (0.01-0.24). In some cases - up to 0.4 (significant), and are not critical and catastrophic. Of practical importance are only the risk factors associated with the nature of participation in hostilities and the anatomical characteristics of the injury. Among the immediate causes of limb loss, only primary traumatic amputation matters. Damage to vascular and nerve structures is not critical for limb loss. The impact of other risk factors may be reduced or eliminated if adequate care is provided., Conclusion: Conclusions: The risks of limb loss in victims of modern hostilities vary within the qualitative characteristics of the minimum-significant risk. The greatest importance in the clinical implementation of risks are risk factors related to the performance of functional duties of servicemen and anatomical features. he use of risk-based analysis must be taken into account in the formation of standards of medical care and treatment protocols for victims of modern hostilities.

Study Question: Does the ovarian sensitivity index (OSI) predict embryo quality, pregnancy and live birth in patients undergoing FSH/hMG stimulation for IVF?, Summary Answer: The OSI is predictive of pregnancy and live birth in older women with a more unfavorable prognosis undergoing FSH/hMG stimulation for IVF., What Is Known Already: The OSI was previously reported to reflect gonadotrophin requirements among high, normal and poor responders and to predict pregnancy potential in younger patients undergoing ovarian stimulation with FSH., Study Design Size Duration: A retrospective cohort study that included 1282 women undergoing IVF with FSH/hMG stimulation was carried out between January 2010 and December 2016., Participants/materials Setting Methods: We evaluated 1282 women who underwent fertility treatment with FSH/hMG stimulation and oocyte retrieval at an academically affiliated private fertility center. OSI was calculated as (oocytes ×1000)/total gonadotrophin dose and grouped into two classes based on a receiver operating characteristic (ROC) curve analysis of a randomly selected development sample comprising one-third of the cycles. The remaining cycles comprised the validation group. ROC curves were also used to compare the predictive value of OSI to that of baseline FSH and anti-Müllerian hormone (AMH). Logistic regression models evaluated the effect of high (OSI >0.83) and low (OSI ≤0.83) on clinical pregnancy and live birth in the validation group. Models were adjusted for female age, baseline FSH, AMH and oocyte yield and gonadotrophin dose., Main Results and the Role of Chance: Women presented with a mean ±SD age of 38.6 ± 5.4 years and showed median AMH levels of 0.65 (95% CI 0.61-0.74) ng/ml. They received 5145 ± 2477 IU of gonadotrophins and produced a median 5.2 (95% CI 5.0-5.5) oocytes. Pregnancy and live birth rates per oocyte retrieval for all women were 20.6% and 15.8%, respectively. Patients with higher OSI (less gonadotrophin required per oocyte retrieved) produced significantly more high-quality embryos than patients with low OSI (3.5 (95% CI 3.2-3.8) versus 0.6 (95% CI 0.5-0.7) ( P  = 0.0001)) and demonstrated higher pregnancy (23.2% versus 9.7%) and live birth rates (8.8% versus 5.3%) than their counterparts ( P  = 0.0001 and P  = 0.0001, respectively). After adjustments for age, baseline AMH and FSH, total gonadotrophin dosage and oocyte yield, an OSI >0.83 was associated with greater odds of pregnancy (odds ratio 2.12, 95% CI 1.30-3.45, P  < 0.003) and live birth (odds ratio 1.91, 95% CI 1.07-3.41, P  < 0.028)., Limitations Reasons for Caution: The results may not be applicable to women with excellent pregnancy potential or FSH-only stimulation., Wider Implications of the Findings: The predictive capacity of OSI for embryo quality, pregnancy and live birth, which is independent of AMH or FSH, may help in counseling patients about their pregnancy potential and live birth chances., Study Funding/competing Interests: Intramural funding from the Center for Human Reproduction and the Foundation for Reproductive Medicine. A.W., V.A.K., D.F.A., D.H.B. and N.G. have received research grant support, travel funds and speaker honoraria from various pharmaceutical and medical device companies: none, however, related to the topic presented here. D.H.B. and N.G. are listed as inventors on already awarded and still pending US patents, claiming beneficial effects on diminished ovarian reserve and embryo ploidy from dehydroepiandrosterone supplementation., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

The purpose of this Commentary is to assess whether the designation by New York State Department of Health of 'sexual and reproductive health services as essential' is consonant with the seemingly divergent objectives of providing patient-centred care and advancing national public health objectives in the resource-constrained setting of a global pandemic., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: Increased serum C-protein (CRP) levels reduce fecundity in healthy eumenorrheic women with 1-2 pregnancy losses. Subclinical systemic inflammation may impede maternal immune tolerance toward the fetal semi-allograft, compromising implantation and early embryonic development. Some miscarriages with normal karyotypes could, therefore, be caused by inflammation. Whether pre-pregnancy CRP relates to karyotypes of spontaneously aborted products of conception (POCs) was investigated., Methods: A study cohort of 100 infertile women with missed abortions who underwent vacuum aspirations followed by cytogenetic analysis of their products of conception tissue was evaluated at an academically affiliated fertility center. Since a normal female fetus cannot be differentiated from maternal cell contamination (MCC) in conventional chromosomal analyses, POC testing was performed by chromosomal microarray analysis. MCC cases and incomplete data were excluded. Associations of elevated CRP with first trimester pregnancy loss in the presence of a normal fetal karyotype were investigated., Results: Mean patients' age was 39.9 ± 5.8 years; they demonstrated a BMI of 23.9 ± 4.6 kg/m 2 and antiMullerian hormone (AMH) of 1.7 ± 2.4 ng/mL; 21.3% were parous, 19.1% reported no prior pregnancy losses, 36.2% 1-2 and 6.4% ≥ 3 losses. Karyotypes were normal in 34% and abnormal in 66%. Adjusted for BMI, women with elevated CRP were more likely to experience euploid pregnancy loss (p = 0.03). This relationship persisted when controlled for female age and AMH., Conclusions: Women with elevated CRP levels were more likely to experience first trimester miscarriage with normal fetal karyotype. This relationship suggests an association between subclinical inflammation and miscarriage.

The size of oocytes was previously reported to be smaller in obese women with polycystic ovary syndrome (PCOS). In the present prospective cohort study, we sought to determine whether oocyte size and morphology are associated with patient characteristics in non-PCOS women. Oocyte and oolemmal diameter were measured, enlarged perivitelline space (PVS) and ooplasmic granulation were assessed in 308 MII oocytes from 77 IVF/ICSI couples. Statistical analysis was undertaken using SAS version 9.4 (SAS institute Inc., USA). Continuous values are presented as mean ± SD and compared using a two-sample t-test or Mann-Whitney U test as appropriate. Categorical parameters are presented as proportions and compared using a Fisher exact test. Logistic and linear regression models were used to control for the effect of age for categorical and continuous variables respectively. P-value < 0.05 was considered statistically significant. Patients presented with a mean age of 40.3±5.0 years, had a BMI of 25.1±6.1 kg/m2, median AMH levels of 0.6 ng/ml and produced a median of 4 oocytes. Mean total oocyte diameter was 163.2±7.4 μm (range 145.8-182.1 μm), while oolemmal diameter was 109.4±4.1 μm (range 98.5-122.3 μm). After adjusting for age and ovarian reserve increasing BMI was associated with decreased total oocyte diameter (p<0.05). Total oocyte diameter was also inversely associated with AMH levels (p = 0.03) and oocyte yield (p = 0.04). In contrast to total oocyte diameter, oolemmal diameter was not related to patient characteristics. Younger women and those with large oocyte yields demonstrated fewer oocytes with ooplasmic granulation (p<0.05 and p = 0.01). After adjustments for age, ooplasmic granulation was also less frequently observed in oocytes from women with higher AMH (p = 0.03) and increasing BMI (p<0.01). Fertilization was more likely in oocytes with larger oolemmal diameter (p = 0.008). Embryos from oocytes with larger total and ooplasmic diameters were more likely to be transferred or frozen (p = 0.004 and p = 0.01). In non-PCOS infertile women, BMI and ovarian function relate to total oocyte diameter. These results expand on previously observed associations between oocyte size and BMI in women with PCOS. They indicate the importance of detailed oocyte assessments, which may aid the currently used criteria for embryo selection and help to better understand how oocyte status is associated with later embryo development., Competing Interests: Author AW: As visiting Associate Scientist at the Center for Human Reproduction AW is entitled to full access to all data and materials of this facility and adheres to safety and confidentiality regulations. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

With steadily improving pregnancy and live birth rates, IVF over approximately the first two and a half decades evolved into a highly successful treatment for female and male infertility, reaching peak live birth rates by 2001-2002. Plateauing rates, thereafter, actually started declining in most regions of the world. We here report worldwide IVF live birth rates between 2004 and 2016, defined as live births per fresh IVF/ICSI cycle started, and how the introduction of certain practice add-ons in timing was associated with changes in these live birth rates. We also attempted to define how rapid worldwide 'industrialization' (transition from a private practice model to an investor-driven industry) and 'commoditization' in IVF practice (primary competitive emphasis on revenue rather than IVF outcomes) affected IVF outcomes. The data presented here are based on published regional registry data from governments and/or specialty societies, covering the USA, Canada, the UK, Australia/New Zealand (combined), Latin America (as a block) and Japan. Changes in live birth rates were associated with introduction of new IVF practices, including mild stimulation, elective single embryo transfer (eSET), PGS (now renamed preimplantation genetic testing for aneuploidy), all-freeze cycles and embryo banking. Profound negative associations were observed with mild stimulation, extended embryo culture to blastocyst and eSET in Japan, Australia/New Zealand and Canada but to milder degrees also elsewhere. Effects of 'industrialization' suggested rising utilization of add-ons ('commoditization'), increased IVF costs, reduced live birth rates and poorer patient satisfaction. Over the past decade and a half, IVF, therefore, has increasingly disappointed outcome expectations. Remarkably, neither the profession nor the public have paid attention to this development which, therefore, also has gone unexplained. It now urgently calls for evidence-based explanations.

Purpose: To investigate the effects of dehydroepiandrosterone (DHEA) supplementation on female sexual function in premenopausal infertile women of advanced ages., Methods: This observational study was conducted in an academically affiliated private fertility center. Patients included 87 premenopausal infertile women, 50 of whom completed the study including the Female Sexual Function Index (FSFI) questionnaires and comprehensive endocrine evaluation before and 4-8 weeks after initiating 25 mg of oral micronized DHEA TID., Results: Age of patients was 41.1 ± 4.2 years, BMI 24.4 ± 6.1 kg/m 2 , 86% were married, and 42% were parous. Following supplementation with DHEA, all serum androgen levels increased (each P < 0.0001), while FSH levels decreased by 2.6 ± 4.4 from a baseline of 10.3 ± 5.4 mIU/mL (P = 0.009). The FSFI score for the whole study group increased by 7% (from 27.2 ± 6.9 to 29.2 ± 5.6; P = 0.0166). Domain scores for desire increased by 17% (P = 0.0004) and by 12% for arousal (P = 0.0122); lubrication demonstrated an 8% trend towards improvement (P = 0.0551), while no changes in domain scores for orgasm, satisfaction, or pain were observed. Women in the lowest starting FSFI score quartile (<25.7), experienced a 6.1 ± 8.0 (34%) increase in total FSFI score following DHEA supplementation. Among these women, improvements in domain categories were noted for desire (40%), arousal (46%), lubrication (33%), orgasm (54%), satisfaction (24%), and pain (25%)., Conclusions: This uncontrolled observational study implies that supplementation with DHEA improves sexual function in older premenopausal women with low baseline FSFI scores.

Low FMR1 variants (CGGn<26) have been associated with premature ovarian aging, female infertility and poor IVF treatment success. Until now, there is little published information concerning possible molecular mechanisms for this effect. We wished to examine whether relative expression of RNA and the FMR1 gene's fragile X mental retardation protein (FMRP) RNA isoforms differ in women with various FMR1 sub-genotypes (normal, low CGGn<26 and/or high CGGn≥34). This prospective cohort study was conducted between 2014 and 2017 in a clinical research unit of the Center for Human Reproduction in New York City. The study involved a total of 98 study subjects, including 18 young oocyte donors and 80 older infertility patients undergoing routine in vitro fertilization (IVF) cycles. The main outcome measure was RNA expression in human luteinized granulosa cells of 5 groups of FMRP isoforms. The relative expression of FMR1 RNA in human luteinized granulosa cells was measured by real-time PCR and a possible association with CGGn was explored. All 5 groups of FMRP RNA isoforms examined were found to be differentially expressed in human luteinized granulosa cells. The relative expression of four FMR1 RNA isoforms showed significant differences among 6 FMR1 sub-genotypes. Women with at least one low allele expressed significantly lower levels of all 5 sets of FRMP isoforms in comparison to the non-low group. While it would be of interest to see whether FMRP is also decreased in the low-group we recognize that in recent years it has been increasingly documented that information flow of genetics may be regulated by non-coding RNA, that is, without translation to a protein product. We, thus, conclude that various CGG expansions of FMR1 allele may lead to changes of RNA levels and ratios of distinct FMRP RNA isoforms, which could regulate the translation and/or cellular localization of FMRP, affect the expression of steroidogenic enzymes and hormonal receptors, or act in some other epigenetic process and therefore result in the ovarian dysfunction in infertility., Competing Interests: N.G. and D.H.B. are listed as co-inventors of two awarded U.S. patents, claiming therapeutic benefits for DHEA, and potentially other androgens, in women with DOR. Both authors have other pending patent applications, regarding DHEA, and other androgens, and the Cover Letter FMR1 gene’s effects on ovaries. N.G. N.G., D.H.B. and V. A. K. are co-inventors on three pending patent applications, claiming potential therapeutic benefit for anti-Müllerian hormone (AMH) in infertile women. They also own share in OvaNova Laboratories, LLC, and N.G. owns shares in Fertility Nutraceuticals, LLC, a company that offers nutraceuticals with potential benefits in female and male infertility. N.G. and D.H.B. are receiving patent royalties from this company. N.G. is also the owner of The CHR, where this research was conducted. Other authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: Alternative ovarian stimulation protocols for in vitro fertilisation (IVF) have grown in popularity. Yet, patient populations best suited for these protocols have not been defined. Our objective was, therefore, to determine national IVF utilisation patterns and live birth rates of various ovarian stimulation protocols., Design: Retrospective cohort study., Setting: Academic-affiliated private fertility centre., Participants: Aggregate data published by Society for Assisted Reproductive Technology for autologous IVF cycles performed in the USA during 2014 and 2015 were analysed. IVF cycles were stratified based on ovarian stimulation protocol: 205 705 conventional stimulations, 4397 minimal stimulations, 2785 natural cycles and 514 in vitro maturation (IVM) cycles. Repeat cycles could not be determined in this analysis., Outcome Measures: Utilisation patterns and age-specific live birth rates for various ovarian stimulation protocols., Results: With advancing female age, utilisation of conventional stimulation protocols decreased, while minimal stimulation and natural cycle IVF increased. Diminished ovarian reserve diagnoses were in all age groups less prevalent in patients undergoing conventional stimulation than with all other protocols. Live birth rates were highest with conventional stimulation at 42.4%, 33.1%, 22.1%, 11.7% and 3.9% for <35, 35-37, 38-40, 41-42 and >42 female age groups, respectively. The difference in live birth rates between conventional stimulation and other protocols widened with advancing age from 1.6-fold to 3.9-fold among women <35 years of age, reaching 4.4-fold to 6.6-fold among women >42 years of age., Conclusions: In comparison to conventional stimulation IVF-minimal stimulation, natural cycle IVF and IVM protocols offer lower but still acceptable live birth rates among young women. These alternative protocols are frequently used in older women and those with diminished ovarian reserve, despite their lower live birth rates. The reasons for this apparent incongruity warrant further careful exploration., Competing Interests: Competing interests: VAK previously served as a consultant to the CDC. The Center for Human Reproduction (CHR) annually routinely reports IVF outcome data to CDC and SART. NG, DHB and VAK are listed as co-owners of several already awarded and still pending US patents, none related to the topic of this manuscript. NG is a shareholder in Fertility Nutraceuticals, LLC and owner of the CHR. NG and DHB receive patent royalties from Fertility Nutraceuticals, LLC. NG and DHB have received research support, travel funding and lecture fees from various Pharma and medical device companies, none, in any way related to this manuscript., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine whether a relationship exists between vitamin D (25OH-D) levels and ovarian reserve parameters (antimüllerian hormone [AMH] and FSH levels) in a large cohort of infertile women with a high prevalence of diminished ovarian reserve., Design: Retrospective cohort study., Setting: Academically affiliated private fertility center., Patient(s): A total of 457 infertile women 21-50 years of age who had baseline hormone measurements., Intervention(s): None., Main Outcome Measure(s): Statistical analyses to determine whether a relationship exists between AMH, FSH, and serum 25OH-D levels., Result(s): As defined by 25OH-D <20.0 ng/mL, 74/457 patients (16.2%) had vitamin D deficiency. AMH and FSH levels did not vary between women with vitamin D deficiency and those with normal levels (0.8 ± 3.0 vs. 0.5 ± 1.6 ng/mL [P=.18] and 9.4 ± 7.2 vs. 9.2 ± 9.5 mIU/mL [P=.54], respectively). Multivariate linear regression analysis of log-transformed AMH and FSH with 25OH-D levels adjusted for age, body mass index, and seasonal variation confirmed lack of association. Receiver operating characteristic (ROC) analysis to determine if 25OH-D levels are predictive of AMH showed areas under the ROC curves (AUCs) for women <38 years of age to be 0.501, 0.554, and 0.511 for AMH threshold values of 0.5 ng/mL, 1.0 ng/mL, and 5.0 ng/mL, respectively. For women ≥38 years respective AUC values were 0.549, 0.545, and 0.557 ng/mL., Conclusion(s): Vitamin D levels were not associated with ovarian reserve in a large group of infertile women with a high prevalence of diminished ovarian reserve. Previously reported vitamin D-associated outcomes in infertility patients may, therefore, be mediated by factors other than ovarian reserve., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Anti-Müllerian hormone (AMH) produced by ovarian granulosa cells (GCs) plays a crucial role in ovarian function. It is used as a diagnostic and/or prognostic marker of fertility as well as for pathophysiological conditions in women. In this study, we investigated the underlying mechanism for regulation of AMH expression in GCs using primary mouse GCs and a human GC tumor-derived KGN cell line. We find that growth differentiation factor 9 (GDF9) and bone morphogenetic factor 15 (BMP15) together (GDF9 + BMP15), but not when tested separately, significantly induce AMH expression in vitro and in vivo (serum AMH). Our results show that GDF9 + BMP15 through the PI3K/Akt and Smad2/3 pathways synergistically recruit the coactivator p300 on the AMH promoter region that promotes acetylation of histone 3 lysine 27 (H3K27ac), facilitating AMH/Amh expression. Intriguingly, we also find that FSH inhibits GDF9 + BMP15-induced increase of AMH/Amh expression. This inhibition occurs through FSH-induced protein kinase A/SF1-mediated expression of gonadotropin inducible ovarian transcription factor 1, a transcriptional repressor, that recruits histone deacetylase 2 to deacetylate H3K27ac, resulting in the suppression of AMH/Amh expression. Furthermore, we report that ovarian Amh mRNA levels are significantly higher in Fshβ-null mice (Fshβ-/-) compared with those in wild-type (WT) mice. In addition, ovarian Amh mRNA levels are restored in Fshβ-null mice expressing a human WT FSHβ transgene (FSHβ-/-hFSHβWT). Our study provides a mechanistic insight into the regulation of AMH expression that has many implications in female reproduction/fertility.

Research Question: What level of IVF pregnancy success is currently possible in women of extremely advanced age?, Design: This study reports on outcomes in women aged 43-51 years at the Centre for Human Reproduction, an academically affiliated private clinical fertility and research centre in New York City., Results: During the study years of 2014-2016, 16 pregnancies were established, all through day 3 transfers. Based on 'intent to treat' (cycle start), clinical pregnancy rates were 4/190 (2.1%), 5/234 (2.1%) and 7/304 (2.3%) and live birth rates were 2/190 (1.1%), 1/234 (0.43%) and 4/304 (1.3%) in 2014, 2015 and 2016, respectively. With reference to embryo transfer, clinical pregnancy rates were 4/140 (2.9%), 5/159 (3.1%) and 7/167 (4.2%) and live birth rates were 2/140 (1.4%), 1/159 (0.63%) and 4/167 (2.4%) for the same years. The results for 2016 also included what are probably the two oldest autologous IVF pregnancies ever reported in the literature. These results were obtained with patient ages, percentage of cycle cancellations and other adverse outcome parameters steadily increasing year by year., Conclusions: Female age above 42 is widely viewed as the ultimate barrier to conception with IVF. Data reported here, although small and preliminary, demonstrate that potential outcomes are better than widely perceived, while pregnancy and live birth rates remain significantly inferior to donor egg recipient cycles. However, for selected women at very advanced ages, especially with higher egg/embryo numbers, autologous oocyte IVF offers a better option than widely acknowledged, if they are given individualized age-specific care., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: Infertile women with severely diminished ovarian reserve who have low birth chances with in vitro fertilization (IVF) are often denied treatment with autologous oocytes. This study was designed to determine age-specific treatment efficacy and clinical characteristics of infertile women with severely diminished ovarian reserve who had live birth following IVF with autologous oocytes., Methods: This retrospective cohort study investigated 291 infertile women who underwent 482 IVF cycles with autologous oocytes during 2004 to 2016 at our academically affiliated private fertility center. All women were aged <45 years and had maximum baseline follicle-stimulating hormone (FSH) levels ≥20 mIU/mL. Main outcome measures included pregnancy, spontaneous abortion, and live birth rates. Patient and treatment characteristics were compared for women who achieved a live birth to those who did not., Results: Live birth rates were 8.6% per treated woman and 6% per started IVF cycle. The spontaneous abortion risk was 27% per clinical pregnancy. Age-specific live birth rates were highest at 17.2% for women <35 years and lowest at 1.9% for women >42 years. Women who achieved live birth were younger than those who did not (38.0 ± 8.0 vs 40.0 ± 6.0; P = .008), had lower FSH levels (25.0 ± 20.0 vs 32.5 ± 31.0; P = .006), and produced more oocytes (3.0 ± 5.0 vs 1.0 ± 2.0; P < .001), as well as transferrable embryos (2.0 ± 2.0 vs 0.0 ± 1.0; P < .001)., Conclusion: Infertile women up to 45 years with severely diminished ovarian reserve achieve better live birth rates than previously reported and should not be denied access to IVF based on elevated FSH levels alone.

Background: Highly Individualized Egg Retrieval (HIER), defined as age-specific early oocyte retrieval (ER), has been demonstrated to avoid premature luteinization in women ≥43. We here investigated whether HIER also applies to younger women with premature ovarian aging (POA), and what best lead follicle size should be for administration of ovulation-triggers., Methods: Fifty-six women ≥43, and 37 POA patients underwent IVF cycles. Granulosa cells (GCs) were isolated, cultures were established, RNA was extracted and real-time PCR analyses performed, with gene expressions at mRNA level investigated for FSH receptor (FSHR), luteinizing hormone receptor (LHCPR), P450 aromatase (CYP19a1) and progesterone receptor (PGR). POA was defined by age < 40, FSH above 95%CI and/or AMH below 95%CI for age. Women ≥43 years were divided into very early retrieval (VER), with human chorionic gonadotropin (hCG) trigger at 13.5-15.5 mm, ER at 16.0-18.0 mm or standard retrievel (SR) at 18.5-20.5 mm; POA patients were divided into ER and SR. Pregnancy rates and and molecular markers of premature luteinization (PL) were main outcome measures., Results: ER resulted in a significantly higher clinical pregnancy rate (16.7%) than VER (5.9%) or SR (6.7%; both P < 0.05). Molecular markers of PL were highest with SR and lowest with VER. In POA, ER improved pregnancy chances even more than in women ≥43 (7.7% with SR vs. 41.7% with ER), while also reducing molecular markers of PL. With low ovarian reserve (LOR), by avoiding PL, ER with hCG trigger at 16.0-18.0 mm, thus, improves clinical pregnancy rates at all ages. As VER demonstrated lowest molecular PL marker but equally poor pregnancy rates as SR, too early ovulation triggers, likely, result in cytoplasmatic immaturity., Conclusions: HIER is even more effective in POA patients than women above age 43, demonstrating that HIER should be further investigated going into even more advanced ages.

Background: A recent report described a new PCOS-like phenotype in lean older infertile women, and was characterized by high age-specific anti-Müllerian hormone (AMH) but hypo- rather than the expected hyper-androgenism. The hypo-androgenism was, furthermore, characterized of, likely, adrenal origin and autoimmune etiology., Patients and Methods: We extracted data on 708 consecutive infertility patients, and separated them into three age-strata, <35, 36-42, and >42 years. In each stratum, we investigated how levels of anti-Müllerian hormone (AMH) and testosterone (T) interrelate between high-AMH (AMH ≥ 75th quantile) and normal AMH (25th-75th quantile) and low-T (total testosterone ≤19.0 ng/dL), normal-T (19.0-29.0 ng/dL) and high-T (>29.0 ng/dL). High-AMH cycles were presumed to reflect PCOS-like patients. Routine in vitro fertilization (IVF) cycle outcomes and clinical phenotypes of patients were then compared between groups with AMH and T as statistical variables., Results: This hypo-androgenic PCOS-like phenotype already exists in age stratum <35 years. It appears to arise from a lean, at very young ages hyper-androgenic PCOS phenotype that develops in comparison to controls (likely autoimmune-induced) insufficiency of the adrenal zona reticularis (low-T and low-DHEAS) and zona fasciculata (low-C), and is characterized by frequent evidence of autoimmunity. A degree of adrenal insufficiency, thus, concomitantly appears to affect adrenal androgen and, to lesser degrees, glucocorticoid production (mineralocorticoids were not investigated)., Conclusions: Here investigated new PCOS-like phenotype demonstrates features compatible with what under Rotterdam criteria has been referred to as PCOS phenotype-D. If confirmed, the observation that the ontogeny of this phenotype already at young ages is, likely, driven by adrenal autoimmunity, supports the position of the androgen excess and PCOS society that the etiology of phenotype-D differs from that of classical hyper-androgenic PCOS of mostly ovarian etiology.

Background: Preimplantation genetic screening (PGS) is increasingly utilized as an adjunct procedure to IVF. Recently healthy euploid live birth were reported following transfer of mosaic embryos. Several recent publications have surmised that the degree of trophectoderm (TE) mosaicism in transferred embryos is predictive of ongoing pregnancy and miscarriage rates., Methods: This is a corrected analysis of previously published retrospective data on vitro fertilization (IVF) cycle outcomes involving replacement of 143 mosaic and 1045 euploid embryos tested by PGS, utilizing high-resolution next-generation sequencing (NGS) of TE and determination of percentages of mosaicism. Receiver operating curves (ROCs) and measurement of area under the curve (AUC) were used to evaluated the accuracy of the predictor variable, proportion of aneuploid cells in a TE biopsy specimen, with IVF outcomes, ongoing pregnancy and miscarriage rates., Results: Confirming findings of the previously published report we also found higher ongoing pregnancy rates (63.3% vs. 39.2%) and lower miscarriage rates (10.2% vs. 24.3%) with euploid embryo transfers than with mosaic embryo transfer. There, however, were no significant differences in ongoing pregnancy or miscarriage rates among mosaic embryo transfers at any threshold of aneuploidy. Based on AUC, TE biopsies predicted ongoing pregnancy for euploid, as well as mosaic embryos, in a range of 0.50 to 0.59 and miscarriage in a range from 0.50 to 0.66 CONCLUSIONS: Degree of TE mosaicism was a poor predictor of ongoing pregnancy and miscarriage.

Background: Improvements in oocyte cryopreservation techniques and establishment of cryopreserved donor oocyte banks have led to improved access to and lower cost of donor oocytes, upending the traditional practice of fresh oocyte donation. The objective of this study was to examine national trends in utilization and live birth rates with fresh versus cryopreserved donor oocytes., Methods: A retrospective analysis of 2013 through 2015 aggregate U.S. national data reported by the Society for Assisted Reproductive Technology which included 30,160 IVF cycles with either fresh or cryopreserved donor oocytes was performed., Results: During the study period utilization of fresh oocyte donations rapidly declined by 32.9%, while cryopreserved oocyte donation increased by 44.4%. Fresh donor oocytes produced significantly higher live birth rates per recipient cycle start than cryopreserved donor oocytes (51.1% vs. 39.7%). Over the three-year study period fresh donor oocytes produced stable live birth rates per recipient cycle start while those with cryopreserved oocytes significantly declined year-by-year., Conclusion: Despite rising popularity of cryopreserved donor oocytes, prospective patients should be counselled that fresh donor oocytes still represent standard of care due to higher live birth rates.

Objective: Our objective was to estimate the contribution of preimplantation genetic screening to in vitro fertilization pregnancy outcomes in donor oocyte-recipient cycles., Study Design: This was a retrospective cross-sectional study of US national data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2005 and 2013. Society for Assisted Reproductive Technology Clinic Outcome Reporting relies on voluntarily annual reports by more than 90% of US in vitro fertilization centers. We evaluated pregnancy and live birth rates in donor oocyte-recipient cycles after the first embryo transfer with day 5/6 embryos. Statistical models, adjusted for patient and donor ages, number of embryos transferred, race, infertility diagnosis, and cycle year were created to compare live birth rates in 392 preimplantation genetic screening and 20,616 control cycles., Results: Overall, pregnancy and live birth rates were significantly lower in preimplantation genetic screening cycles than in control cycles. Adjusted odds of live birth for preimplantation genetic screening cycles were reduced by 35% (odds ratio, 0.65, 95% confidence interval, 0.53-0.80; P < .001)., Conclusion: Preimplantation genetic screening, as practiced in donor oocyte-recipient cycles over the past 9 years, has not been associated with improved odds of live birth or reduction in miscarriage rates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Members of the transforming growth factor-beta (TGF-beta) superfamily are key regulators of various physiological processes. Anti-Müllerian hormone (AMH) which is also commonly known as Müllerian-inhibiting substance (MIS) is a member of the TGF-beta superfamily and an important regulator of reproductive organ differentiation and ovarian follicular development. While AMH has been used for diagnostic purposes as a biomarker for over 15 years, new potential therapeutic applications of recombinant human AMH analogues are now emerging as pharmacologic agents in reproductive medicine. Therapeutic uses of AMH in gonadal tissue may provide a unique opportunity to address a broad range of reproductive themes, like contraception, ovulation induction, onset of menopause, and fertility preservation, as well as specific disease conditions, such as polycystic ovarian syndrome (PCOS) and cancers of the reproductive tract. This review explores the most promising therapeutic applications for a novel class of drugs known as AMH analogues with agonist and antagonist functions.

The Centre for Disease Control and Prevention (CDC) publicly reports assisted reproductive technology live-birth rates (LBR) for each US fertility clinic under legal mandate. The 2014 CDC report excluded 35,406 of 184,527 (19.2%) autologous assisted reproductive technology cycles that involved embryo or oocyte banking from LBR calculations. This study calculated 2014 total clinic LBR for all patients utilizing autologous oocytes two ways: including all initiated assisted reproductive technology cycles or excluding banking cycles, as done by the CDC. The main limitation of this analysis is the CDC report did not differentiate between cycles involving long-term banking of embryos or oocytes for fertility preservation from cycles involving short-term embryo banking. Twenty-seven of 458 (6%) clinics reported over 40% of autologous cycles involved banking, collectively performing 12% of all US assisted reproductive technology cycles. LBR in these outlier clinics calculated by the CDC method, was higher than the other 94% of clinics (33.1% versus 31.1%). However, recalculated LBR including banking cycles in the outlier clinics was lower than the other 94% of clinics (15.5% versus 26.6%). LBR calculated by the two methods increasingly diverged based on proportion of banking cycles performed by each clinic reaching 4.5-fold, thereby, potentially misleading the public., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to determine the utilization and live birth rates of assisted reproductive technology (ART) modalities among various racial and ethnic groups in recent years., Methods: We reviewed ART data reported to the Society for Assisted Reproductive Technologies Clinic Outcome Reporting System (SART CORS) for autologous ART and third-party ART (3ART) cycles which involved donor oocytes, sperm, embryos and gestational carrier, performed in the U.S. between 2004 and 2013. To gauge demand by various racial/ethnic groups for ART services, we examined fertility rates and demographics of the entire U.S. birth cohort over the same time interval., Results: Of 1,132,844 autologous ART cycles 335,462 resulted in a live birth (29.6%). An additional, 217,030 3ART cycles resulted in 86,063 live births (39.7%). Hispanic and Black women demonstrated high fertility and lower utilization rates of autologous ART and 3ART. Caucasian and Asian women exhibited lower fertility rates and higher autologous ART and 3ART utilization. Autologous ART resulted in higher live birth rates among Caucasian and Hispanic women and lower rates among Asian and especially Black women. 3ART improved live birth rates in all races/ethnicities, though Black women experienced lower live birth rates with most modalities. Spontaneous abortion rates were higher among Black women following autologous ART and some 3ART modalities than those among Caucasian women., Conclusion: Utilization of ART is inversely related to fertility rates. Autologous ART produces lower live birth rates among Asian and Black women. 3ART results in relatively low live birth rates among Black women., Trial Registration: SART CORS #57 , Registered 5/14/2015.

Background: Premutation range CGGn repeats of the FMR1 gene denote risk toward primary ovarian insufficiency (POI), also called premature ovarian failure (POF). This prospective cohort study was undertaken to determine if X-chromosome inactivation skew (sXCI) is associated with variations in FMR1 CGG repeat length and, if so, is also associated with age adjusted antimüllerian hormone (AMH) levels as an indicator of functional ovarian reserve (FOR)., Methods: DNA samples of 58 women were analyzed for methylation status and confirmation of CGG n repeat length. Based on previously described FMR1 genotypes, there were 18 women with norm FMR1 (both alleles in range of CGG n=26-34 ), and 40 women who had at least one allele at CGG n<26 or CGG >34 ( not-norm FMR1). As part of a routine evaluation of ovarian reserve, patients at our fertility center have their serum AMH assessed at first visit. Regression models were used to test the association of ovarian reserve, as indicated by serum AMH, with sXCI., Results: sXCI was significantly lower among infertility patients with norm FMR1 (6.5 ± 11.1, median and IQR) compared to those with not-norm FMR1 (12.0 ± 14.6, P = 0.005), though among young oocyte donors the opposite effect was observed. Women age >30 to 38 years old demonstrated greater ovarian reserve in the presence of lower sXCI as evidenced by significantly higher AMH levels (GLM sXCI&#95;10%, f = 11.27; P = 0.004)., Conclusions: Together these findings suggest that FMR1 CGG repeat length may have a role in determining X-chromosome inactivation which could represent a possible mechanism for previously observed association of low age adjusted ovarian reserve with FMR1 variations in repeat length. Further, larger, investigations will be required to test this hypothesis.

Background: It has become increasingly apparent that the trophectoderm (TE) at blastocyst stage is much more mosaic than has been appreciated. Whether preimplantation genetic screening (PGS), utilizing a single TE biopsy (TEB), can reliably determine embryo ploidy has, therefore, increasingly been questioned in parallel., Methods: We for that reason here established 2 mathematical models to assess probabilities of false-negative and false-positive results of an on average 6-cell biopsy from an approximately 300-cell TE. This study was a collaborative effort between investigators at The Center for Human Reproduction in New York City and the Center for Studies in Physics and Biology and the Brivanlou Laboratory of Stem Cell Biology and Molecular Embryology, the latter two both at Rockefeller University in New York City., Results: Both models revealed that even under best case scenario, assuming even distribution of mosaicism in TE (since mosaicism is usually clonal, a highly unlikely scenario), a biopsy of at least 27 TE cells would be required to reach minimal diagnostic predictability from a single TEB., Conclusions: As currently performed, a single TEB is, therefore, mathematically incapable of reliably determining whether an embryo can be transferred or should be discarded. Since a single TEB, as currently performed, apparently is not representative of the complete TE, this study, thus, raises additional concern about the clinical utilization of PGS.

Referring to two recent publications, we here propose that clinical reproductive immunology has for decades stagnated because reproductive medicine, including assisted reproduction (AR), has failed to accept embryo implantation as an immune system-driven process, dependent on establishment of maternal tolerance toward the implanting fetal semi-allograft (and complete allograft in cases of oocyte donation). Pregnancy represents a biologically unique period of temporary (to the period of gestation restricted) tolerance, otherwise only known in association with parasitic infections. Rather than investigating the immune pathways necessary to induce this rather unique state of tolerance toward the rapidly growing parasitic antigen load of the fetus, the field, instead, concentrated on irrelevant secondary immune phenomena (i.e., "immunological noise"). It, therefore, does not surprise that interesting recent research, offering new potential insights into maternal tolerance during pregnancy, was mostly published outside of the field of reproductive medicine. This research offers evidence for existence of inducible maternal tolerance pathways with the ability of improving maternal fecundity and, potentially, reducing such late pregnancy complications as premature labor and preeclampsia/eclampsia due to premature abatement of maternal tolerance. Increasing evidence also suggests that tolerance-inducing immune pathways are similar in successful pregnancy, successful organ transplantation and, likely also in the tolerance of "self" (i.e., prevention of autoimmunity). Identifying and isolating these pathways, therefore, may greatly benefit all three of these clinical areas, and research in reproductive immunology should be accordingly redirected.

How anti-Müllerian hormone (AMH) and testosterone (T) interrelate in infertile women is currently largely unknown. We, therefore, in a retrospective cohort study investigated how infertile women with high-AMH (AMH ≥75th quantile; n=144) and with normal-AMH (25th-75th quantile; n=313), stratified for low-T (total testosterone ≤19.0ng/dL), normal-T (19.0-29.0ng/dL) and high-T (>29.0ng/dL) phenotypically behaved. Patient age, follicle stimulating hormone (FSH), dehyroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol (C), adrenocorticotrophic hormone (ACTH), IVF outcomes, as well as inflammatory and immune panels were then compared between groups, with AMH and T as variables. We identified a previously unknown infertile PCOS-like phenotype, characterized by high-AMH but, atypically, low-T, with predisposition toward autoimmunity. It presents with incompatible high-AMH and low-T (<19.0ng/dL), is restricted to lean PCOS-like patients, presenting delayed for tertiary fertility services. Since also characterized by low DHEAS, low-T is likely of adrenal origina, and consequence of autoimmune adrenal insufficiency since also accompanied by low-C and evidence of autoimmunity. DHEA supplementation in such patients equalizes low- to normal-T and normalizes IVF cycle outcomes. Once recognized, this high-AMH/low-T phenotype is surprisingly common in tertiary fertility centers but, currently, goes unrecognized. Its likely adrenal autoimmune etiology offers interesting new directions for investigations of adrenals control over ovarian function via adrenal androgen production., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The use of in vitro fertilization that includes third-party in vitro fertilization is increasing. However, the relative contribution of third-party in vitro fertilization that includes the use of donor oocytes, sperm, or embryo and a gestational carrier to the birth cohort after in vitro fertilization is unknown., Objective: The purpose of this study was to examine the contribution of third-party in vitro fertilization to the in vitro fertilization birth cohort over the past decade., Study Design: This retrospective analysis investigated 1,349,874 in vitro fertilization cycles that resulted in 421,525 live births and 549,367 liveborn infants in the United States from 2004-2013. Cycles were self-reported by fertility centers to a national registry: Society for Assisted Reproductive Technologies Clinic Outcome Reporting System., Results: Third-party in vitro fertilization accounted for 217,030 (16.1%) of all in vitro fertilization cycles, 86,063 (20.4%) of all live births, and 115,024 (20.9%) of all liveborn infants. Overall, 39.7% of third-party in vitro fertilization cycles resulted in a live birth, compared with 29.6% of autologous in vitro fertilization cycles. Use of third-party in vitro fertilization increased with maternal age and accounted for 42.2% of all in vitro fertilization cycles and 75.3% of all liveborn infants among women >40 years old. Oocyte donation was the most common third-party in vitro fertilization technique, followed by sperm donation. Over the study period, annual cycle volume and live birth rates gradually increased for both autologous in vitro fertilization and third-party in vitro fertilization (P<.0001 for all). Live birth rates were the highest when multiple third-party in vitro fertilization modalities were used, followed by oocyte donation., Conclusion: Third-party in vitro fertilization use and efficacy have increased over the past decade, now comprising >20% of the total in vitro fertilization birth cohort. In women who are >40 years old, third-party in vitro fertilization has become the dominant treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Assisted Reproductive Technology (ART) has undergone considerable changes over the last decade, with consequences on ART outcomes in different regions of the world being unknown., Methods: We conducted a systematic review of published national and regional ART registry data to assess how changes in clinical practice between 2004 and 2013 have impacted outcomes in Australia and New Zealand, Canada, Continental Europe, the United Kingdom (U.K.), Japan, Latin America, and the United States (U.S.). The data reflect 7,079,145 total ART cycles utilizing both fresh and previously cryopreserved embryos from autologous oocytes that resulted in 1,454,724 live births. This review focused on the following measures: ART cycle volume, use of cryopreserved embryos, single embryo transfer (SET), live birth rates in fresh and frozen-thawed cycles, and perinatal outcomes in recent years., Results: SETs and utilization of frozen-thawed embryos increased worldwide over the study period. In 2012 SET utilization in all ART cycles was highest in Japan and Australia/New Zealand (82.6% and 76.3% respectively) and lowest in Latin America (16.0%). While gradual improvements in live birth rates were observed in most regions, some demonstrated declines. By 2012-2013, fresh cycle live birth rates were highest in the U.S. (29%) and lowest in Japan (5%). In Japan, the observed decline in fresh cycle live birth rate coincided with transition to minimal stimulation protocols, transfer of frozen-thawed rather than fresh embryos, and implementation of an SET policy. Similarly, implementation of an SET policy in parts of Canada was followed by a decline in fresh cycle live birth rate. Increasing live birth rates in frozen-thawed embryo cycles, seen all over the world, partially compensated for declines in fresh ART cycles. During 2012-2013 Australia/New Zealand and Japan reported the lowest multiple delivery rates of 5.6 and 4% respectively while the US had the highest of 27%. In recent years, preterm delivery rates in all regions ranged between 9.0 to 16.6% for singletons, 53.9 to 67.3% for twins, and 91.4 to 100% for triplets and higher order multiples. Inconsistencies in the way perinatal outcome data are presented by various registries, made comparison between regions difficult., Conclusions: ART practices are characterized by outcome differences between regions. International consensus on the definition of ART success, which accounts for perinatal outcomes, may help to standardize worldwide ART practice and improve outcomes., Trial Registration: PROSPERO ( CRD42016033011 ).

Purpose of Review: Utilization of cryopreserved instead of fresh donor oocytes has rapidly increased in recent years. Whether treatment outcomes are comparable has, however, remained controversial., Recent Findings: More than 24% of initiated oocyte donation cycles in the USA during 2013-2014 involved previously cryopreserved oocytes. The use of cryopreserved-donated oocytes may simplify logistics and lower costs per treatment cycle. Whether cryopreserved donor oocytes also lower costs per live birth is still undetermined as they result in lower live birth rates in comparison to fresh donor oocyte cycles. National data regarding the safety of donated oocytes, including miscarriage rates and neonatal health outcomes, are lacking., Summary: Currently available data on cryopreserved-donated oocytes are incomplete and, therefore, still insufficient to claim equivalency between fresh and cryopreserved donor oocytes. Until sufficient data are available, patients should be advised about advantages and disadvantages of both methods of oocyte donation, and the use of cryopreserved oocytes should be considered only with caution and appropriate informed consent. Because banking of donated human oocytes facilities their commercial trade, it challenges basic ethical considerations, which have been the basis of oocyte donation since its inception.

In poor prognosis patients undergoing in vitro fertilization, advance determinations of likely oocyte yields are especially important since oocyte numbers to large degree determine in vitro fertilization cycle outcomes. Based on baseline follicle stimulating hormone and anti-müllerian hormone levels at time of initial presentation, we here, therefore, determined at all ages the probabilities of obtaining 1-≥5 oocytes in a retrospective analysis of 1554 consecutive patients undergoing in vitro fertilization cycles at an academically affiliated private fertility center. At lowest levels (≤2.5 mIU/mL), Follicle stimulating hormone at all ages was highly predictable for ≥1 oocyte (88-96 %). Probabilities declined and diverged between ages with increasing follicle stimulating hormone, though narrowed again at high follicle stimulating hormone. Anti-Müllerian hormone demonstrated at higher levels (2.5-≥5 ng/ml) at all ages almost perfect probabilities (99-100 %). With declining anti-Müllerian hormone, age categories, however, increasingly diverged, though to lesser degree than follicle stimulating hormone. In poor prognosis patients, follicle stimulating hormone and anti-Müllerian hormone, thus, offer at different ages very specific probabilities for retrieval of 1-≥5 oocytes. Since oocyte numbers are associated with embryo numbers, and numbers of transferable embryos with live birth rates, here presented probability tables should facilitate improved prognostication of poor prognosis patients. Discrepancies in here reported probabilities between follicle stimulating hormone and anti-müllerian hormone also further define follicle stimulating hormone and anti-müllerian hormone in their respective abilities to represent functional ovarian reserve at different ages.

Problem: Autoimmunity is thought to be an important cause of premature ovarian senescence, characterized by abnormal ovarian reserve markers. Anti-Mullerian hormone (AMH) has emerged as the most reliable marker for ovarian reserve. We here investigated whether non-specific immune markers are associated with a low age-specific AMH., Method of Study: To test the hypothesis that autoimmunity may predispose to low AMH, we investigated in 351 female infertile patients whether panels positive for non-specific immune tests (antinuclear antibody, antiphospholipid antibodies [APAs], lupus anticoagulant, antithyroid antibodies, and total immunoglobulin levels) are associated with low AMH levels. Analysis of covariance was performed to determine statistical significance of associations., Results: Age of infertile women was 38.6 ± 5.3 years. A total of 50 women (14.2%) had abnormally elevated levels of one or more APA. Even after age adjustments, the presence of at least one APA was significantly associated with a low AMH (P<.0066). No one specific APA or other immune marker demonstrated an association with AMH., Conclusions: APAs but no other immune markers appear associated with decreased levels of AMH, supporting the hypothesis that non-specific autoimmunity may adversely affect ovarian reserve., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: To preclude transfer of aneuploid embryos, current preimplantation genetic screening (PGS) usually involves one trophectoderm biopsy at blastocyst stage, assumed to represent embryo ploidy. Whether one such biopsy can correctly assess embryo ploidy has recently, however, been questioned., Methods: This descriptive study investigated accuracy of PGS in two ways. Part I: Two infertile couples donated 11 embryos, previously diagnosed as aneuploid and, therefore, destined to be discarded. They were dissected into 37 anonymized specimens, and sent to another national laboratory for repeat analyses to assess (i) inter-laboratory congruity and (ii) intra-embryo congruity of multiple embryo biopsies in a single laboratory. Part II: Reports on human IVF cycle outcomes after transfer of allegedly aneuploid embryos into 8 infertile patients., Results: Only 2/11 (18.2 %) embryos were identically assessed at two PGS laboratories; 4/11 (36.4 %), on repeat analysis were chromosomally normal, 2 mosaic normal/abnormal, and 5/11 (45.5 %) completely differed in reported aneuploidies. In intra-embryo analyses, 5/10 (50 %) differed between biopsy sites. Eight transfers of previously reported aneuploid embryos resulted in 5 chromosomally normal pregnancies, 4 delivered and 1 ongoing. Three patients did not conceive, though 1 among them experienced a chemical pregnancy., Conclusions: Though populations of both study parts are too small to draw statistically adequately powered conclusions on specific degrees of inaccuracy of PGS, here presented results do raise concerns especially about false-positive diagnoses. While inter-laboratory variations may at least partially be explained by different diagnostic platforms utilized, they cannot explain observed intra-embryo variations, suggesting more frequent trophectoderm mosiaicsm than previously reported. Together with recentl published mouse studies of lineages-specific degrees of survival of aneuploid cells in early stage embryos, these results call into question the biological basis of PGS, based on the assumption that a single trophectoderm biopsy can reliably determine embryo ploidy.

Outcome measures of IVF success, which account for effectiveness of IVF and perinatal outcome risks, have recently been described. The association between number of embryos transferred in average and poor-prognosis IVF patients, and the chances of having good or poor IVF and perinatal outcomes, was investigated. Good IVF and perinatal outcome was defined as the birth of a live, term, normal-weight infant (≥2500 g). Poor IVF and perinatal outcome was defined as no live birth or birth of a very low weight neonate (<1500 g) or severe prematurity (birth at <32 weeks gestation). Each neonate was analysed as a separate outcome. A total of 713 IVF cycles in 504 average and poor-prognosis patients from January 2010 to December 2013 were identified. The odds of having good IVF and perinatal outcomes increased by 28% for each additional embryo transferred. The odds of poor IVF and perinatal outcome decreased by 32% with an additional embryo transferred. The likelihood of live birth with good perinatal outcome in average- and poor-prognosis patients after IVF increases with additional embryos being transferred. These data add to recently reported evidence in favour of multiple embryo transfer in older women and those with average or poor IVF prognosis., (Copyright © 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Previously manual human embryology in many in vitro fertilization (IVF) centers is rapidly being replaced by closed embryo incubation systems with time-lapse imaging. Whether such systems perform comparably to manual embryology in different IVF patient populations has, however, never before been investigated. We, therefore, prospectively compared embryo quality following closed system culture with time-lapse photography (EmbryoScope™) and standard embryology. We performed a two-part prospectively randomized study in IVF (clinical trial # NCT92256309). Part A involved 31 infertile poor prognosis patients prospectively randomized to EmbryoScope™ and standard embryology. Part B involved embryos from 17 egg donor-recipient cycles resulting in large egg/embryo numbers, thus permitting prospectively alternative embryo assignments to EmbryoScope™ and standard embryology. We then compared pregnancy rates and embryo quality on day-3 after fertilization and embryologist time utilized per processed embryo., Results: Part A revealed in poor prognosis patients no differences in day-3 embryo scores, implantation and clinical pregnancy rates between EmbryoScope™ and standard embryology. The EmbryoScope™, however, more than doubled embryology staff time (P < 0.0001). In Part B, embryos grown in the EmbyoScope™ demonstrated significantly poorer day-3 quality (depending on embryo parameter between P = 0.005 and P = 0.01). Suspicion that conical culture dishes of the EmbryoScope™ (EmbryoSlide™) may be the cause was disproven when standard culture dishes demonstrated no outcome difference in standard incubation., Conclusions: Though due to small patient numbers preliminary, this study raises concerns about the mostly uncontrolled introduction of closed incubation systems with time lapse imaging into routine clinical embryology. Appropriately designed and powered prospectively randomized studies appear urgently needed in well-defined patient populations before the uncontrolled utilization of these instruments further expands., Trial Registration: NCT02246309 Registered September 18, 2014.

Objective: To assess effectiveness of preimplantation genetic screening (PGS) in fresh IVF cycles., Design: Reanalysis of retrospective US national data., Setting: Not applicable., Patient(s): A total of 5,471 fresh autologous IVF cycles with PGS and 97,069 cycles without PGS, reported in 2011-2012 to the Centers for Disease Control and Prevention., Intervention(s): Not applicable., Main Outcome Measure(s): Cycles that reached ET, miscarriage rates, live birth rates per cycle and per transfer., Result(s): More PGS than non-PGS cycles reached ET (64.2% vs. 62.3%), suggesting favorable patient selection bias for patients using PGS. Nevertheless, live births rates per cycle start (25.2% vs. 28.8%) and per ET (39.3% vs. 46.2%) were significantly better in non-PGS cycles, whereas miscarriage rates were similar (13.7% vs. 13.9%). With a maternal age >37 years significantly more cycles in the PGS group reached ET (53.1% vs. 41.9%), suggesting a significant selection bias for more favorable patients in the PGS population. This bias rather than the PGS procedure may partially explain the observed improved live birth rate per cycle (17.7% vs. 12.7%) and lower miscarriage rate (16.8% vs. 26.0%) in the older PGS group., Conclusion(s): Overall, PGS decreased chances of live birth in association with IVF. National improvements in live birth and miscarriage rates reported with PGS in older women are likely the consequence of favorable patient selection biases., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Women above age 40 years in the US now represent the most rapidly growing age group having children. Patients undergoing in vitro fertilization (IVF) are rapidly aging in parallel. Especially where egg donations are legal, donation cycles, therefore, multiply more rapidly than autologous IVF cycles. The donor oocytes, however, are hardly ever a preferred patient choice. Since with use of own eggs, live birth rates decline with advancing age but remain stable (and higher) with donor eggs, older patients always face the difficult and very personal choice between poorer chances with own and better chances with donor oocytes. Physician contribution to this decision should in our opinion be restricted to accurate outcome information for both options. Achievable pregnancy and live birth rates in older women are, however, frequently underestimated, thereby mistakenly biasing fertility providers, private insurance companies and even regulatory government agencies. Restriction on access to IVF for older women is then often the consequence. In this review, we summarize the limited published data on best treatments of 'older' ovaries, while also addressing treatment approaches that should be avoided in older women. This focused review, therefore, to a degree is subjective. Research addressing aging ovaries in IVF has been disappointingly sparse, and has in our opinion too heavily concentrated on methods of embryo selection (ES), which, especially in older women, not only fail to improve IVF outcomes, but actually, negatively affect live birth chances. We conclude that, aside from breakthroughs in gamete creation, only pharmacological interventions into early (small growing follicle stages) follicle maturation will offer new potential to positively impact oocyte and embryo quality and, therefore, IVF outcomes. Research, therefore, should be accordingly redirected., (© 2016 Society for Endocrinology.)

Background: Though outcome models have been proposed previously, it is unknown whether cutoffs in clinical pregnancy and live birth rates at all ages are able to classify in vitro fertilization (IVF) patients into good-, intermediate- and poor prognosis., Methods: We here in 3 infertile patient cohorts, involving 1247, 1514 and 632 women, built logistic regression models based on 3 functional ovarian reserve (FOR) parameters, including (1) number of good quality embryos, (2) follicle stimulating hormone (FSH, mIU/mL) and (3) anti-Müllerian hormone (AMH, ng/mL), determining whether clinical pregnancy and live birth rates can discriminate between good, intermediate and poor prognosis patients., Results: All models, indeed, allowed at all ages for separation by prognosis, though cut offs changed with age. In the embryo model, increasing embryo production resulted in linear improvement of IVF outcomes despite transfer of similar embryo numbers; in the FSH model outcomes and FSH levels related inversely, while the association of AMH followed a bell-shaped polynomial pattern, demonstrating "best" outcomes at mid-ranges. All 3 models demonstrated increasingly poor outcomes with advancing ages, though "best" AMH even above age 43 was still associated with unexpectedly good pregnancy and delivery outcomes. Excessively high AMH, in contrast, was at all ages associated with spiking miscarriage rates., Conclusions: At varying peripheral serum concentrations, AMH, thus, demonstrates hithero unknown and contradictory effects on IVF outcomes, deserving at different concentrations investigation as a potential therapeutic agent, with pregnancy-supporting and pregnancy-interrupting properties.

Problem: To determine in women with recurrent pregnancy loss (RPL) and/or implantation failure (RIF) the prevalence of chronic endometritis (CE), systemic inflammation and autoimmunity, and whether they relate., Method of Study: This retrospective study examined inflammatory (adiponectin, CRP, leptin, and IL6) and autoimmune (total immunoglobulins, ANA, thyroid antibodies, antiphospholipid antibodies) markers in a group of 55 women with RPL/RIF. A diagnosis of CE was reached by endometrial biopsy, demonstrating CD138-positive plasma cells on histology. The prevalence of markers of systemic inflammation and autoimmunity was compared between women with and without CE., Results: Among all RPL/RIF patients, 32.7% demonstrated at least one positive inflammatory marker, 61.8% at least one autoimmune marker, and 45.5% CE. Moreover, CE patients did not differ in systematic inflammatory or autoimmune profiles from those without CE., Conclusions: Endometritis and elevated inflammatory and autoimmune markers are common in women with RPL/RIF, but endometritis cannot be predicted based on either peripheral inflammatory or autoimmune markers., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)