RISK-ORIENTED ANALYSIS OF LIMB LOSS IN VICTIMS OF MODERN HOSTILITIES.

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.

Reproductive healthcare during a pandemic: a New York state of mind.

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.

Euploid miscarriage is associated with elevated serum C-reactive protein levels in infertile women: a pilot study.

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/m2 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.

Degree of mosaicism in trophectoderm does not predict pregnancy potential: a corrected analysis of pregnancy outcomes following transfer of mosaic embryos.

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.

Older women using their own eggs? Issue framed with two oldest reported IVF pregnancies and a live birth.

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.

Systematic review of worldwide trends in assisted reproductive technology 2004-2013.

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 ).

Effect of race and ethnicity on utilization and outcomes of assisted reproductive technology in the USA.

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.

A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use.

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.

Association of skewed X-chromosome inactivation with FMR1 CGG repeat length and anti-Mullerian hormone levels: a cohort study.

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 CGGn 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 CGGn<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_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.

CDC-reported assisted reproductive technology live-birth rates may mislead the public.

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.

Impact of preimplantation genetic screening on donor oocyte-recipient cycles in the United States.

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.

Utilization of third-party in vitro fertilization in the United States.

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.

Redirecting reproductive immunology research toward pregnancy as a period of temporary immune tolerance.

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.

Potential therapeutic applications of human anti-Müllerian hormone (AMH) analogues in reproductive medicine.

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.

Definition by FSH, AMH and embryo numbers of good-, intermediate- and poor-prognosis patients suggests previously unknown IVF outcome-determining factor associated with AMH.

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.

The importance of adrenal hypoandrogenism in infertile women with low functional ovarian reserve: a case study of associated adrenal insufficiency.

BACKGROUND: Low testosterone (T), whether due to ovarian and/or adrenal insufficiency, usually results in poor follicle maturation at small growing follicle stages. The consequence is a phenotype of low functional ovarian reserve (LFOR), characterized by poor granulosa cell mass, low anti-Müllerian hormone and estradiol but rising follicle stimulating hormone. Such hypoandrogenism can be of ovarian and/or adrenal origin. Dehydroepiandrosterone sulfate (DHEAS) is exclusively produced by adrenals and, therefore, reflects adrenal androgen production in the zona reticularis. We here determined in a case study of infertile women with LFOR the presence of adrenal hypoandrogenism, its effects on ovarian function, and the possibility of presence of concomitant adrenal insufficiency (AI), thus reflecting insufficiency of all three adrenal cortical zonae. METHODS: We searched our center's anonymized electronic research database for women with LFOR, who were also characterized by peripheral adrenal hypoandrogenemia (total testosterone < 16.9 ng/dL) and low DHEAS (<76.0 µg/dL). Among 225 women with LFOR, we identified 29 (12.9 %). The adrenal function of so identified women were further investigated with morning cortisol and ACTH levels and/or standard ACTH stimulation tests. We also determined the prevalence of classical AI (insufficiency glucocorticoid production by zona fasciculata) in hypoandrogenic women with LFOR, and impact of adrenal hypoandrogenism on ovaries. RESULTS: Among 14/28 women with adrenal hypoandrogenism due to insufficiency of the zona reticularis available for follow up, 4 (28.6 %) also demonstrated previously unrecognized classical primary, secondary or tertiary AI due to insufficiency of the zona fasciculata. An additional patient with presenting diagnosis of seemingly primary ovarian insufficiency (POI), demonstrated extremely low T and DHEAS levels, a diagnosis of Addison's disease, and was on glucocorticoid but not androgen supplementation. As her dramatic improvement in ovarian function criteria after androgen supplementation confirmed, her correct diagnosis, therefore, was actually secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism. CONCLUSIONS: Women with LFOR, characterized by low T and DHEAS, are also at risk for AI, while women with AI may be at risk for adrenal induced hypoandrogenism and, therefore, SOI. A currently undetermined percentage of POI patients actually are, likely, affected by SOI, a for prognostic reasons highly significant difference in diagnosis.

What affects functional ovarian reserve, thyroid function or thyroid autoimmunity?

BACKGROUND: Thyroid dysfunction is the most common autoimmune endocrine disorder in women of reproductive age, and is associated with menstrual irregularities, anovulation and infertility. Whether it is thyroid function or thyroid autoimmunity that affects functional ovarian reserve (FOR, i.e., the small growing ovarian follicle pool) reflected in anti-Müllerian hormone (AMH) has, however, remained under dispute. METHODS: We investigated in 225 infertile women whether thyroid function, after adjustment for thyroid autoimmunity, affects FOR within what is considered normal thyroid function (TSH, 0.4-4.5µIU/mL) by assessing AMH levels in reference to TSH levels, stratified for TSH < or ≥3.0µIU/mL. Thyroid autoimmunity was defined by presence of anti-thyroid peroxidase, -thyroglobulin and/or -thyroid receptor antibodies. RESULTS: Mean age of studied women was 38.4 ± 5.0 years; their mean AMH was 1.3 ± 2.0 ng/mL and mean TSH 1.8 ± 0.9 µIU/mL. Thyroid autoimmunity was present in 11.1 % of patients. Women with TSH <3.0µIU/mL presented with significantly higher AMH compared to those with TSH ≥3.0µIU/Ml (P = 0.03). This difference remained significant after adjustment for thyroid autoimmunity as well as age (P = 0.02). CONCLUSIONS: Even after adjustment for thyroid autoimmunity and age, TSH <3.0µIU/mL in euthyroid infertility patients is associated with significantly better FOR (higher AMH) than TSH ≥3.0µIU/mL. This observation suggests a direct beneficial effect of lower TSH levels on follicular recruitment, and warrants investigations of thyroxin supplementation in infertile women with TSH levels ≥3.0µIU/mL in attempts to improve FOR.

Different effectiveness of closed embryo culture system with time-lapse imaging (EmbryoScope(TM)) in comparison to standard manual embryology in good and poor prognosis patients: a prospectively randomized pilot study.

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.

Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos.

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.

IVF outcomes in average- and poor-prognosis infertile women according to the number of embryos transferred.

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.