Recent clomiphene citrate exposure does not impact subsequent clinical outcomes in single euploid frozen embryo transfer cycles.

STUDY QUESTION: Do infertile couples who recently utilized clomiphene citrate (CC) for ovulation induction or ovarian stimulation (<90 days previously) followed by a single euploid embryo transfer (SEET) have lower implantation potential compared with patients who were not exposed to CC within 90 days before embryo transfer (ET)? SUMMARY ANSWER: There does not appear to be an association between recent CC exposure and lower implantation potential in patients who undergo a frozen embryo transfer (FET) of euploid embryos. WHAT IS KNOWN ALREADY: Clomiphene has been found to be associated with lower pregnancy rates when compared against other ovarian stimulation medications. The majority of published research about the effects of CC on implantation potential suggest an anti-estrogenic effect on the endometrium. Quality evidence and information about utilization of CC and its effect on implantation potential after euploid ETs is lacking in the literature. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study with propensity score matching was carried out. We included all patients that underwent an autologous SEET from September 2016 to September 2022 at a single academic-private ART center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study group included patients that had utilized CC during either ovulation induction cycles and/or controlled ovarian stimulation at least 90 days before FET. A propensity score-matched control group of patients that were unexposed to CC within 90 days prior to SEET was used for comparisons. The primary outcome was positive pregnancy test (defined as a positive serum ß-hCG measured 9 days after ET), with other outcomes including clinical pregnancy, ongoing pregnancy, biochemical pregnancy loss, and clinical pregnancy loss rates per SEET. Multivariate regression analyses fitted with generalized estimating equations were utilized to analyze if there was an association between CC utilization and IVF outcomes. Furthermore, the study evaluated the cumulative effect of CC and endometrial receptivity in vivo and subsequent IVF outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 593 patients with utilization of CC in <90 days before ET were compared with 1779 matched controls. Positive pregnancy test rates were comparable among the control group and the CC exposed groups, respectively (74.3% versus 75.7%, P = 0.79), as were clinical pregnancy (64.0% versus 65.0%, P = 0.60), ongoing pregnancy (51.8% versus 53.2%, P = 0.74), biochemical pregnancy loss (15.7% versus 14.03%, P = 0.45), and clinical pregnancy loss rates were also comparable among cohorts (17.1% versus 18.1%, P = 0.71). No association was found between utilization of clomiphene and lower implantation rates (adjusted odds ratio 0.95, 95% CI 0.76-1.18). Also, no differences were observed in sub-analyses based on multiple CC utilization periods. Finally, no association was found between the number of consecutive cumulative clomiphene cycles and sub-optimal IVF outcomes. LIMITATIONS, REASONS FOR CAUTION: The study has inherent bias that originated from its retrospective design. Serum levels of CC were not measured and sample size for the sub-analyses was small. WIDER IMPLICATIONS OF THE FINDINGS: There does not appear to be an association between recent CC exposure and lower implantation potential in patients who undergo a FET of euploid embryos. This finding remains consistent, even in patients who undergo multiple, consecutive clomiphene cycles prior to ET. There were no long-term effects of CC on endometrial development and clinical characteristics examined in this study. Patients that utilized CC medication prior to a SEET cycle for either ovarian stimulation or ovulation induction, can be assured that there is no evidence of a residual effect of recent CC administration that could jeopardize their pregnancy probability. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this study. A.C. is advisor and/or board member of Sema4 (stakeholder in data) and Progyny. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Biological relevance of trophectoderm morphology: initial ß-hCG measurements correlate with trophectoderm grading on euploid frozen embryo transfers.

OBJECTIVE: To analyze the correlation between TE grading and initial ß-hCG serum level after single euploid embryo transfer. Secondarily, to explore the association between TE grading with subsequent IVF outcomes. DESIGN: Retrospective cohort analysis. SETTING: Single, academic, private infertility and assisted reproductive care institute. PATIENTS OR OTHER PARTICIPANTS: Infertility patients who underwent a single euploid embryo transfer that resulted in a positive pregnancy test. INTERVENTION(S): ß-hCG measurements. MAIN OUTCOME MEASURE(S): Correlation between TE grade with first ß-hCG measurement. Second outcome measurements included ongoing pregnancy, biochemical pregnancy loss, and clinical pregnancy loss rates. RESULTS: 2,798 cases were analyzed. A significant difference in initial ß-hCG measurement among groups (TE A: median 143.4 mIU/mL IQR 79.2-211.2; TE B: 119 mIU/mL IQR 57.1-177.8; TE C: 82.4 mIU/mL IQR 36.3-136.4, p ≤ 0.0001) was observed. There was a significant correlation found between the TE grade and ß-hCG measurements (p ≤ 0.0001, r2 = 0.10). TE grade was not associated with higher odds of biochemical pregnancy loss (TE A vs. TE B: aOR 1.01 CI95% 0.97-1.05; TE A vs. TE C: aOR 1.03 CI95% 0.98-1.08), or higher odds of clinical pregnancy loss (TE A vs. TE B: aOR 1.02 CI95% 0.98-1.05; TE A vs. TE C: aOR 1.03 CI95% 0.98-1.07). CONCLUSIONS: In patients with euploid embryos, TE grade correlates with the first pregnancy test measurement of ß-hCG. We propose this finding helps to appoint a relevant link between morphology assessment and early embryo development in vivo.

Parental chromosomal heteromorphisms are not associated with an increased risk of embryo aneuploidy.

OBJECTIVE: Although chromosomal heteromorphisms are commonly found in the general population, some researchers have suggested a correlation with higher rates of embryo aneuploidy. This study aimed to assess the rates of embryo aneuploidy in couples who carry a chromosome heteromorphism. METHODS: The study included couples who had G-banding karyotype testing and underwent an IVF/PGT-A cycle between January 2012 and March 2018. The participants were classified by couple karyotype: Group A: ≥1 patient reported to be a heterochromatic variant carrier; Group B: both partners reported to be "normal". We assessed the rates of aneuploidy among the groups. We ran a multivariate regression analysis to assess the relationship between heterochromatic variants and the rates of embryo aneuploidy. RESULTS: Of the 946 couples analyzed, 48 (5.0%) reported being a carrier of ≥1 heterochromatic variant. We had 869 IVF/PGT-A cycles included in the analysis (Group A: n=48; Group B: n=82). There were no significant differences in embryo ploidy rates among the groups. The heterochromatic chromosome variant was not associated with increased likelihoods of aneuploidy (OR=1.04, CI:95% 0.85- 1.07; p=0.46). Finally, the gender of the heterochromatic variant carrier had no association with increased likelihood of aneuploidy (OR 1.02, CI 95% 0.81-1.28, p=0.82). CONCLUSIONS: Our study showed no association between parental heterochromatic chromosome variants and subsequent embryo aneuploidy rates. Ploidy rates do not appear to be negatively associated with couples when at least one patient is reported to be a carrier of a heterochromatic variant on the karyotype.

Late follicular phase progesterone elevation during ovarian stimulation is not associated with decreased implantation of chromosomally screened embryos in thaw cycles.

STUDY QUESTION: What is the impact of a late follicular phase progesterone elevation (LFPE) during controlled ovarian hyperstimulation (COH) on embryonic competence and reproductive potential in thaw cycles of preimplantation genetic testing for aneuploidy (PGT-A) screened embryos? SUMMARY ANSWER: Our study findings suggest that LFPE, utilizing a progesterone cutoff value of 2.0 ng/ml, is neither associated with impaired embryonic development, increased rate of embryonic aneuploidy, nor compromised implantation and pregnancy outcomes following a euploid frozen embryo transfer (FET) cycle. WHAT IS KNOWN ALREADY: Premature progesterone elevation during COH has been associated with lower pregnancy rates due to altered endometrial receptivity in fresh IVF cycles. Also, increased levels of progesterone (P) have been suggested to be a marker for ovarian dysfunction, with some evidence to show an association between LFPE and suboptimal embryonic development. However, the effect of LFPE on embryonic competence is still controversial. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis in a single, academic ART center from September 2016 to March 2020. In total, 5244 COH cycles for IVF/PGT-A were analyzed, of those 5141 were included in the analysis. A total of 23 991 blastocysts underwent trophectoderm biopsy and PGT analysis. Additionally, the clinical IVF outcomes of 5806 single euploid FET cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohorts were separated in two groups: Group 1: oocytes retrieved from cycles with normal P levels during ovulation trigger (P ≤ 2.0 ng/ml); Group 2: oocytes retrieved after cycles in which LFPE was noted (P > 2.0 ng/ml). Extended culture and PGT-A was performed. Secondly, IVF outcomes after a single euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE: Four thousand nine hundred and twenty-five cycles in Group 1 were compared with 216 cycles on Group 2. Oocyte maturity rates, fertilization rates and blastulation rates were comparable among groups. A 65.3% (n = 22 654) rate of utilizable blastocysts was found in patients with normal P levels and were comparable to the 62.4% (n = 1337) observed in those with LFPE (P = 0.19). The euploidy rates were 52.8% (n = 11 964) and 53.4% (n = 714), respectively, albeit this difference was not statistically significant (P = 0.81). Our multivariate analysis was fitted with a generalized estimating equation (GEE) and no association was found with LFPE and an increased odds of embryo aneuploidy (adjusted odds ratio 1.04 95% CI 0.86-1.27, P = 0.62). A sub-analysis of subsequent 5806 euploid FET cycles (normal P: n = 5617 cycles and elevated P: n = 189 cycles) showed no differences among groups in patient's BMI, Anti-Müllerian hormone (AMH), endometrial thickness at FET and number of prior IVF cycles. However, a significant difference was found in patient's age and oocyte age. The number of good quality embryos transferred, implantation rate, clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate and clinical pregnancy loss rates were comparable among groups. Of the registered live births (normal P group: n = 2198; elevated P group: n = 52), there were no significant differences in gestational age weeks (39.0 ± 1.89 versus 39.24 ± 1.53, P = 0.25) and birth weight (3317 ± 571.9 versus 3 266 ± 455.8 g, P = 0.26) at delivery, respectively. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and probable variability in the study center's laboratory protocol(s), selected progesterone cutoff value and progesterone assay techniques compared to other ART centers may limit the external validity of our findings. WIDER IMPLICATIONS OF THE FINDINGS: Based on robust sequencing data from a large cohort of embryos, we conclude that premature P elevation during IVF stimulation does not predict embryonic competence. Our study results show that LFPE is neither associated with impaired embryonic development nor increased rates of aneuploidy. Embryos obtained from cycles with LFPE can be selected for transfer, and patients can be reassured that the odds of achieving a healthy pregnancy are similar to the embryos exposed during COH cycles to physiologically normal P levels. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this study. Dr A.B.C. is advisor and/or board member of Sema 4 (Stakeholder in data), Progyny and Celmatix. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NA.

Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population.

OBJECTIVE: Genetic carrier screening has the potential to identify couples at risk of having a child affected with an autosomal recessive or X-linked disorder. However, the current prevalence of carrier status for these conditions in developing countries is not well defined. This study assesses the prevalence of carrier status of selected genetic conditions utilizing an expanded, pan-ethnic genetic carrier screening panel (ECS) in a large population of Mexican patients. METHODS: Retrospective chart review of all patients tested with a single ECS panel at an international infertility center from 2012 to 2018 were included, and the prevalence of positive carrier status in a Mexican population was evaluated. RESULTS: Eight hundred five individuals were analyzed with ECS testing for 283 genetic conditions. Three hundred fifty-two carriers (43.7%) were identified with 503 pathogenic variants in 145 different genes. Seventeen of the 391 participating couples (4.34%) were identified as being at-risk couples. The most prevalent alleles found were associated with alpha thalassemia, cystic fibrosis, GJB2 nonsyndromic hearing loss, biotinidase deficiency, and familial Mediterranean fever. CONCLUSION: Based on the prevalence and severity of Mendelian disorders, we recommend that couples who wish to conceive regardless of their ethnicity background explore carrier screening and genetic counseling prior to reproductive medical treatment.

Conservative treatment versus surgical excision of ovarian dermoid cysts: Impact on ovarian stimulation and IVF cycle success.

OBJECTIVE: To analyze outcomes of IVF treatment among women diagnosed with an ovarian dermoid cyst (DC). METHODS: Retrospective analysis of women with an ovarian DC who underwent IVF with fresh blastocyst transfer at a single center in New York from January 2010 to March 2018. Outcomes were compared between women with conservative treatment and those with surgical excision of the DC. Multivariate logistic regression was used to assess associations between variables and the presence of a DC during treatment. RESULTS: Overall, 119 women with a DC were included. No differences were found in demographic characteristics, controlled ovarian hyperstimulation parameters, and IVF outcomes between women with an intact DC (n=65, 54.6%) and those who underwent cystectomy (n=54, 45.4%) (all P<0.05). Similarly, there was no difference in anti-Mϋllerian hormone and basal antral follicle count among women with a DC (respectively, ß=-0.1, P=0.8, and ß=-1.0, P=0.28) or resected DC (respectively, ß=0.9, P=0.07, and ß=1.5, P=0.08) as compared with control women with no DC (n=352). CONCLUSION: Ovarian reserve, embryo implantation and IVF success rates were not lower in the presence of an ovarian DC. Surgical therapy, if indicated, can be safely postponed until family planning goals have been achieved.

Infertile patients with inflammatory bowel disease have comparable in vitro fertilization clinical outcomes to the general infertile population.

To assess clinical outcomes of females diagnosed with Inflammatory Bowel Disease (IBD) and infertility, which underwent in vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy. (PGT-A). Retrospective cohort study comparing clinical outcomes of patients with Inflammatory bowel disease who underwent IVF with PGT-A with a subsequent euploid single embryo transfer (SET) against a matched control group. Thirty-eight patients with an IBD diagnosis were compared to 114 controls. There was no significant difference in cycle outcomes among IBD and Control cohorts [implantation rate (71.0% vs. 78.0% (p = .68)], clinical pregnancy rate [50.0% vs. 60.5% (p = .68)], live birth [62.9% vs. 73.0% (p = .06)] multiple pregnancy rate [0% vs. 1.1% (p = .25)] and clinical pregnancy loss rate [10.5% vs. 5.7% (p = .54)]. An IBD diagnosis was not found to significantly modify the odds of implantation [adjusted OR = 0.6 (95% CI -1.2 to 0.8)]. Additionally, the odds of implantation in patients with IBD were not altered by having ulcerative colitis or Crohn's disease diagnosis. (OR = 0.4 95% CI 0.1-1.9). Patients diagnosed with IBD who undergo a SET have clinical outcomes comparable to the general infertile population. Patients and physicians can be reassured that an IBD diagnosis does not impair IVF treatment outcomes.SYNOPSISInfertile patients with inflammatory bowel disease who utilized a single, euploid blastocyst transfer had IVF success rates comparable to the general infertile population.

What is the reproductive potential of day 7 euploid embryos?

STUDY QUESTION: What is the rate of euploidy and the reproductive potential of embryos biopsied after 6 days of development? SUMMARY ANSWER: Embryos biopsied after 6 days of development have higher rates of aneuploidy; however, day 7 euploid embryos selected at transfer can achieve acceptable pregnancy rates and live birth (LB) outcomes. WHAT IS KNOWN ALREADY: Recent publications have shown promising treatment results after euploid day 7 embryo transfers (ETs), albeit these studies were limited by small sample sizes. Whereas the current clinical standard has been to discard embryos that do not reach expansion by day 6 of development, the lack of robust data surrounding the clinical utility of day 7 embryos warrants further evaluation. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis in a single, academic in vitro fertilization (IVF) center from January 2012 to March 2018. A total of 25 775 embryos underwent trophectoderm (TE) biopsy and preimplantation genetic testing for aneuploidy (PGT-A). Additionally, the clinical IVF outcomes of 3824 single, euploid frozen embryo transfer (FET) cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohorts were segregated by day of TE biopsy following oocyte retrieval (day 5, day 6 or day 7). PGT-A was performed to identify embryonic ploidy rates. Secondly, IVF and LB outcomes after single, euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE: A total of day 5 (n = 12 535), day 6 (n = 11 939) and day 7 (n = 1298) embryos were included in the study analysis. The rate of embryo euploidy was significantly lower in day 7 blastocysts compared to day 5 or day 6 cohorts (day 7 = 40.5%; day 5 = 54.7%; day 6 = 52.9%; (P < 0.0001)). After adjusting for age, anti-Müllerian hormone, BMI, embryo quality and number of embryos biopsied, there was a significant association between aneuploidy and embryos biopsied on day 7 when compared to day 5 biopsied embryos (OR = 1.34, CI 95% 1.09-1.45, P = 0.001) and day 6 biopsied embryos (OR = 1.26, CI95% 1.07-1.16, P < 0.001).A sub-analysis of subsequent 3824 single, euploid FET cycles (day 5: n = 2321 cycles; day 6: n = 1381 cycles; and day 7: n = 116 cycles) showed significant differences among cohorts in implantation, clinical pregnancy, LB and clinical loss rates. There was a significant decrease in the odds of implantation, clinical pregnancy and LB, but no association with clinical loss or multiple pregnancy rates in patients who utilized day 7-biopsied embryos during treatment. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and potential variability in the study center's laboratory protocol(s) compared to other reproductive treatment centers may limit the external validity of our findings. Additionally, patients who transferred euploid embryos, biopsied on day 7 of development due to an absence of day 5 or day 6 counterparts, may have introduced selection bias in this study. WIDER IMPLICATIONS OF THE FINDINGS: Embryonic developmental stage, morphological grade and ploidy status are paramount factors affecting ET selection and implantation potential. This study reveals that embryos ineligible for TE biopsy on day 5 or day 6 of development may benefit from extended culture to day 7. Our study demonstrates patient benefit when extended culture to day 7 of development is routinely performed for embryos failing to meet biopsy criteria by day 5 or 6. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this manuscript. Dr Alan Copperman is Advisor or Board Member of Sema 4 (Stake holder in Data), Progyny and Celmatix. TRIAL REGISTRATION NUMBER: This retrospective analysis was approved by an Institutional Review Board (WIRB PRO NUM: 20161791; Study Number: 1167398).

Endometrial preparation before the transfer of single, vitrified-warmed, euploid blastocysts: does the duration of estradiol treatment influence clinical outcome?

OBJECTIVE: To investigate whether the duration of estrogen administration before euploid embryo transfer affects clinical outcome. DESIGN: Retrospective cohort study. SETTING: Private, academic fertility center. PATIENT(S): Patients (n = 1,439) undergoing autologous freeze-only in vitro fertilization with preimplantation genetic testing (PGT) followed by endometrial preparation with estrogen and progesterone in a frozen, euploid blastocyst transfer cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome was live birth, and secondary outcomes included implantation, clinical pregnancy, early pregnancy loss, live birth, infant birthweight, low birth weight, infant gestational age at delivery, and preterm birth. RESULT(S): The duration of estrogen administration (mean: 17.5 ± 2.9 days; range: 10-36 days) before frozen embryo transfer did not impact implantation (odds ratio [OR] 0.99; 95% confidence interval [CI], 0.95-1.03), clinical pregnancy (OR 0.98; 95% CI, 0.94-1.01), early pregnancy loss (OR 1.03; 95% CI, 0.95-1.12), or live birth (OR 0.99; 95% CI, 0.95-1.03). The duration of estrogen exposure did not affect infant birthweight (in grams) (ß= -10.65 ± 8.91) or the odds of low birth weight (OR 0.87; 95% CI, 0.68-1.13). For every additional day of estrogen administration, we observed a reduction in gestational age at delivery (in weeks) (ß= -0.07 ± 0.03), but the odds of preterm delivery were not affected (OR 1.05; 95% CI, 0.95-1.17). CONCLUSION(S): Variation in the duration of estradiol supplementation before progesterone initiation does not impact frozen, euploid blastocyst transfer outcome. The duration of estrogen administration was inversely correlated with gestational age at delivery, but this did not translate into an increase in preterm delivery. Further studies are required on the downstream effects of endometrial preparation on the placental-endometrium interface.

Istmocele: una revisión sistemática de la literatura / Istmocele: a systematic review of literature

Resumen OBJETIVO: Revisar la bibliografía de la prevalencia, factores de riesgo, síntomas, diagnósticos y tratamiento de las pacientes con istmocele. MÉTODO: Búsqueda electrónica en las bases de datos: PubMed, EMBASE y Google Scholar. Se utilizaron los siguientes términos, palabras y sus combinaciones: "Cesarean section defect, uterine niche, isthmocele, uterine sacculation, uterine diverticulum, uterine pouch, isthmocele diagnosis, segmentocele y isthmocele treatment". La variable primaria estudiada fueron los síntomas asociados con el istmocele. Las variables secundarias: prevalencia, factores de riesgo, diagnóstico y tratamiento. RESULTADOS: Se reunieron 549 artículos de los que se eliminaron 288 por duplicidad y 228 no cumplieron los criterios de inclusión; al final solo se analizaron 33 artículos. El istmocele tiene una prevalencia de 15 a 84% en mujeres con antecedente de cesárea. Su incidencia se correlaciona directamente con la cantidad de cesáreas previas. Su aparición puede ser sintomática o asintomática. La manifestación clínica más común es el sangrado uterino anormal, que sucede en 28.9 a 82% de los casos. Incluso 88% se diagnostican en el ultrasonido transvaginal. La histeroscopia quirúrgica se asoció con disminución de los síntomas en 56.9 a 100%. CONCLUSIONES: El istmocele suele identificarse de manera fortuita en el ultrasonido transvaginal y casi siempre es asintomático. Puede ocasionar sangrado uterino anormal e infertilidad secundaria. Su prevalencia depende del método diagnóstico utilizado. La histeroscopia es el método de tratamiento más efectivo.

Abstract OBJECTIVE: Review the literature on the prevalence, risk factors, symptoms, diagnoses and treatment of patients with isthmocele. METHOD: An electronic search was performed using the following databases: PubMed, EMBASE and Google Scholar. The following terms, words and their combinations were used: "Cesarean section defect, uterine niche, isthmocele, uterine sacculation, uterine diverticulum, uterine pouch, isthmocele diagnosis, segmentocele y isthmocele treatment". The primary outcome was the symptoms associated with a cesarean scar defect. The secondary outcomes were prevalence, risk factors, diagnosis and treatment of istomocele. RESULTS: 549 articles were collected, of which 288 were eliminated due to duplication and 228 did not meet the inclusion criteria; In the end, only 33 articles were analyzed. A prevalence of 15 to 84% was found in women with a previous caesarean section. The prevalence of this alteration is correlated with the number of cesarean sections; the greater the number of caesarean sections, the greater the risk of developing an isthmocele. Its presence can be symptomatic or asymptomatic. The most common symptom is abnormal uterine bleeding, occurring in a 28.9% to 82% of the patients. Up to 88% of cases are diagnosed by a transvaginal ultrasound. A surgical hysteroscopy was associated with a 56.9% to a 100% improvement of symptoms. CONCLUSIONS: Isthmocele is commonly identified incidentally through a transvaginal ultrasound and is usually asymptomatic. It can cause abnormal uterine bleeding and secondary infertility. Its prevalence depends on the diagnostic method used. A surgical hysteroscopy is the most effective treatment method.

Embryo aneuploidy is not impacted by selective serotonin reuptake inhibitor exposure.

OBJECTIVE: To study whether maternal exposure to selective serotonin reuptake inhibitors (SSRIs) has any influence on rates of blastocyst aneuploidy and/or in vitro fertilization (IVF) cycle outcomes. DESIGN: Retrospective cohort analysis. SETTING: Private and academic IVF center. PATIENT(S): Patients who underwent IVF with preimplantation genetic treatment with trophectoderm biopsy (n = 4,355 cycles) and patients who underwent a single-embryo transfer (SET) between January-2012 and June-2017 (n = 2,132 cycles). INTERVENTION(S): Comprehensive chromosome screening and euploid SET. MAIN OUTCOME MEASURE(S): Odds of embryo aneuploidy. RESULT(S): Of 19,464 embryos analyzed, 3.9% (n = 743) were exposed to a SSRI, and the remaining 96.1% (n = 18,721) were not. The embryo euploid rate was 52.1%, and the aneuploid rate was 42.5%; 5.4% of the reports were inconclusive. No differences were found in clinical and IVF characteristics among the cohorts. After controlling for cofounders, there was no statistically significant associations between exposure to SSRIs and the odds of aneuploidy (adjusted odds ratio [OR] 0.04; 95% confidence interval [CI], -0.04-0.09). In a subanalysis including 2,132 thawed SET cycles, no differences were observed in implantation rate (71.3% vs. 70.1%; OR 0.60; 95% CI, 0.60-1.47), clinical pregnancy rate (58.2% vs. 59.7%; OR 0.70; 95% CI, 0.70-1.61), loss rate (18.5% vs. 11.49%; OR 1.54; 95% CI, 0.94-2.54), or multiple pregnancy rate (0.6% vs. 0; OR 0.7; 95% CI, 0.02-7.32) between cohorts. CONCLUSION(S): Patients exposed to SSRIs in vivo are not susceptible to an increased rate of embryo aneuploidy in IVF. The IVF outcomes of patients exposed to SSRIs do not differ from those of unexposed patients.

Hatching status before embryo transfer is not correlated with implantation rate in chromosomally screened blastocysts.

STUDY QUESTION: Do the reproductive outcomes from the transfer of fully hatched (FH) blastocysts differ from those of not fully hatched (NFH) blastocysts? SUMMARY ANSWER: Biochemical pregnancy rate (BPR), implantation rate (IR), live birth rate (LBR) and early pregnancy loss (EPL) rate are similar in FH and NFH single euploid blastocyst embryo transfers. WHAT IS KNOWN ALREADY: The use of extended culture and PGS often leads to transfer of an embryo that is well developed and frequently FH from the zona pellucida. Without the protection of the zona, an FH embryo could be vulnerable to trauma during the transfer procedure. To date, no other study has evaluated the reproductive competence of an FH blastocyst transfer. STUDY DESIGN, SIZE, DURATION: The retrospective study included 808 patients who underwent 808 cycles performed between September 2013 and July 2015 at a private academic IVF center. Of these, 436 cycles entailed transfer of a NFH blastocyst (n = 123 fresh transfer, n = 313 frozen/thawed embryo transfer (FET)) and 372 cycles entailed transfer of an FH blastocyst (n = 132 fresh, 240 FET). Fresh and FET cycles and associated clinical outcomes were considered separately. LBR was defined as the delivery of a live infant after 24 weeks of gestation. PARTICIPANTS/MATERIALS, SETTING, METHOD: Trophectoderm biopsies were performed on Day 5 (d5) or 6 (d6) for embryos meeting morphology eligibility criteria (set at ≥3BC). Morphologic grading was determined using a modified Gardner-Schoolcraft scale prior to transfer. A single euploid embryo was selected for transfer per cycle on either the morning of d6, for fresh transfers or 5 days after progesterone supplementation for patients with transfer in an FET cycle. Embryos were classified as NFH (expansion Grade 3, 4 or 5) or FH (expansion Grade 6) cohorts. The main outcome measure was IR. MAIN RESULTS AND THE ROLE OF CHANCE: In the fresh transfer group, IR was similar between NFH and FH cycles (53.7% versus 55.3%, P = 0.99, odds ratio (OR) 0.9; 95% confidence interval (CI) 0.6-1.5). Secondary outcomes were also statistically similar between groups: BPR (65.9% versus 66.7%, OR 1.0; 95% CI: 0.6-1.6), LBR (43.1% versus 47.7%, P = 0.45, OR 1.2; 95% CI: 0.7-1.9) and EPL rate (22.8% versus 18.2%, OR 1.3; 95% CI: 0.7-2.4). After adjusting for age, BMI, endometrial thickness at the LH surge and oocytes retrieved in a logistic regression (LR) model, the hatching status remained not associated with IR (P > 0.05). In the FET cycles, IR was similar between NFH and FH cycles (62.6% versus 61.7%, OR 1.0; 95% CI: 0.7-1.5). Secondary outcomes were similar between groups: BPR (74.1% versus 72.9%, respectively, OR 1.1; 95% CI: 0.7-1.6), LBR (55.0% versus 50.0%, OR 0.8; 95% CI: 0.6-1.1) and EPL rate (18.9% versus 22.9%, respectively, OR 0.8; 95% CI: 0.5-1.2). After adjusting for age, BMI, endometrial thickness at the LH surge and oocytes retrieved in an LR model, the hatching status was not shown to be associated with implantation (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: Limitations include the retrospective design and data from a single institution. Additionally, the study was limited to patients that developed high-quality blastocysts suitable for biopsy. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that FH embryos are not more fragile or less likely to implant when compared to NFH counterparts. We found no evidence of altered IR or other clinical outcomes in the transfer of FH euploid embryos. STUDY FUNDING/COMPETING INTERESTS: JG is funded by MSTP grant T32 GM007280 (NIH). No additional funding was received. There are no conflicts of interest to declare..

Do elevated TSH levels predict early pregnancy loss in ART patients?

INTRODUCTION: The upper limit of normal TSH has been revised from 5 mIU/L to 2.5 mIU/L. We sought to evaluate IVF patients and the association between abnormal TSH and early pregnancy loss. METHODS: A retrospective study of patients who had TSH levels measured within the 2 weeks prior to their fresh autologous IVF cycles (2002-2014). Cohorts were stratified by oocyte age (<35, [35-38), [38-41), [41-43) and ≥43 years), and TSH level [(0-0.5], (0.5-2.5], (2.5-5], and (5-23) mIU/L]. Patients were followed until pregnancy loss or delivery. Model was assessed by chi-square of ANOVA with significance at p < 0.05. RESULTS: TSH was abnormally elevated (>5 mIU/L), mildly elevated ((2.5-5] mIU/L) or suppressed (≤0.5 mIU/L) in 46, 317 and 65 of the 1201 total cycles, respectively. Treatment resulted in 630 pregnancies, 524 clinical pregnancies and 409 deliveries. Pregnancy loss rates were increased in patients ≥38 yo (p < 0.001) but not [35-38) yo (p = 0.40) compared with those <35 yo. Early pregnancy loss rate was not associated with TSH level (p > 0.30) compared with euthyroid patients after adjusting for oocyte age. CONCLUSION: Early pregnancy loss rate in IVF patients appears to have no relation to recent TSH levels.

Reproductive outcome is optimized by genomic embryo screening, vitrification, and subsequent transfer into a prepared synchronous endometrium.

PURPOSE: The aim of this study is to compare implantation and live birth rates (LBR) between fresh euploid embryo transfers versus cryo-all cycles with a subsequent embryo transfer into a prepared endometrium. MATERIAL AND METHODS: This is a retrospective cohort study. Patients who underwent an IVF cycle with PGS with trophectoderm biopsy from January 2011 to July 2015 were included. Patients were divided into three groups: "Fresh Only," "Frozen Embryo Transfer ('FET) Only," and "Fresh ET then FET." For "Fresh Only" group (n = 345), PGS results were received within 24 h. For "FET Only" group (n = 514), results were expected after 24 h, and embryos were cryopreserved after biopsy; only FET was performed in this group (no fresh transfer). For "FET with a previous fresh ET" (n = 139) group, patients underwent a fresh ET with a subsequent FET, in which the same cohort of embryos was utilized. The main outcome measures were pregnancy rate (PR), clinical PR, implantation rate (IR), LBR, and early pregnancy loss rate. RESULTS: IRs were statistically higher in the "FET Only" group when compared to the "Fresh Only" group (59.5 vs. 50.6%, p < 0.01) and the "FET with a previous fresh ET" (59.5 vs. 50.6%, p < 0.05). LBR was statistically significant in the "FET Only" group when compared to the "Fresh Only" group (57.6 vs. 46.5 %, p < 0.005) but not when compared to "FET with a previous fresh ET" group (57.6 vs. 47.7%, p = 0.07). CONCLUSIONS: This analysis suggests euploid embryos to be more likely to implant and achieve a LBR in a synthetic FET cycle than in a fresh cycle.

Comparision of Letrozole with Timed Intercourse Versus Clomiphene Citrate with Intrauterine Insemination in Patients with Unexplained Infertility.

OBJECTIVE: To evaluate outcomes of patients with unexplained infertility who underwent letrozole (LET)- stimulated controlled ovarian stimulation (COS) with timed sexual intercourse (IC) as compared to patients treated with clomiphene citrate (CC) and intrauterine insemination (IUI). STUDY DESIGN: A non- randomized, retrospective study where unexplained in- fertility patients (n=7,764). underwent a COS cycle with both LET and timed IC or with CC and IUI from January 2010-June 2014. One group consisted of patients who completed a COS cycle with LET and were instructed to have sexual IC. The other included patients were treated with CC and underwent IUI. Pregnancy rates (PRs) were compared between groups. RESULTS: No statistical difference was observed in each group's age or serum follicule-stimulating hor- mone levels. A statistical significance in LET versus CC-stimulated groups was observed for mean endome- trial thickness (8.3 ± 1.7 vs. 7.9 ± 1.8 mm) and follicular response (2.0 ± 1.0 vs. 2.3 ± 1.3), respectively. Clinical PRs after timed IC were significantly higher in the LET versus CC-stimulated group (15.0% vs 11.8%). Clinical PRs after timed IUI were also significantly higher in the LET versus CC-stimulated group (12.3% vs. 11.5%). Moreover, clinical PRs in LET with IC were significant- ly higher than CC with IUI (15.0% vs. 11.5%). CONCLUSION: Unexplained infertility patients who underwent LET stimulation with IC werefound to have better pregnancy out- comes as compared to those who underwent timed IC.or IUI with CC stimulation.

Embryo selection versus natural selection: how do outcomes of comprehensive chromosome screening of blastocysts compare with the analysis of products of conception from early pregnancy loss (dilation and curettage) among an assisted reproductive technology population?

OBJECTIVE: To compare the incidence of numerical chromosomal abnormalities (NCAs) reported after preimplantation genetic screening (PGS) analysis compared with that reported after cytogenetic analysis of products of conception after spontaneous abortion. DESIGN: Retrospective study. SETTING: Private academic in vitro fertilization center. PATIENT(S): Cytogenetic reports of patients who underwent an IVF cycle with PGS of at least one biopsied embryo were compared with cytogenetic analysis reported from patients who had dilation and curettage (D&C) for the treatment of a spontaneous abortion after assisted reproductive technology (ART) treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Frequencies for each numerical chromosomal abnormality from both groups were compared. RESULT(S): A total of 1,069 NCAs were reported after PGS (trisomy 54.3%, monosomy 45.7%, no polyploidies), resulting in a trisomy/monosomy ratio of 0.82. A total of 447 NCAs was reported after D&C (trisomy 83%, polyploidy 10.7%, monosomy 6.3%). The aneuploidies most frequently identified were similar in both groups and included 15, 16, 18, 21, and 22. Monosomies (n = 28, 6.3%) were rarely observed in the group that underwent D&C after ART. CONCLUSION(S): This review provides an analysis of the most commonly identified NCAs after PGS and in first-trimester D&C samples in an infertile population utilizing ART. Although monosomies comprised >50% of all cytogenetic anomalies identified after PGS, there were very few identified in the post-D&C samples. This suggests that although monosomies occur frequently in the IVF population, they commonly do not implant. Despite this difference, this study demonstrated that the specific NCAs observed after PGS analysis and D&C were comparable.

Maximum basal FSH predicts reproductive outcome better than cycle-specific basal FSH levels: waiting for a "better" month conveys limited retrieval benefits.

BACKGROUND: Elevated follicle stimulating hormone (FSH) is associated with poor vaginal oocyte retrieval (VOR) outcomes and cycle cancellations but intercycle variability in basal FSH reportedly does not predict ovarian response. METHODS: We conducted a retrospective cohort study of basal FSH (n = 15573 cycles) in couples (n = 9132) who initiated IVF cycle(s) with basal estradiol (E2) <100 pg/mL between 2002 and 2014 to reevaluate this hypothesis. The most recent (current) FSH, maximum FSH (Max FSH) and prior cycle maximum basal FSH (PMax FSH) were computed for each cycle. Metaphase II (MII) oocyte counts were modeled by age, stimulation type, prior peak E2 level, prior MII count, Max FSH, PMax FSH and current FSH. Antral follicle counts, pregnancy, clinical pregnancy and live birth rates were modeled as secondary outcomes. RESULTS: Max FSH level distinguished completed cycles from cancelled cycles better than PMax FSH or current FSH (AUC of 0.72, 0.71 and 0.61, respectively, p < 0.001). Fewer MIIs were retrieved (5.7 ± 3.8) in cycles with Max FSH >13 mIU/mL (n = 1475) than those with ≤13 mIU/mL (n = 11978) (11.6 ± 7.1) (p < 0.001). Max FSH was a better predictor of MII count than PMax FSH or current FSH after controlling for age, stimulation type, prior peak E2 level and prior MII count. Additional MIIs were retrieved on average in cycles with PMax FSH >13 mIU/mL (n = 1930) whose current FSH was ≤13 mIU/ml rather than >13 mIU/ml (p < 0.01) after controlling for age, cycle number and stimulation type. However, no improvement in pregnancy or live birth rate was detected. CONCLUSIONS: Max FSH is the best FSH-based predictor of ovarian reserve. Retrieval benefits from waiting for a "better" month appear to exist but are limited.

Endometrial pattern, but not endometrial thickness, affects implantation rates in euploid embryo transfers.

OBJECTIVE: To evaluate the relationship of endometrial thickness (EnT) and endometrial pattern (EnP) to euploid embryo transfer (ET) outcomes. DESIGN: Retrospective cohort. SETTING: Private academic clinic. PATIENT(S): Patients (n = 277; age 36.1 ± 4.0 years) whose embryos (n = 476) underwent aneuploidy screening with fresh (n = 176) or frozen (n = 180) ET from July 2010 to March 2014. INTERVENTION(S): The EnT and EnP were measured on trigger day and at ET. Patients were stratified by age and cycle type (fresh or frozen). Cycle data were combined at trigger day, but separated at ET day. MAIN OUTCOME MEASURE(S): Outcome measures were implantation rate, pregnancy rate, and clinical pregnancy rate. Analysis was conducted using χ(2) analysis and Fisher's exact test. RESULT(S): A total of 234 gestational sacs, 251 pregnancies, and 202 clinical pregnancies resulted from 356 cycles. The EnT (9.6 ± 1.8 mm; range: 5-15 mm) at trigger day (n = 241 cycles), as a continuous or categorical variable (≤8 vs. >8 mm), was not associated with implantation rate, pregnancy rate, or clinical pregnancy rate. The EnT at day of fresh ET (9.7 ± 2.2 mm; range: 4.4-17.9 mm) (n = 176 cycles) or frozen ET (9.1 ± 2.1 mm; range: 4.2-17.7 mm) (n = 180 cycles) was not associated with implantation rate, pregnancy rate, or clinical pregnancy rate. Type 3 EnP at trigger day was associated with increased serum progesterone at trigger and a decreased implantation rate, compared with type 2 EnP. The EnP at fresh or frozen ET was not associated with implantation rate, pregnancy rate, or clinical pregnancy rate. CONCLUSION(S): Within the study population, EnT was not significantly associated with clinical outcomes of euploid ETs. A type 3 EnP at trigger day suggests a prematurely closed window of implantation.

Beauty, brains or health: trends in ovum recipient preferences.

BACKGROUND: What do ovum donation (OD) recipients request most from their ideal donor: beauty, brains, health or physical self-resemblance? Previous data have shown recipients primarily requested "similar appearance or gene pool." We consider the possibility that these criteria may have changed due to a positive social shift towards OD participation and have evaluated recipients' requests for donor criteria over a span of 5 years. METHODS: Donor trait preferences of OD recipients (n=438) enrolled in a private, academic OD program from 2008-2012 were assessed in this retrospective cohort analysis. Requests were categorized by appearance, ethnicity, intellect, ability, and mental health. Statistical analyses were conducted by Cochran-Armitage trend tests with significance at p<0.05. RESULTS: The percentage of requests for "health" increased steadily from 2008 (50%) to 2012 (72%) (p<0.05). The percentage of requests for "intelligence" were highest in 2012 (55%), increasing from 2008 (18%) (p<0.05). Requests for "athletic ability" rose from 2008 (1%) to 2012 (17%) (p<0.05). Recipients requested a "similar gene pool" most in 2009 (40%) and least in 2012 (25%), though this trend did not reach statistical significance. CONCLUSIONS: Our study demonstrates an increase in the percentage of OD recipients' requests for health, athleticism, and intelligence over our 5-year analysis. It appears that the current recipient is more likely to request a donor with practical traits that would serve their offspring overall quality of life rather than self-reflective traits such as physical resemblance or their genetic composition. We believe that improved awareness and acceptance of OD as a treatment of infertility will continue to inform practical considerations and approaches toward donor recruitment and the donor-recipient matching process.

Should ICSI be recommended routinely in patients with four or fewer oocytes retrieved?

PURPOSE: To determine if patients with a low response to controlled ovarian hyperstimulation during IVF benefit from intracytoplasmic sperm injection (ICSI) METHODS: Retrospective analysis of 350 IVF cycles in which four or fewer oocytes were retrieved. Severe male factor cases were excluded from analysis. Conventional insemination (CI) and ICSI were compared, with primary outcome measures of fertilization rate, implantation rate, clinical pregnancy rate per embryo transfer, and pregnancy loss rate. RESULT(S): Fertilization rates per oocyte retrieved for CI and ICSI were comparable (51.5% vs. 51.8%). Parallel implantation rates (22% vs. 25%), clinical pregnancy rates (32.8% vs. 33.3%), and loss rates (26.7% vs. 39.5%) were also noted. No difference in cancelled cycles was reported. CONCLUSION(S): Our results demonstrate that in the presence of normal semen parameters, low egg number is not an indication to perform ICSI.