Impact of stimulation with luteinizing hormone activity on IVF outcomes in patients with polycystic ovary syndrome.

Objective: To compare in-vitro fertilization (IVF) outcomes in polycystic ovary syndrome (PCOS) patients treated with follicle stimulating hormone (FSH) alone or FSH and luteinizing hormone (LH), under freeze-all gonadotropin-releasing hormone (GnRH) antagonist protocols. Material and Methods: This retrospective study at a university center included PCOS patients, who underwent freeze-all GnRH antagonist IVF cycles between January 2013 and December 2019. They were divided into FSH-only and FSH + LH groups, focusing on pregnancy and live birth rates. Results: The study included 82 patients: 43 received FSH + LH and 39 FSH only. Baseline characteristics were similar, except for higher thyroid stimulating hormone levels in the FSH-only group. The FSH + LH group required a lower mean ± standard deviation total dose of FSH (1271.5±376.7 vs. 1407.2±645.3 IU, p=0.02), had a shorter mean cycle length (7.3±3.4 vs. 8.3±1.6 days, p=0.004), and had a higher mean number of follicles stimulated (36.9±15.9 vs. 35.9±9.7, p=0.008) compared to the FSH-only group. No significant differences in pregnancy and live birth rates were noted at first transfer, but the cumulative live birth rate was significantly higher in the FSH-only group [30 of 39 (76.9%) vs. 24 of 43 (55.8%), p=0.044]. Conclusion: LH supplementation in PCOS patients undergoing GnRH antagonist IVF protocols may impair cumulative live birth rates, despite lowering FSH requirement and reducing IVF cycle length. These results highlight the complex role of LH in IVF outcomes for PCOS patients, suggesting a need for further large studies to fully understand the impact of LH in such treatments.

PGT pregnancies have a similar risk for post-partum complications as naturally conceived pregnancies.

RESEARCH QUESTION: Do preimplantation genetic testing (PGT) pregnancies have higher post-partum complications compared with naturally conceived pregnancies? DESIGN: Retrospective cohort study conducted in 2008-2020 at the Shaare Zedek Medical Center (SZMC), including all patients aged 18-45 years old who conceived following PGT with a singleton live birth >24 weeks. Data were collected from computerized hospital databases and patient files. There were two control groups: (i) pregnancies following IVF-ICSI (intracytoplasmic sperm injection); (ii) four neighbourhood controls for each case delivery (two women delivered before and two after) of women with naturally conceived pregnancies. RESULTS: Overall, 120 PGT, 779 IVF-ICSI and 3507 naturally conceived deliveries were included. Demographic variables were similar apart from slightly higher age in the PGT (P = 0.003) and ICSI (P = 0.002) groups (31.07 ± 4.38 PGT, 31.66 ± 5.03 ICSI, 28.77 ± 5.72 naturally conceived). Composite post-partum placental-related complications (manual lysis of placenta, revision of uterine cavity, haemoglobin drop ≥3 g/dl, post-partum haemorrhage, need for blood transfusion) were more prevalent in both the PGT and IVF-ICSI groups as opposed to naturally conceived (20.0% versus 18.9% versus 10.3%, respectively, P < 0.001, P = 0.007). In a multivariate regression model PGT was not found to be independently associated with composite post-partum placental-related complications (adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.83-2.15), while IVF-ICSI pregnancies had increased risk (aOR 1.52, 95% CI 1.20-1.97) compared with natural conception. No difference was found between fresh and frozen cycles or between day 3 and day 5 embryo transfer. CONCLUSIONS: PGT pregnancies have a comparable risk of post-partum placental-related complications to naturally conceived pregnancies, unlike IVF-ICSI pregnancies. It is possible that infertility itself is the main mediator for post-partum complications in IVF-ICSI pregnancies.

Among high responders, is oocyte development potential different in Rotterdam consensus PCOS vs non-PCOS patients undergoing IVF?

PURPOSE: To evaluate the oocyte potential to develop to blastocyst in Rotterdam consensus PCOS in women with hyper-responses requiring freeze-all embryos. METHODS: Retrospective, single-academic center, cohort study of 205 patients who underwent freeze-all antagonist IVF cycles for OHSS risk between 2013 and 2019. Women in the PCOS group (n = 88) were diagnosed per the 2003 Rotterdam criteria. Control patients (n = 122) had no evidence of hyperandrogenism or menstrual disturbance. Data was compared by t-tests, chi-squared tests, or multivariate logistic regression (SPSS). Frozen blastocysts were Gardner's grade BB or better. RESULTS: There was no difference in terms of number of oocytes collected (PCOS vs non-PCOS 27.7 ± 9.4 vs 25.9 ± 8.2, p = 0.157), number of MII (20.7 ± 8.0 vs 19.1 ± 6.6, p = 0.130), number of 2PN fertilized (15.6 ± 7.4 vs 14.4 ± 5.9, p = 0.220), and number of frozen blastocysts (7.8 ± 4.9 vs 7.1 ± 3.8, p = 0.272). In addition, fertilization rates (74 ± 17% vs 75 ± 17%, p = 0.730), blastulation rates per 2PN (51 ± 25% vs 51 ± 25%, p = 0.869), and blastulation rates per mature oocytes (37 ± 18% vs 37 ± 15%, p = 0.984) were all comparable between PCOS and controls, respectively. Moreover, there was no difference when comparing PCOS and controls in pregnancy rates (45/81 vs 77/122, p = 0.28) and clinical pregnancy rates (34/81 vs 54/122, p = 0.75), respectively. Multivariate logistic regression controlling for confounders failed to alter these results. CONCLUSION: PCOS subjects do not seem to have altered oocyte potential as measured by number of MII oocytes collected, fertilization, and blastulation rates when compared to high-responder controls, with similar magnitude of stimulation.

Extended fertility at highly advanced reproductive age is not related to anti-Müllerian hormone concentrations.

RESEARCH QUESTION: Is extended fertility at the advanced reproductive age of 43-47 years associated with high anti-Müllerian hormone (AMH) concentrations? DESIGN: Prospective cohort study including 98 women aged 43-47 years old with a spontaneous conception who were tested for AMH concentrations 1-4 days and 3-11 months post-partum. AMH concentrations at 3-11 months post-partum were further compared with AMH concentrations in healthy age-matched controls that last gave birth at ≤42 years old. Women with current use of combined hormonal contraceptives (CHC), ovarian insult or polycystic ovary syndrome were excluded. Power analysis supported the number of participating women. RESULTS: Median AMH concentrations did not differ between the extended fertility (n = 40) and control (n = 58) groups (0.50 versus 0.45 ng/ml, P = 0.51). This remained when analysing by age (≥ or <45 years old). AMH concentrations and women's age did not correlate within the extended fertility group (r = 0.017, P = 0.92); a weak negative correlation was found within the control group (r = -0.23, P = 0.08). AMH was significantly higher 3-11 months post-partum (0.50 ng/ml [0.21-1.23]) than 1-4 days post-partum (0.18 ng/ml [0.06-0.40]), P < 0.001. The two results for each participant were highly correlated (r = 0.82, P < 0.001). The extended fertility and control groups were similar regarding age, age at menarche, past CHC use and history of fertility concern. Parity differed but showed no significant correlation with AMH. CONCLUSIONS: Serum AMH concentrations that reflect ovarian reserve do not seem to predict reproductive potential at highly advanced age. Thus, additional factors such as oocyte quality should also be considered in evaluating reproductive potential. AMH suppression that is associated with pregnancy at 1-4 days post-partum recovers at 3-11 months post-partum in women of highly advanced reproductive age.

Leukocyte Telomere Length Correlates with Extended Female Fertility.

Current social trends of delayed reproduction to the fourth and fifth decade of life call for a better understanding of reproductive aging. Demographic studies correlated late reproduction with general health and longevity. Telomeres, the protective ends of eukaryotic chromosomes, were implicated in various aging-associated pathologies and longevity. To examine whether telomeres are also associated with reproductive aging, we measured by Southern analysis the terminal restriction fragments (TRF) in leukocytes of women delivering a healthy infant following a spontaneous pregnancy at 43-48 years of age. We compared them to age-matched previously fertile women who failed to conceive above age 41. The average TRF length in the extended fertility group (9350 bp) was significantly longer than in the normal fertility group (8850 bp; p-value = 0.03). Strikingly, excluding women with nine or more children increased the difference between the groups to over 1000 bp (9920 and 8880 bp; p-value = 0.0009). Nevertheless, we observed no apparent effects of pregnancy, delivery, or parity on telomere length. We propose that longer leukocyte telomere length reflects higher oocyte quality, which can compensate for other limiting physiological and behavioral factors and enable successful reproduction. Leukocyte telomere length should be further explored as a novel biomarker of oocyte quality for assessing reproductive potential and integrating family planning with demanding women's careers.

Transvaginal Sonography Post-Office Hysteroscopy as a Screening Tool for Tubal Patency: A Reliable and Feasible Technique in an Outpatient Setting.

OBJECTIVE: To determine feasibility and accuracy of post-hysteroscopic transvaginal ultrasonography (TVUS) measurement of pelvic fluid accumulation as a screening method for tubal patency (TP). METHODS: We conducted a retrospective cohort study of 85 patients who underwent uterine cavity assessment by office hysteroscopy at our university-affiliated fertility centre from November 2019 to October 2020. During the study period, two-dimensional (2D) TVUS was performed pre- and post-hysteroscopy to evaluate TP. Patient records were reviewed for demographics, diagnosis, and prior/subsequent TP testing. Predictive values for TP were calculated. RESULTS: Pelvic fluid accumulation post-hysteroscopy was found in 65.9% of patients (56). Accumulation of fluid was seen with the use of as little as 10-50 mL of saline. Using more fluid did not increase the likelihood of demonstrating TP (P = 0.17). A trend towards more false-negative results for TP was observed when less fluid was used (7.7% with 10-50 mL vs. 3.8% with 60-190 mL and 1.3% with 200-760 mL; P = 0.10). The positive predictive value (PPV) of TVUS post-hysteroscopy in comparison to known patency/occlusion was 100%; negative predictive value (NPV) was 33%; sensitivity was 82.8%; and specificity was 100%. Similar values were seen in a second analysis that included patients with highly suspected patent or occluded tubes (n = 60); presumed predictive values were: PPV 100%, NPV 42%, sensitivity 78.8%, and specificity 100%. The use of more fluid did not increase pain (P = 0.75). This finding remains after accounting for confounders (e.g., pre-medication, endometrial biopsy). CONCLUSION: TVUS pre- and post-hysteroscopy is feasible in an outpatient setting, and can serve as a reliable screening tool for TP. When hysteroscopy is performed and TP is not known, TVUS can be added for screening, potentially omitting the need for more invasive examinations. With limited non-urgent ambulatory services, it is of upmost importance to maximize information from a single procedure.

Do oral ovulation induction agents offer benefits in women 38 to 43 years of age undergoing insemination cycles?

OBJECTIVE: To compare the success of ovulation induction using oral agents versus gonadotropins (GTs) in women ≥38 years old. STUDY DESIGN: A retrospective cohort study was performed including all first to third stimulated IUI cycles conducted after the age of 38 years in a single academic fertility center between 01/2011 and 03/2018. RESULTS: A total of 1596 IUI cycles were included. 240 cycles were with clomiphene citrate (CC), 176 letrozole cycles and 1180 gonadotropin (GTs) cycles. The GTs group were older (p < 0.001), had lower antral follicular count (p < 0.001), and thicker endometrium (p < 0.001) compared to the oral agent groups. The letrozole group had a less mature follicles (p = 0.004) at the time of triggering compared to the other groups. No difference in pregnancy or clinical pregnancy rates was observed after controlling for confounders when comparing the 3-groups. 5 multiple pregnancies occurred, all in the GTs group. The groups were subdivided by age; 38-39 years old (N = 750) and 40-43 years old (N = 846). Nevertheless, no statistical difference was observed in pregnancy rates and clinical pregnancy rates between oral agents and GTs when controlling for the confounding effects among women at age 38-39 (p = 0.47, p = 1.0; respectively) and among women 40-43-years-old (p = 0.16, p = 1.0; respectively). CONCLUSIONS: Clearly costs of oral agents are lower and they are more patient friendly than GTs, therefore oral agents should be first line for ovarian stimulation and IUI in women 38-43-years of age.

Blastocyst morphology has no relationship with serum ß-hCG levels and live birth rates once pregnant.

OBJECTIVE: What is the role of blastocyst morphology on day16 ß-hCG serum levels and pregnancy outcomes among patients who conceived through IVF cycles with single fresh Gardner's scored blastocyst transfers. STUDY DESIGN: A retrospective cohort study conducted at a single academic fertility center between January 2013 and December 2017. A total of 643 pregnancies were included in the study. RESULTS: The patients were divided into 5 groups according to Gardner's blastocysts grade of the ICM and the TE (grade), and into 4 groups according to blastocyst Gardner's degree of blastocoel expansion (stage). No significant differences were found between the different morphologic groups and day16 ß-hCG serum levels, clinical pregnancy rates and live births. A weak significant correlation was observed between Gardner's blastocysts grade and day 16 ß-hCG (Correlation Coefficient r= -0.098, p = .014) this correlation remained significant after controlling for confounders. (r= -0.099 p = . 013). A weak significant correlation was observed between Gardner's stage and day 16 ß-hCG (Correlation Coefficient r = 0.086, p = 0.029) this correlation lost significance after controlling for confounders. (r = 0.055, p = 0.340). When evaluating predictors of live birth using multivariate logistic regression, blastocyst grade (p = 0.33) and stage (p = 0.65), at transfer, were not associated with live births, when controlling for confounding effects. CONCLUSION: Once the patient conceives after IVF with single blastocyst, none of the morphological parameters have a strong impact on the day16 serum level of ß-hCG. Among women who conceived, blastocyst grade and stage were not associated with live births.

Preimplantation genetic testing (PGT) for copy number variants of uncertain significance (CNV- VUS) in the genomic era: to do or not to do?

PURPOSE: To review cases of couples presented to our PGT-unit with copy number variants (CNVs) classified as variants of uncertain significance (VUS) in order to better understand their needs. METHODS: Retrospective cohort study conducted in a tertiary medical-center, 2014-2019. We reviewed files of all couples applying for genetic counseling with CNVs classified as VUS. The main outcomes measured: number of VUS findings and their description, PGT-M procedures planned and performed, IVF cycles, clinical pregnancy, and live birth rates (LBR). VUS were classified according to the American-College of Medical-Genetics and Genomics classification at time of first consultation, and updated-December 2018. RESULTS: Twenty-four couples presented with a total of 30 VUS. Twelve couples (50%) had isolated VUS and 12 (50%) had VUS diagnosed in addition to a pathogenic mutation. Initially, nine findings (30%) were defined as VUS; eight (27%) as likely benign (b-VUS); and 13 (43%) as likely pathogenic (p-VUS). PGT-M was recommended for 17/30 CNVs (56.6%), 12 (70%) of which, isolated VUS. No couple had other indications for IVF. To date, nine couples performed PGT-M for isolated VUS; LBR per-couple-55.5%. Five couples performed PGT-M for both pathogenic findings and VUS, LBR-80%. After reviewing VUS classifications, 30% remained unchanged, 20% were more severely defined, and 50% less severely defined. CONCLUSION: The genomic era enables detection of VUS whose definition is subject to change as additional information becomes available. The uncertainty of variants' clinical significance and changes in VUS definition over time complicates genetic counseling. Revised guidelines for VUS interpretation and reevaluation of patient counseling before each pregnancy must be practiced when counseling them regarding the justification of PGT-M for their diagnosed VUS.

COVID-19 pandemic effect on early pregnancy: are miscarriage rates altered, in asymptomatic women?

PURPOSE: To evaluate the effect of the COVID-19 pandemic state on early, first-trimester pregnancies. METHODS: A retrospective cohort study conducted at a university-affiliated fertility center in Montreal, Quebec, since the COVID-19 shut down, March 13 until May 6, 2020. Included: all women who came for a first-trimester viability scan during the study period (Study group) and between March 1, 2019 and May 17, 2019, approximately one year prior (Control). The study population denied symptoms of COVID-19. We reviewed all first trimester scans. Early first-trimester pregnancy outcomes (Viable pregnancy, arrested pregnancy including biochemical pregnancy loss and miscarriage, and ectopic pregnancy) were measured as total number and percentage. A multivariate analysis was performed to control for other potentially significant variables, as was a power analysis supporting sample size. RESULTS: 113 women came for a first-trimester viability scan in the study period, and 172 in the control period (5-11 weeks gestational age), mean maternal age 36.5 ± 4.5 and 37.2 ± 5.4 years (p = 0.28). Viable clinical pregnancy rate was not different between the two groups (76.1 vs. 80.2% in the pandemic and pre-pandemic groups p = 0.41). No significant difference was seen in the total number of arrested pregnancies (defined as the sum of biochemical, 1st trimester miscarriages, and blighted ova) (22.1 vs. 16.9% p = 0.32), or in each type of miscarriage. CONCLUSION: The COVID-19 pandemic environment does not seem to affect early first-trimester miscarriage rates in asymptomatic patients.

Trends in ovarian hyperstimulation syndrome hospitalization rates in the USA: an ongoing concern.

Ovarian hyperstimulation syndrome (OHSS) is a serious, almost exclusively, iatrogenic complication of ovarian stimulation. Many techniques have been developed over the past 25 years to decrease OHSS risks, and most have been in common use for 15-20 years. In view of these techniques, it could be hypothesized that severe OHSS rates would decrease or almost disappear. According to the US National ART Surveillance System, rates did not change significantly between 2000 and 2009, at 106 OHSS cases per 10,000 IVF cycles annually. In the present study, OHSS-related hospital admissions were evaluated to establish whether a decline has occurred in OHSS admissions since the development of preventative strategies. A retrospective-population-based study was conducted using data from the Health-Care Cost and Utilization Project-Nationwide-Inpatient-Sample database between 2004 and 2014 inclusively. Between 2004 and 2008, admissions of OHSS decreased in absolute numbers and rates; however, these statistics plateaued, remaining stable between 2008 and 2014. Despite this, OHSS remains a concern and is clearly not a disease of the past. The financial burden of OHSS hospitalizations likely persists. Although techniques have resulted in a decrease in OHSS admissions since 2004, this change has plateaued, and therefore efforts to further reduce OHSS must continue.

Fertility care in the era of commercial direct-to-consumer home DNA kits: issues to ponder.

Recently, we have witnessed a shift in the nature of genetic testing. What was once solely in the hands of the scientific community is now easily accessible to anyone. Commercial companies such as Veritas Genetics, Ancestry, and 23andMe offer cheap direct-to-consumer home DNA kits that are branded as a "health and ancestry service." These tests are gaining in popularity, and it is estimated that since their marketing, over 30 million people worldwide have provided their DNA samples. The implications of this new genetic era are diverse, ranging from the individuals personal health assessment, to family genealogy and ancestry, and the complexity of establishing an enormous population-based genetic database. Unique implications of commercial DNA tests on fertility patients and heath care providers, such as in the case of gamete donation, are important to acknowledge and have implications for reproductive care.

The impact of epidural analgesia on the mode of delivery in nulliparous women that attain the second stage of labor.

Objective: We aimed to evaluate the impact of epidural analgesia on the mode of delivery of nulliparous women with a term single fetus in vertex presentation (NTSV) that attained the second stage of labor.Study design: A single-center retrospective study provided a strict and constant department protocol for epidural analgesia practice and obstetric interventions, between 2005 and 2014. Epidural users were compared to nonusers. The primary outcome was the mode of delivery. Secondary outcomes were diagnosis of prolonged second stage of labor and maternal and neonatal morbidities. The outcomes were evaluated by adjusted multivariate analyses (Adjusted Odds Ratios (aOR), 95% CI).Results: During the study period, 25,643 NTSV attained the second stage of labor; 18 676 (73%) epidural users and 6967 (27%) nonusers. Epidural users had an increased risk of instrumental delivery 2.48, [2.22-2.76], along with a lower risk of cesarean delivery 0.38, [0.29-0.50]. Notably, the diagnosis of prolonged second stage of labor was comparable among the study groups 0.99, [0.89-1.12]. The epidural users had a significantly higher risk of early postpartum hemorrhage 1.15, [1.04-1.27]. The risk for neonatal morbidity was comparable among the study groups 1.21 [0.90-1.63].Conclusion: Epidural analgesia in a population of NTSV that attains the second stage of labor is associated with a higher risk of instrumental delivery, nonetheless with a reduced risk of cesarean delivery; independent of the length of the second stage of labor is and safe for the neonate.

Recurrent intrauterine growth restriction: characteristic placental histopathological features and association with prenatal vascular Doppler.

PURPOSE: Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality, carrying a 20% recurrence rate. The placental disease is a cardinal factor among IUGR underlying processes. This study describes placental histopathological features (HPf) characteristic of recurrent IUGR (rIUGR) and assesses association with antenatal Doppler studies. METHODS: We conducted a retrospective case-control study, between the years 2005-2016, evaluating 34 placentae of 17 women with rIUGR, and 59 placentae of a gestational age-matched control. Doppler studies within a week prior to delivery were analyzed for the rIUGR group. RESULTS: Placental HPf characteristic of rIUGR is maternal and fetal vascular malperfusion lesions; maternal accelerated villous maturation and villous infarcts, repetitive feature rate 88.8% (95% CI 37.2-97), and fetal chorionic plate/stem villous thrombi, repetitive feature rate 66.6% (95% CI 30-90.3). Among women with abnormal Doppler, 83.3% had a placenta HPf of maternal vascular malperfusion lesions and 66.7% presented with a hypertensive disorder. CONCLUSIONS: Women with rIUGR are a unique group of patients characterized by repetitive placental HPf of both maternal and fetal vascular malperfusion lesions. Specifically, maternal vascular malperfusion lesions are associated with abnormal Doppler findings. In conclusion, characteristic placental HPf may serve as predictors of future IUGR recurrence, thus offering early recognition of pregnancies that require "high-risk" antenatal care.

Comparison of hematologic indices and markers of infection in umbilical cord and neonatal blood.

OBJECTIVE: Evaluation of a neonate for suspected early neonatal sepsis routinely includes blood tests such as complete blood count, C-reactive protein (CRP) and culture. In order to obviate the need for venepuncture, we prospectively compared these tests in paired samples from umbilical cord and peripheral venous blood drawn during the first hours after birth in both preterm and term infants. METHODS: Paired blood samples were studied from asymptomatic neonates with risk factors for early sepsis. Data were collected on maternal and neonatal factors that may have influenced the correlation between the tests. RESULTS: Three hundred fifty pairs of samples were studied. Significant correlation between umbilical cord and peripheral venous samples was found for white blood cell (WBC; r = 0.683) and platelets (PLT) (r = 0.54). Correlation for hemoglobin was lower (r = 0.36). No cases of early neonatal sepsis were detected. However, contamination rates were 12% in umbilical cord blood and 2.5% in peripheral venous blood cultures. WBC rose after birth and the 90th percentile rose from 22 500 in umbilical cord blood to 29 700 in peripheral blood. CONCLUSIONS: Screening for sepsis with umbilical cord CBC may be useful provided normal ranges are adjusted accordingly.