Is a day 7 blastocyst predictive of the reproductive potential of sibling day 5 and day 6 blastocysts?

PURPOSE: To explore if a day 7 blastocyst is predictive of the reproductive potential of sibling day 5 or day 6 blastocysts? METHODS: Retrospective cohort of autologous frozen embryo transfers (FET), February 2019 to April 2022. Cycles divided into groups 1 to 5, according to the day of embryo cryopreservation and the presence of a day 7 blastocyst sibling within the cohort: group 1/group 2-day 5 blastocyst without/with a day 7 sibling, group 3/group 4-day 6 blastocyst without/with a day 7 sibling, group 5-day 7 blastocyst. Clinical, ongoing pregnancy and miscarriage rates, cycle, and patient characteristics are reported. Multivariable generalized estimating equations (GEE) logistic regression analysis accounts for confounders and assesses the effect of a sibling day 7 blastocyst on ongoing pregnancy rates of day 5 or day 6 blastocyst FETs. RESULTS: Ongoing pregnancy rates are 38.4%, 59.5%, 30.8%, 32.7%, and 4.4% in groups 1-5, respectively. When correcting for maternal age, number of oocytes retrieved and discarded per cohort, and ploidy, embryos cryopreserved on either day 6 or day 7 have reduced odds of ongoing pregnancy after FET compared to day 5 blastocysts (OR = 0.76, IQR [0.61-0.95], p-value = 0.01). However, the presence of a day 7 sibling does not significantly affect odds of ongoing pregnancy of day 5 or day 6 blastocysts compared to the same-day blastocyst without a day 7 sibling (p-value = 0.20 and 0.46, respectively). This finding is consistent within both the Preimplantation Genetic Testing for Aneuploidy (PGT-A) unscreened and screened (euploid) embryo subgroups. CONCLUSIONS: Day of embryo cryopreservation significantly affects ongoing pregnancy rates. However, day 7 embryos within a cohort do not affect the reproductive potential of sibling day 5 and day 6 blastocysts, suggesting that slow embryo development is an embryo-specific trait.

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.

Long-term pituitary down-regulation pretreatment for endometriosis - chronicles of guidelines and recommendations.

It was suggested in the 1980s that long-term pituitary down-regulation by a gonadotrophin-releasing hormone agonist, termed the ultra-long protocol, inducing a hypo-oestrogenic state, might improve reproductive outcomes in women with endometriosis. Subsequently, international guidelines strongly supported the long-term pituitary down-regulation protocol in women with endometriosis based on a Cochrane review from 2006. The recently published European Society for Human Reproduction and Embryology guideline, based on the updated Cochrane review from 2019 and newer evidence, has reversed this recommendation. This paper explores the past and current evidence that led to these recommendations and calls for a consideration of refinement of the international guidelines to include additional factors and evaluate whether a paradigm shift is needed in the approach to endometriosis-related infertility. We believe that this can optimize evidence-based patient-centred care and benefit women worldwide and improve the design of future studies.

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.

Application of Prospect Theory in Obstetrics by Evaluating Mode of Delivery and Outcomes in Neonates Born Small or Appropriate for Gestational Age.

Importance: Antenatal diagnosis of fetal weight is challenging, and the detection rate of fetal growth restriction (FGR) is low. Neonates with FGR are known to have an increased rate of obstetric intervention during labor, but the association of antenatal fetal weight estimation with mode of delivery and neonatal outcomes among neonates who are small and appropriate for gestational age (SGA and AGA) has not been reported. Objective: To evaluate the association of antenatal fetal weight estimation with mode of delivery and neonatal outcomes among neonates who are SGA and AGA, applying psychological concepts of cognitive bias and prospect theory to a model of clinical behavior. Design, Setting, and Participants: This cohort study was conducted between 2019 and 2020 using data from 2006 to 2018 at a tertiary care center in Jerusalem, Israel. Participants were 100 198 term singleton neonates without anomalies who were categorized into 4 groups according to the presence of an antenatal suspicion of FGR and final birth weight. Neonates with false positives (FPs; ie, group 1-FP: those with suspected FGR who were AGA) and neonates with true positives (TPs; ie, group 2-TP: those with suspected FGR who were SGA) were compared with neonates with AGA antenatal fetal weight estimation, including neonates with false negatives (FNs; ie, group 3-FN: those not suspected to have FGR who were SGA) and neonates with true negatives (TNs; ie, group 4-TN: those not suspected to have FGR who were AGA). Data were analyzed from July 2019 to July 2020. Exposures: Fetal weight estimation was performed according to sonographic and clinical evaluation at admission to labor, with FGR defined as a birth weight less than the 10th percentile for gestational age. Sonographic fetal weight estimation was performed according to Hadlock formula. Clinical weight estimation was performed by trained obstetricians. Main Outcomes and Measures: The primary outcomes were obstetric intervention and mode of delivery; the secondary outcomes were neonatal Apgar score (with low Apgar score defined as <7) and neonatal intensive care unit (NICU) admission rates. Results: Among 100 198 neonates eligible for the study (50941 [50.8%] male neonates), there were 5671 neonates in group 1-FP, 3040 neonates in group 2-TP, 8508 neonates in group 3-FN, and 82 979 neonates in group 4-TN. Mean (SD) maternal age was 28.6 (5.7) years. Among 8711 neonates with suspected FGR, 34.9% were below the 10th percentile at birth, while 65.1% were AGA. Neonates with suspected FGR had a significantly increased rate of induction of labor (group 1-FP: 649 neonates [11.4%] and group 2-TP: 969 neonates [31.9%]) compared with neonates in group 3-FN (1055 neonates [12.4%]) and group 4-TN (7136 neonates [8.6%]) (P < .001) and a significantly increased rate of cesarean delivery (group 1-FP: 915 neonates [16.1%] and group 2-TP: 556 neonates [18.3%] vs group 3-FN: 1106 neonates [13.0%] and group 4-TN: 6588 neonates [7.9%]; P < .001). Increased NICU admission was found for neonates who were SGA compared with neonates who were AGA (group 2-TP: 182 neonates [6.0%] and group 3-FN: 328 neonates [3.9%] vs group 1-FP: 51 neonates [0.9%] and group 4-TN: 704 neonates [0.8%]; P <.001), as was increased rate of low Apgar score (eg, at 1 minute: group 2-TP: 149 neonates [4.9%] and group 3-FN: 384 neonates [4.5%] vs group 1-FP: 124 neonates [2.2%] and group 4-TN: 1595 neonates [1.9%]; P < .001). In a multivariable model comparing group 1-FP, group 2-TP, and group 3-FN with group 4-TN, suspicion of FGR was independently associated with increased risk of caesarean delivery among neonates in group 1-FP (odds ratio, 1.72; 95% CI, 1.56-1.88; P < .001). Conclusions and Relevance: This study found that antenatal diagnosis of FGR was independently associated with an increase in risk of caesarean delivery by 70% in neonates who were AGA without improvement in neonatal outcomes. These findings suggest that such outcomes may be explained by application of prospect theory and may be associated with cognitive bias in clinical decision-making.

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.

The maternal leukocyte count at admission for labor is indicative of early maternal postpartum infectious morbidity and adverse neonatal outcome.

OBJECTIVES: Investigate the association between maternal leukocyte count at admission for labor and postpartum infectious maternal morbidity (PPIM) following vaginal delivery. STUDY DESIGN: Retrospective cohort study, 2005-2017. Afebrile women, term, singleton, vaginal delivery included. Maternal leukocyte/differential at admission for labor and 24 h postpartum were analyzed as continuous values and quintiles. Pre/postpartum difference (Δleukocyte) was calculated. The primary outcome was maternal PPIM, early and late. The secondary outcome was adverse neonatal outcomes (ANO). RESULTS: 58,174 eligible deliveries out of168,979 (34.4 %); 1068 (1.8 %) women with PPIM. The rate rose linearly from 1.4 % for the lowest admission for labor leukocyte quantile to 2.7 % for the highest quantile, p for trend <0.001. The women with early PPIM had significantly higher admission levels of leukocytes (mean): 12.04 ± 3.43 vs. 11.18 ± 2.86 × 10^3/µl; neutrophils, 9.48 ± 3.46 vs. 8.40 ± 2.67 × 10^3/µl; and monocytes 0.76 ± 0.25 vs. 0.72 ± 0.23 × 10^3/µl); p < 0.001 for all. The mean leukocyte count for women with PPIM diagnosis, including only postpartum fever, was 12.06 ± 2.64; significantly higher than in the non-PPIM group, p = 0.014. A Δleukocyte value of >3.7 × 10^3/µl is significantly associated with PPIM, aOR 2.10 [1.82-2.41]. No significant association between leukocyte count or Δleukocyte and maternal readmission rate due to infectious complications. 386 neonates (0.7 %) had records of ANO and 64 neonates (0.1 %) had records of neonatal sepsis, positive linear association; p for trend < 0.001. The maternal Δleukocyte value of >3.7 × 10^3/µl was found to be significantly associated with the risk for ANO, aOR 1.5[1.19-1.90]. CONCLUSION: In healthy women, an elevated level of the leukocyte count at admission for labor and the Δleukocyte are significant risk predictors of PPIM and ANO.

Intrapartum fetal monitoring and perinatal risk factors of neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) in term infants, is a major cause of neonatal mortality and severe neurologic disability. OBJECTIVES: To identify in labor fetal monitoring characteristic patterns and perinatal factors associated with neonatal HIE. STUDY DESIGN: Single-center retrospective case-control study between 2010 and 2017. Cases clinically diagnosed with neonatal HIE treated by therapeutic hypothermia according to strict criteria (HIE-TH) were compared to a group of neonates born in the same period, gestational age-matched diagnosed with fetal distress according to fetal monitoring interpretation that was followed by prompt delivery, without subsequent HIE or therapeutic hypothermia (No-HIE). The primary outcome of the study was the electronic fetal monitoring (EFM) pattern during 60 min prior to delivery; the secondary outcome was the identification of perinatal associated factors. RESULTS: 54 neonates with HIE were treated by therapeutic hypothermia. EFM parameters most predictive of HIE-TH were indeterminate baseline heart rate OR = 47.297, 95% (8.17-273.76) p < 0.001, bradycardia OR = 15.997 95% (4.18-61.18) p < 0.001, low variability OR = 10.224, 95% (2.71-38.45) p < 0.001, higher baseline of the fetal heart rate calculated for each increment of 1 BPM OR = 1.0547, 95% (1.001-1.116) p = 0.047. Rupture of a previous uterine cesarean scar and placental abruption were characteristic of the HIE-TH group 14.8% vs. 1% p < 0.05; and 16.7% vs. 6% p < 0.05, respectively. Adverse neonatal outcomes also differed significantly: HIE-TH had a higher rate of neonatal seizures 46.2% vs. 0% p < 0.001 and mortality 7.7% vs. 0% p < 0.001. CONCLUSIONS: Characteristic fetal monitoring pattern prior to delivery together with acute obstetric emergency events are associated with neonatal HIE, neurological morbidity, and mortality.

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.

Maternal and neonatal outcomes following a proactive peripartum multidisciplinary management protocol for placenta creta spectrum as compared to the urgent delivery.

BACKGROUND: Adherent and invasive placenta, termed Placenta Creta Spectrum (PCS), is associated with increased maternal morbidity and mortality. Incidence and risk factors for Placenta Creta are on the rise and call to optimize the obstetric care for this condition. OBJECTIVES: We sought to compare maternal and neonatal outcomes between a ProActive Peripartum Multidisciplinary Approach (PAMA) as compared to the urgent management of the Placenta Creta Spectrum patients. STUDY DESIGN: We conducted a single-center prospective observational study between 2005-2016. PCS patients registered with the implementation of a PAMA protocol 2014-2016 epoch(E2) were compared with the pre-PAMA 2005-2013 epoch(E1), managed by urgent team recruitment. The PAMA protocol is grounded on a continuum of care; A. Antenatal: PCS risk assessment based on clinical history and imaging, surgical, anesthesia, urological consults and designation of a dedicated team to be present at planned surgery; B. Delivery: planned at 34-35 weeks, massive transfusion protocol activation, insertion of ureteral catheters, vertical uterine incision, placement of vessel loops on the iliac vessels, avoidance of active placenta delivery, followed by the decision of hysterectomy or uterine repair; C. Post-operative care: intensive care admission. We evaluated maternal and neonatal outcomes. RESULTS: During the study period 158,438 deliveries were registered in our institution; we identified a total of 72 PCS cases (0.05%): 50(69.4%) in E1 and 22 (30.6%) in E2. Patient characteristics were comparable among epochs. Significantly, patients in E2 vs. E1 had fewer events of massive blood transfusion 36.0% vs. 13.6%, p = 0.05; were transfused less RBC units: median 4 vs. 1.5, p = 0.012, had no transfusion-related respiratory complications and hemorrhage control re-laparotomies. Hysterectomy and hollow visceral injury rates were comparable (72% vs. 63.7%, 26% vs. 22%; respectively). The hysterectomy pathology assessment was available for the majority of the cases in both epochs; percreta diagnosis rate significantly increased in E2. The neonatal outcome was similar among the epochs. CONCLUSIONS: Institution of a PAMA protocol for PCS resulted in eliminating the urgent deliveries and in reducing the associated significant hemorrhagic related maternal morbidity, with no increase in the rate of hysterectomy or adverse neonatal outcome.

Ureaplasma urealyticum: the Role as a Pathogen in Women's Health, a Systematic Review.

PURPOSE OF REVIEW: To evaluate the role of Ureaplasma urealyticum as a genital pathogen in women's health. Three aspects were analyzed: (1) preterm delivery (PTD); (2) female infertility; and (3) lower genital tract pathology including pelvic inflammatory disease (PID), cervicitis, and genital discomfort (discharge, burning). RECENT FINDINGS: A systematic review was performed. Searching PUBMED and EMBASE for published articles from January 2003 to September 2017 using the key word "Ureaplasma urealyticum" yielded 1835 manuscripts. These were further screened using defined inclusion criteria: (1) original peer-reviewed observational studies; (2) English language; (3) U. urealyticum was specifically isolated; (4) present "cases"/"exposed" and "controls"/"unexposed" to enable calculating an association between U. urealyticum and the outcome studied. Altogether, 32 studies were included that underwent quality scoring based on methodology, sample size, study population, and method of identification of U. urealyticum. The association of U. urealyticum and PTD was inconsistent between the studies. Eight of the ten prospective studies failed to show an association between U. urealyticum and PTD, yet four of the six case control studies found a positive association. Regarding female infertility and genital discomfort, five of the six studies for each of these topics failed to find an association. Only two studies met the inclusion criteria for cervicitis with conflicting conclusions. Unfortunately, none of the studies met the inclusion criteria for PID. It seems that U. urealyticum has a limited role as a pathogen in female infertility, cervicitis, PID, and genital discomfort. The role as a pathogen in PTD is unclear and future studies are needed to address this issue.

Intrapartum fetal heart rate patterns of trisomy 21 fetuses: A case-control study.

BACKGROUND/AIM: To determine whether there are specific characteristic intrapartum heart rate patterns for fetuses with trisomy 21(T21). BACKGROUND STUDY DESIGN/PATIENTS: Intrapartum fetal heart rate (FHR) tracings of T21 fetuses were compared to those of euploid fetuses in a retrospective, observational, matched, case-control study. The study group consisted of 42 fetuses with T21 and 42 matched euploid controls. Matching was designed to accommodate possible confounders. The sign test and McNemar's test were used for categorical variables. The paired t test was used for comparison between quantitative variables. RESULTS: Intrapartum baseline FHR of fetuses with T21 was found to be slightly decreased compared to controls (122.5 vs 129.05 beats per minute, p=0.028). No differences were detected in the presence of periodic changes, or FHR variability between the groups. CONCLUSION: When evaluating intrapartum FHR of fetuses with T21, decreased baseline FHR can be expected.

Fertility preservation in girls.

Children that undergo treatment for cancer are at risk of suffering from subfertility or hormonal dysfunction due to the detrimental effects of radiotherapy and chemotherapeutic agents on the gonads. Cryopreservation of ovarian tissue prior to treatment offers the possibility of restoring gonadal function after resumption of therapy. Effective counseling and management of pediatric patients is crucial for preserving their future reproductive potential. The purpose of this article is to review recent literature and to revise recommendations we made in a 2007 article. Pediatric hemato-oncology, reproductive endocrinology, surgery, anesthesia and bioethics perspectives are discussed and integrated to propose guidelines for offering ovarian cryopreservation to premenarcheal girls with cancer.

Fertility considerations and preservation in haemato-oncology patients undergoing treatment.

The improved survival rates among patients with haematological malignancies, such as lymphoma and leukaemia, are shifting areas of focus towards understanding and preventing treatment-induced sequelae. Of these, infertility is one of the most devastating consequences for patients with reproductive potential. The degree of treatment-induced gonadal dysfunction depends on age and gender-related differences, the type and dosage of chemotherapy used and the field and cumulative dose of abdomino-pelvic irradiation. There is also the interesting phenomenon of reduced pre-treatment fertility among male lymphoma patients. At present, the only established methods of fertility preservation are cryopreservation of sperm, oocytes and embryos, as well as gonadal shielding and transposition of ovaries during irradiation. Several other methods, such as cryopreservation and subsequent transplantation of gonadal tissue and the gonadoprotective role of hormonal suppression, are under investigation. Pre-pubertal patients present a unique constellation of fertility considerations, especially as embryo and sperm cryopreservation are not applicable to this age group.