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Purpose First trimester miscarriage is a major concern in IVF-ET treatments, accounting for one out of nine clinical pregnancies and for up to one out of three recognized pregnancies. To develop a machine learning classifier for predicting the risk of cleavage-stage embryos to undergo first trimester miscarriage based on time-lapse images of preimplantation development. Methods Retrospective study of a 4-year multi-center cohort of 391 women undergoing intra-cytoplasmatic sperm injection (ICSI) and fresh single or double embryo transfers. The study included embryos with positive indication of clinical implantation based on gestational sac visualization either with first trimester miscarriage or live-birth outcome. Miscarriage was determined based on negative fetal heartbeat indication during the first trimester. Data were recorded and obtained in hospital setting and research was performed in university setting. Results A minimal subset of six non-redundant morphodynamic features were screened that maintained high prediction capacity. Features that account for the distribution of the nucleolus precursor bodies within the small pronucleus and pronuclei dynamics were highly predictive of miscarriage outcome as evaluated using the SHapley Additive exPlanations (SHAP) methodology. Using this feature subset, XGBoost and random forest models were trained following a 100-fold Monte-Carlo cross validation scheme. Miscarriage was predicted with AUC 0.68 to 0.69. Conclusion We report the development of a decision-support tool for identifying the embryos with high risk of miscarriage. Prioritizing embryos for transfer based on their predicted risk of miscarriage in combination with their predicted implantation potential is expected to improve live-birth rates and shorten time-to-pregnancy.

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.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.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.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.The primary outcomes were obstetric intervention and mode of delivery; the secondary outcomes were neonatal Apgar score (with low Apgar score defined as7) and neonatal intensive care unit (NICU) admission rates.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).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.

Research question What are the reproductive choices and retrospective reflections of women at least 4 years after planned oocyte cryopreservation (POC)? Design This was an internet survey, using the REDCap application, of women who underwent POC, at a single-centre university-affiliated IVF unit, 4–8 years before the survey. The questionnaire addressed reproductive choices and outcomes following POC. Results Seventy-nine women who underwent POC during 2011–2014 were invited to participate, and 70 (89%) responded. Mean age at cryopreservation was 37.1 ± 2.4 (range 30–41) years, mean age at study participation 42.6 ± 2.6 (range 35–48) years, and mean time from first cryopreservation cycle to study participation 5.5 ± 1.3 (range 4–8) years. The main retrospectively reported reason for POC was not wanting to become pregnant without a partner (59, 84%). During the follow-up period, 44 women (63%) attempted to conceive either naturally or by assisted reproductive technology using fresh or cryopreserved oocytes. Of those, 28 women achieved a live birth (64% of those who tried to conceive). Fourteen respondents (20% of all respondents) reported using their cryopreserved oocytes, and three (21%) achieved a birth using those oocytes. Fifteen women (34%) of those who tried to conceive used donor spermatozoa. Conclusions The most common reasons for not using frozen oocytes were achieving pregnancy without frozen oocytes or preferring not to have a child without a partner. A considerable proportion of women who had POC and were not interested in being a single parent by choice eventually try to conceive using donor spermatozoa several years later.

Pregestational genetic testing of embryos is the conventional tool in detecting genetic disorders (fetal aneuploidy and monogenic disorders) for in vitro fertilization (IVF) procedures. The accepted clinical practice for genetic testing still depends on biopsy, which has the potential to harm the embryo. Noninvasive genetic prenatal testing has not yet been achieved. In this study, embryos with common genetic disorders created through IVF were tested with an artificially intelligent nanosensor array. Volatile organic compounds emitted by the culture fluid of embryos were analyzed with chemical gas sensors. The obtained results showed significant discrimination between the embryos with different genetic diseases and their wild-types. Embryos were obtained from the same clinical center for avoiding differences based on clinical and demographical characteristics. The achieved discrimination accuracy was 81% for PKD disease, 90% for FRAX disease, 85% for HOCM disease, 90% for BRCA disease, and 100% for HSCR disease. These proof-of-concept findings might launch the development of a noninvasive approach for early assessment of embryos by examining the culture fluid of the embryos, potentially enabling noninvasive diagnosis and screening of genetic diseases for IVF.

Many genetic disorders associated with intellectual disability are characterized by unique behavioral phenotypes which may have serious psychological consequences such as increasing the risk for sexual abuse (SA). Prader–Willi Syndrome (PWS), a severe neurogenetic syndrome with uncontrollable hyperphagia and high threshold for pain, is an excellent example of this issue. The absence of reports on SA in PWS highlights the lack of awareness to the topic. Our aim was to report on SA in individuals with PWS, describe its unique characteristics, and offer recommendations for its prevention. Caregivers of all individuals with genetically confirmed PWS living in the only two residential facilities designated for PWS in Israel were interviewed for a history of sexual behavior and abuse, and medical data were collected from their files. SA was reported in a quarter of the sample. In most of the cases (78%), food reward was used by the perpetrators to attract their victims. Age at SA ranged from 11 to 29 years. Most of the individuals did not disclose the event and some continued to initiate inappropriate sexual activity to obtain food. Characteristics unique to PWS, such as food-seeking behaviors and high threshold for pain, likely contribute to the risk for SA. These findings suggest that syndrome-specific programs for SA prevention should be considered for individuals with any genetic syndrome with behavioral problems that may increase SA risk.

Objective: Neonatal intensive care unit (NICU) admission among term neonates is associated with significant morbidity and mortality, as well as high healthcare costs. A comprehensive NICU admission risk assessment using an integrated statistical approach for this rare admission event may be used to build a risk calculation algorithm for this group of neonates prior to delivery. Methods: A single-center case–control retrospective study was conducted between August 2005 and December 2019, including in-hospital singleton live born neonates, born at ≥37 weeks’ gestation. Analyses included univariate and multivariable models combined with the machine learning gradient-boosting model (GBM). The primary aim of the study was to identify and quantify risk factors and causes of NICU admission of term neonates. Results: During the study period, 206,509 births were registered at the Shaare Zedek Medical Center. After applying the study exclusion criteria, 192,527 term neonates were included in the study; 5292 (2.75%) were admitted to the NICU. The NICU admission risk was significantly higher (ORs [95%CIs]) for offspring of nulliparous women (1.19 [1.07, 1.33]), those with diabetes mellitus or hypertensive complications of pregnancy (2.52 [2.09, 3.03] and 1.28 [1.02, 1.60] respectively), and for those born during the 37th week of gestation (2.99 [2.63, 3.41]; p < 0.001 for all), adjusted for congenital malformations and genetic syndromes. A GBM to predict NICU admission applied to data prior to delivery showed an area under the receiver operating characteristic curve of 0.750 (95%CI 0.743–0.757) and classified 27% as high risk and 73% as low risk. This risk stratification was significantly associated with adverse maternal and neonatal outcomes. Conclusion: The present study identified NICU admission risk factors for term neonates; along with the machine learning ranking of the risk factors, the highly predictive model may serve as a basis for individual risk calculation algorithm prior to delivery. We suggest that in the future, this type of planning of the delivery will serve different health systems, in both high- and low-resource environments, along with the NICU admission or transfer policy.

Introduction BRCA1/BRCA2 mutation carriers often undergo risk-reducing salpingo-oophorectomy (RRSO) before natural menopause, raising the issue of hormonal replacement treatment (HRT) use. There is conflicting evidence on the effect of HRT on breast cancer (BC) risk, and there are limited data on risk based on age at exposure. In the general population, HRT users have an increased BC risk (hazard ratio = 1.34). We assessed the impact of short-term HRT use on BC risk among healthy BRCA1/2 mutation carriers, with emphasis on age at exposure to HRT. Methods A retrospective cohort of 306 consecutive healthy BRCA1/2 mutation carriers who had undergone RRSO was followed up for a mean of 7.26 years. We compared BC incidence over time in carriers who received HRT with that in those who did not receive. Results Thirty-six of the carriers were diagnosed with BC, 20 of 148 patients (13.5%) in the HRT group compared with 16 of 155 (10.3%) in the non-HRT group (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 0.7–2.7). In women who were aged 45 years or younger at RRSO, HRT did not affect BC rates. However, in those older than 45 years at RRSO, BC rates were significantly higher in HRT users than in non-users (OR = 3.43, p Conclusions In BRCA1/BRCA2 carriers in this study, short-term post-RRSO HRT use was associated with a threefold risk of BC in carriers older than 45 years. These results suggest that risk may be related to time of exposure to HRT around the natural age of menopause, even among BRCA1/2 carriers. Further studies are needed for validation and to guide future recommendations.

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.

Do preimplantation genetic testing (PGT) pregnancies have higher post-partum complications compared with naturally conceived pregnancies?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 birth24 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.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.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.

To report outcome of planned oocyte cryopreservation (POC) in the first 8 years of this treatment in our center.A retrospective study in a university-affiliated medical center.A total of 446 women underwent POC during 2011-2018. Fifty-seven (13%) women presented to use these oocytes during the study period (until June 2021). POC was performed at a mean age of 37.9 ± 2.0 (range 33-41). Age at thawing was 43.3 ± 2.1 (range 38-49). A total of 34 (60%) women transferred their oocytes for thawing at other units. Oocyte survival after thawing was significantly higher at our center than following shipping to ancillary sites (78 vs. 63%, p = 0.047). Forty-nine women completed their treatment, either depleting their cryopreserved oocytes without conceiving (36) or attaining a live birth (13)-27% live birth rate per woman. Only one of eleven women who cryopreserved oocytes aged 40 and older had a live birth using thawed oocytes.Women should be advised to complete planned oocyte cryopreservation before age 40, given low success rates in women who underwent cryopreservation at advanced reproductive age. In this study, oocyte shipping was associated with lower survival rate. These findings may be relevant for women considering POC and utilization of cryopreserved oocytes.

The majority of human embryos, whether naturally or in vitro fertilized (IVF), do not poses the capacity to implant within the uterus and reach live birth. Hence, selecting the embryos with the highest developmental potential to implant is imperative for improving pregnancy rates without prolonging time to pregnancy. The developmental potential of embryos can be assessed based on temporal profiling of the discrete morphokinetic events of preimplantation development. However, manual morphokinetic annotation introduces intra- and inter-observer variation and is time-consuming. Using a large clinically-labeled multicenter dataset of video recordings of preimplantation embryo development by time-lapse incubators, we trained a convolutional neural network and developed a classifier that performs fully automated, robust, and standardized annotation of the morphokinetic events with R-square 0.994 accuracy. To delineate the morphokinetic heterogeneity of preimplantation development, we performed unsupervised clustering of high-quality embryo candidates for transfer, which was independent of maternal age and blastulation rate. Retrospective comparative analysis of transfer versus implantation rates reveals differences between embryo clusters that are distinctively marked by poor synchronization of the third meiotic cell-cleavage cycle. We expect this work to advance the integration of morphokinetic-based decision support tools in IVF treatments and deepen our understanding of preimplantation heterogeneity.

OBJECTIVES Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by mental retardation, morbid obesity, and endocrine and behavior disorders. We previously showed in a small group of patients that PWS may have a unique prenatal phenotype. We aimed to characterize clinical and ultrasonic features in a larger series of pregnancies with a PWS fetus. METHODS We retrospectively interviewed all mothers of children with PWS followed in the Israel national multidisciplinary PWS clinic. We compared details of the PWS pregnancy with the pregnancies of healthy siblings and with data from the general population. Medical records including ultrasound reports, obstetric records, and genetic results were analyzed. RESULTS Distinct prenatal features of PWS pregnancies included abnormal fetal growth [fetal growth restriction (FGR) (37.3%), increased head to abdominal circumference ratio (44.8%), decreased abdominal circumference (49.2%)], markedly decreased fetal movements (DFM) (80.4%), and polyhydramnios (42.0%) (P

Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I-arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse-transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT-1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin-associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.

Background and Aim: Polyhydramnios is associated with an increased risk of various adverse pregnancy outcomes, yet complications during labor have not been sufficiently studied. We assessed the labor and perinatal outcomes of idiopathic polyhydramnios during term labor. Methods: Retrospective cohort study at a tertiary medical center between 2010 and 2014. Women with idiopathic polyhydramnios defined as an amniotic fluid index (AFI) greater than 24 cm or a deep vertical pocket (DVP) > 8 cm (cases) were compared with women with a normal AFI (5–24 cm) (controls). Statistics: Descriptive, means ± SDs, medians + IQR. Comparisons: chi-square, Fisher’s exact test, Mann–Whitney Test, multivariate logistic models. Results: During the study period 11,065 women had ultrasound evaluation completed by a sonographer within two weeks of delivery. After excluding pregnancies complicated by diabetes (pre-gestational or gestational), fetal anomalies, IUFD, multifetal pregnancies, elective cesarean deliveries (CD) or missing data, we included 750 cases and 7000 controls. The degree of polyhydramnios was mild in 559 (75.0%) cases (AFI 24–30 cm or DVP 8–12 cm), moderate in 137 (18.0%) cases (30–35 cm or DVP 12–15 cm) and severe in 54 (7.0%) cases (AFI >35 cm or DVP > 15 cm). Idiopathic polyhydramnios was associated with a higher rate of CD 9.3% vs. 6.2%, p = 0.004; a higher rate of macrosomia 22.8% vs. 7.0%, p < 0.0001; and a higher rate of neonatal respiratory complications 2.0% vs. 0.8%, p = 0.0001. A multivariate regression analysis demonstrated an independent relation between polyhydramnios and higher rates of CD, aOR 1.62 (CI 1.20–2.19 p = 0.002) and composite adverse neonatal outcome aOR 1.28 (CI 1.01–1.63 p = 0.043). Severity of polyhydramnios was significantly associated with higher rates of macrosomia and CD (p for trend

To examine the association between primary cesarean delivery and the mode of conception in the subsequent delivery among women without a history of infertility.A retrospective study. Women with the first two consecutive deliveries in our medical center were included. Excluded were women who conceived following fertility treatments or were older than 35 years at their first delivery.Twenty-three thousand four hundred and twenty-seven women were included in the study. Of those, 2215 (9.5%) underwent cesarean delivery in their first delivery, while 21,212 (90.5%) delivered vaginally. Univariate analysis revealed that women with primary cesarean delivery compared to women how delivered vaginally had higher rates of fertility treatments at the subsequent delivery (2.5Among women without a history of infertility, cesarean delivery in the first delivery is not independently associated with fertility treatments in the subsequent delivery.

In IVF treatments, extended culture to single blastocyst-transfer is the recommended protocol over cleavage-stage transfer. However, evidence-based criteria for assessing the heterogeneous implications on implantation outcome are lacking. To estimate the causal effect of blastocyst-transfer on implantation outcome, we assembled a multicenter dataset of embryo time-lapse imaging. The data includes a natural source of randomness and has a strong claim for satisfying the assumptions needed for valid causal inference. By fitting a causal forest model, we assessed the ‘Transfer Lift’, which quantifies the probability difference in embryo implantation if transferred as a blastocyst versus cleavage-stage. Blastocyst transfer increased the average implantation rate, however we revealed a subpopulation of negative Transfer Lift embryos whose implantation potential is predicted to increase via cleavage-stage transfer. We provide day-of-transfer decision-support tools that are retrospectively estimated to improve implantation rate by 32%, thus demonstrating the efficacy of embryo-level causal inference in reproductive medicine.One Sentence SummaryA causal inference model predicts the heterogeneous effect of prolonged incubation to blastocyst transfer on embryo implantation, thus providing means for optimizing pregnancy rates in IVF treatments.

Is extended fertility at the advanced reproductive age of 43-47 years associated with high anti-Müllerian hormone (AMH) concentrations?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.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 (≥ or45 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]), P0.001. The two results for each participant were highly correlated (r = 0.82, P0.001). 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.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.

Study question Do preimplantation genetic testing (PGT) pregnancies have higher pregnancy and delivery complications compared to naturally conceived (NC) pregnancies? Summary answer PGT pregnancies do not have increase pregnancy complications but do have increased post-partum complications. What is known already There is limited data about the outcome of PGT cycles regarding pregnancy complications. Previous reports show that PGT pregnancies are similar to NC pregnancies regarding birth weight and preterm delivery rate. Patients performing PGT are less likely to have infertility as a background problem, and therefore it is important to evaluate pregnancy complications in this specific population. Study design, size, duration A retrospective cohort study, between 2008–2020 in Shaare Zedek Medical center (SZMC). Demographic, background variables, treatment cycle information, and delivery data were collected from computerized hospital databases and patient files. Participants/materials, setting, methods All patients aged 18–45 that conceived following PGT treatment in the IVF unit and gave birth in SZMC were included in the study. We used two control groups: (1) women with spontaneous pregnancies (SP) who gave birth in SZMC. We used four “neighborhood control” for each PGT patient (two women delivered before and two after the case delivery). (2) pregnancies following ICSI with four neighborhood control for each. Main results and the role of chance 135 deliveries following PGT, 924 ICSI, and 4199 NC. Demographic variables were similar except PGT, and ICSI women were slightly older (30.93 ±4.33 PGT, 31.70±4.98 ICSI, 28.75±5.69 spontaneous, p 3 gram, revision or lysis) was 2.4, 95%CI [1.6–3.7]. We did not find any difference between fresh and frozen cycles in either placental complications, preterm delivery, or post-partum complications in the PGT group. Limitations, reasons for caution A single-center retrospective study. Included only pregnancies both conceived and delivered in SZMC. Wider implications of the findings: Physicians should be aware of PGT pregnancies as risk factors for post-partum placental complications and handle the third stage of the delivery with caution. Trial registration number 0351–18-SZMC

Study question What are the success rates of social oocyte cryopreservation (SOC) at advanced age? Summary answer In this study, one in four women who underwent SOC above age 35 had a delivery. What is known already While SOC is gaining popularity, reports on delivery rates are limited due to low utilization rates. Study design, size, duration Retrospective data collection of all woman who underwent SOC between 2011–2018, and presented for treatment using cryopreserved oocytes until January 2021. Participants/materials, setting, methods: Review of patient records (including both IVF and antenatal/postnatal) and laboratory data in a university affiliated hospital-based IVF unit. Main results and the role of chance: A total of 448 women underwent SOC during 2011–2018. 50 (11.2%) women returned to use these oocytes until the end of January 2021. Women who returned to use their oocytes underwent cryopreservation at mean age of 38.2±2.2. 46 (92%) of participants were above 35 at time of cryopreservation. Number of oocytes cryopreserved was 11.3±9.7. Mean time from cryopreservation to thawing was 5.5±1.8years (range 1–9 years). and age at thawing was 43.4±2.1 (range 40–49). Nearly half of patients initially attempted to conceive before using their cryopreserved oocytes, mostly by ART using fresh oocytes. Mean number of oocytes thawed and oocytes survived per women was 9.7±6.2 and 6.1±4.9 respectively (post thawing survival rate 65.4±35%). Mean number of embryos transferred, at one or more attempts was 2.6±2.1 per women. Eleven women gave birth or had an ongoing pregnancy > 20 weeks at time of analysis. All deliveries resulted from cryopreservation at age 36 and older (delivery rate 23.9% per women). Limitations, reasons for caution: We report our initial experience of women who underwent SOC at a single center. Most women who returned to use their oocytes had undergone SOC at advanced age, therefore not necessarily reflecting outcome for younger patients attempting to preserve fertility using this technology. Wider implications of the findings: Considering modest success rates of SOC in our cohort, women considering SOC are advised to do so at an earlier age. Trial registration number Not applicable

About 50% of premature neonates (PN) are treated with transfusion of packed red blood cells (PRBC) collected from adult donors, which has been suggested to potentially provoke PN pathologies, characterized as blood circulation disorders. RBC have properties that are key determinants of blood circulation, primarily the cell deformability. In previous studies we have shown that transfusion of RBC with reduced deformability impaired the transfusion outcome. Although RBC of PN (PN-RBC) are larger, and their microvessels are narrower than those of adults, their blood circulation is very efficient, pointing to the possibility that the deformability of adults' PRBC is inferior to that of PN-RBC, and that treating PN with PRBC transfusion might, therefore, introduce a risk to the recipients. This would infer that PN should be given RBC with high deformability. However, since using PN-RBC is not feasible, the use of cord blood RBC (CB-RBC) is a sound alternative, assuming that the deformability of CB-RBC is comparable to that of PN-RBC.The present study is aimed at testing this hypothesis. We compared the deformability of (1) RBC of PN vs. the PRBC they received, and (2) PN-RBC vs. their autologous CB-RBC. 1. The deformability of the transfused PRBC is indeed inferior to that of PN-RBC. 2. The deformability of CB-RBC is equivalent to that of PN-RBC. This study supports the notion that treating PN with transfusion of adults' PRBC has the potential to introduce a circulatory risk to the recipients, while CB-RBC, with their superior deformability, provides a safer and more effective PN-specific transfusion therapy.

ObjectiveDevelop a machine learning classifier for predicting the risk of cleavage-stage embryos to undergo first trimester miscarriage based on time-lapse images of preimplantation development.DesignRetrospective study of a 4-year multi-center cohort of women undergoing intra-cytoplasmatic sperm injection (ICSI). The study included embryos with positive indication of clinical implantation based on gestational sac visualization either with first trimester miscarriage or live birth outcome. Miscarriage was determined based on negative fetal heartbeat indication during the first trimester.SettingData were recorded and obtained in hospital setting and research was performed in university setting.Patient(s)Data from 391 women who underwent fresh single or double embryo transfers were included.Intervention(s)None.Main Outcome Measure(s)A minimal subset of six non-redundant morphodynamic features were screened that maintain high prediction capacity. Using this feature subset, XGBoost and Random Forest models were trained following a 100-fold Monte-Carlo cross validation scheme. Feature importance was scored using the SHapley Additive exPlanations (SHAP) methodology. Miscarriage versus live-birth outcome prediction was evaluated using a non-contaminated balanced test set and quantified in terms of the area under the receiver operating characteristic (ROC) curve (AUC), precision-recall curve, positive predictive value (PPV), and confusion matrices.Result(s)Features that account for the distribution of the nucleolus precursor bodies within the small pronucleus and pronuclei dynamics were highly predictive of miscarriage outcome. AUC for miscarriage prediction of validation and test set embryos using both models was 0.68-to-0.69. Clinical utility was tested by setting two classification thresholds accounting for high sensitivity 0.73 with 0.6 specificity and high specificity 0.93 with 0.33 sensitivity.Conclusion(s)We report the development of a decision-support tool for identifying the embryos with high risk of miscarriage. Prioritizing embryos for transfer based on their predicted risk of miscarriage in combination with their predicted implantation potential will improve live-birth rates and shorten time-to-pregnancy.CapsuleThe risk of first trimester miscarriage of cleavage stage embryos is predicted with AUC 68% by screening a minimal subset of six non-redundant morpho-dynamic features and training a machine-learning classifier.

Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is an age-associated rise in oocyte aneuploidy. We show that prior to the occurrence of significant aneuploidy (at the age of 9 months in mouse females), epigenetic changes occur and impact oocyte quality and maturation ability. At this age- we observe a reduction in heterochromatin marks in mouse oocytes. This decrease is apparent in both constitutive heterochromatin and facultative heterochromatin marks but is absent in active euchromatic marks which remain constant. A decrease of heterochromatin marks with age is also observed in human GV oocytes from IVF treatments. Heterochromatin loss with age is associated with an elevation in retrotransposon RNA transcription and processing, an elevation in retrotransposon protein expression, elevation in DNA repair proteins nuclear localization and oocyte maturation defects. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and processing and oocyte maturation defects. Collectively, our work demonstrates an early stage of oocyte aging, characterized by the loss of heterochromatin associated chromatin marks and activation of retrotransposons which cause DNA damage and impair oocyte maturation. We hypothesize that this heterochromatin loss serves as an oocyte associated “epigenetic clock” and is exploited by the cell as an oocyte QC mechanism.One Sentence SummaryOocyte aging includes an early pre-aneuploidy phase when loss of repressive chromatin marks occurs as well as retrotransposon activation and egg maturation defects.

Investigate the association between maternal leukocyte count at admission for labor and postpartum infectious maternal morbidity (PPIM) following vaginal delivery.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).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 trend0.001. 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); p0.001 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 of3.7 × 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 trend0.001. The maternal Δleukocyte value of3.7 × 10^3/μl was found to be significantly associated with the risk for ANO, aOR 1.5[1.19-1.90].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.

Many genetic disorders associated with intellectual disability are characterized by unique behavioral phenotypes which may have serious psychological consequences such as increasing the risk for sexual abuse (SA). Prader-Willi Syndrome (PWS), a severe neurogenetic syndrome with uncontrollable hyperphagia and high threshold for pain, is an excellent example of this issue. The absence of reports on SA in PWS highlights the lack of awareness to the topic. Our aim was to report on SA in individuals with PWS, describe its unique characteristics, and offer recommendations for its prevention. Caregivers of all individuals with genetically confirmed PWS living in the only two residential facilities designated for PWS in Israel were interviewed for a history of sexual behavior and abuse, and medical data were collected from their files. SA was reported in a quarter of the sample. In most of the cases (78%), food reward was used by the perpetrators to attract their victims. Age at SA ranged from 11 to 29 years. Most of the individuals did not disclose the event and some continued to initiate inappropriate sexual activity to obtain food. Characteristics unique to PWS, such as food-seeking behaviors and high threshold for pain, likely contribute to the risk for SA. These findings suggest that syndrome-specific programs for SA prevention should be considered for individuals with any genetic syndrome with behavioral problems that may increase SA risk.

Funding policy and medico-legal climate are part of physicians’ reality and might permeate clinical decisions. This study evaluates the influence of maternal age and government funding on obstetrician/gynecologist recommendation for invasive prenatal testing (i.e. amniocentesis) for Down syndrome (DS), and its association with the physician’s assessment of the risk of liability for medical malpractice unless they recommend amniocentesis. Israeli physicians (N = 171) completed a questionnaire and provided amniocentesis recommendations for women at 18 weeks gestation with normal preliminary screening results, identical except aged 28 and 37. Amniocentesis recommendations were reversed for the younger (‘yes’ regardless of testing results: 6.4%; ‘no’ regardless of testing results: 31.6%) versus older woman (‘yes’ regardless of testing results: 40.9%; ‘no’ regardless of testing results: 7.0%; χ2 = 71.55, p < .01). About half of the physicians endorsed different recommendations per scenario; of these, 65.6% recommended amniocentesis regardless of testing results for the 37-year-old woman. Physicians routinely performing amniocentesis and those advocating for amniocentesis for all women ≥ age 35 were approximately twice as likely to vary their recommendations per scenario. Physicians who perceived risk of liability for malpractice as large were nearly one-and-a-half times more likely to vary recommendations. The results indicate physicians’ recommendations are influenced by maternal age, though age is already incorporated in prenatal DS risk evaluations. The physician’s assessment of the risk that they will be sued unless they recommend amniocentesis may contribute to this spurious influence.

Neonatal hypoxic-ischemic encephalopathy (HIE) in term infants, is a major cause of neonatal mortality and severe neurologic disability.To identify in labor fetal monitoring characteristic patterns and perinatal factors associated with neonatal HIE.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.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.Characteristic fetal monitoring pattern prior to delivery together with acute obstetric emergency events are associated with neonatal HIE, neurological morbidity, and mortality.

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. 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. 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. 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.

Background: Group B streptococcus (GBS) is a significant cause of neonatal morbidity and mortality. GBS maternal colonization status was found to be transient, intermittent, or chronic and screenin...

To examine whether embryo biopsy for preimplantation genetic diagnosis (PGD) influences neonatal outcomes.Prospective follow-up cohort.Tertiary university-affiliated medical center.242 children born after PGD, 242 children born after intracytoplasmic sperm injection (ICSI) (158 singletons and 42 twins pairs in each group), and 733 children born after a spontaneous conception (SC) (493 singletons, 120 twins pairs), matched for maternal age, parity, and body mass index.None.Gestational age, birth weight, prematurity (37 and34 weeks), low birth weight (2,500 g, very low birth weight,1,500 g), and intrauterine growth restriction (10th percentile for gestational age).For singletons, the mean birth weight was higher after SC compared with ICSI but not compared with PGD. Mean gestational ages were lower after PGD and ICSI compared with SC. The low birth weight and intrauterine growth restriction rates were 4.4%, 12.0%, and 5.7% and 5.1%, 9.5%, and 5.5% for PGD, ICSI, and SC, respectively. Similar results were found when controlled for the number of embryos transferred and cryopreservation. The results for twins exhibited similar but less statistically significant trends. Polar body and blastomere biopsies provided similar outcomes.Embryo biopsy itself did not cause intrauterine growth restriction or low birth weight compared with SC, despite lower gestational ages with PGD. The worsened outcomes in ICSI compared with PGD pregnancies may be due to the infertility itself.

Myotonic dystrophy (DM) is the most common form of muscular dystrophy in adults. There are conflicting reports about its effect on female fertility. This study investigated ovarian reserve and IVF-preimplantation genetic diagnosis (PGD) outcome in women with DM1. A total of 21 women undergoing PGD for DM1 were compared with 21 age- and body mass index-matched women undergoing PGD for other diseases. Ovarian reserve markers, response to stimulation, embryo quality and clinical pregnancy and live birth rates were compared. Day-3 FSH concentration was higher, while anti-Mullerian hormone concentration and antral follicle count were lower in the DM1 group (median, range: 6.9 (1.8-11.3) versus 5.7 (1.5-10.7)IU/l; 0.9 (0.17-5.96) versus 2.68 (0.5-9.1)ng/ml; and 13 (0-63) versus 23 (8-40) follicles, respectively, all P < 0.05). Total FSH dose was higher (5200 versus 2250 IU, P = 0.004), while the numbers of oocytes retrieved (10 versus 16, P < 0.04) and metaphase-II oocytes (9 versus 12, P < 0.03) were lower in the DM1 group. The number of cycles with top-quality embryos and the clinical pregnancy rate were lower in the DM1 group. In conclusion, there is evidence of diminished ovarian reserve and less favourable IVF-PGD outcome in women with DM1. Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults. There is evidence of subfertility in males affected with the disease but conflicting reports about the effect of the disease on female fertility. The aim of our study was to investigate ovarian reserve and IVF-PGD results in women with DM. Twenty-one women undergoing preimplantation genetic diagnosis (PGD) treatment for DM were compared to 21 age- and BMI matched women undergoing PGD treatment for other diseases. The two groups were compared for antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) levels (the best known markers of ovarian reserve and fertility potential), ovarian response, embryo quality and pregnancy and live birth rates. AFC and the AMH levels were statistically significant lower in the DM group. Total medication dose needed for ovarian stimulation was higher, the number of oocytes and mature oocytes retrieved, and the number of cycles with top quality embryos were lower in the DM group compared to the controls. In conclusion, there is evidence of diminished ovarian reserve, and less favorable IVF-PGD outcome in women with DM. Therefore, we recommend advising these women about the possibility of early decreasing ovarian function in order to prevent any delay in reproductive planning.

To evaluate the effect of elective induction at term for women with gestational diabetes mellitus (GDM) on the risk for cesarean delivery. This is a retrospective case–control matched study, based on a single-center computerized database, 2005–2011. The medical records were reviewed for GDM management and glycemic control. For the study, two groups were defined: Group 1, women diagnosed with GDM with an estimated fetal weight

ObjectiveThe aim of this study is to evaluate the relation between carrying a BRCA1/2 mutation and fertility using the level of anti-müllerian hormone (AMH), which has been previously shown to be an accurate marker of ovarian reserve and fertility potential.Patients and MethodsForty-one healthy BRCA1/2 mutation carriers, aged 26 to 40 years, attending a multidisciplinary breast and ovarian cancer surveillance clinic, were tested for AMH levels using a 2-site ELISA. Levels were compared with those of our general population and with well-established normograms of the general population.ResultsThe mean age of carriers was 33.2 years (26–39 years; SD, 3.99 years). The mean parity of carriers was 1.97 (0–7; SD, 1.49). All women carried at least 1 Ashkenazi Jewish founder mutation. The AMH levels for most carriers were in the reference range, 2.71 ± 0.59 ng/mL (approximately 50th percentile of normograms). These levels were similar to those in the control group, in which the AMH levels were 2.02 ± 0.12 ng/mL (P = 0.27).ConclusionsThe AMH levels of healthy BRCA1/2 mutation carriers are similar to those of noncarrier women matched for age; therefore, their ovarian reserve is comparable. This is the only study, to the best of our knowledge, that directly examines ovarian reserve in a relatively large group of carriers with an accurate marker. The results of this study may possibly give reassurance to female carriers concerning fertility potential.

Fertility treatments are responsible for the rise in high order pregnancies in recent decades and their associated complications. Reducing the number of embryos returned to the uterus will reduce the rate of high order pregnancies.To explore whether obstetric history and parity have a role in the clinician's decision making regarding the number of embryos transferred to the uterus during in vitro fertilization (IVF).In a retrospective study for the period August 2005 to March 2012, data of twin deliveries24 weeks were collected, including parity, mode of conception (IVF vs. spontaneous), gestational age at delivery, preeclampsia, birth weight, admission to the neonatal intensive care unit (NICU), and Apgar scores.A total of 1651 twin deliveries24 weeks were record- ed, of which 959 (58%) were at term (37 weeks). The early preterm delivery (PTD) rate (32 weeks) was significantly lower with increased parity (12.6%, 8.5%, and 5.6%, in women with 0, 1, and ≥ 2 previous term deliveries, respectively). Risks for PTD (37 weeks), preeclampsia and NICU admission were significantly higher in primiparous women compared to those who had one or more previous term deliveries. Primiparity and preeclampsia, but not IVF, were significant risk factors for PTD.The risk for PTD in twin pregnancies is significantly lower in women who had a previous term delivery and decreases further after two or more previous term deliveries. This finding should be considered when deciding on the number of embryos to be transferred in IV.

Whether intra- and early post-partum hemorrhage is influenced by ABO blood groups remains unknown. Therefore, we compared women with O to non-O blood groups with regard to maternal post-partum hemorrhage and transfusion need. This retrospective study was conducted in a single tertiary center between 2005 and 2014. For the purpose of the study, parturients were categorized as O and non-O blood groups. Data included all deliveries but excluded patients with missing blood grouping or hemoglobin values, and/or stillbirth. Drop in hemoglobin was defined as hemoglobin concentration at admission for delivery minus lowest hemoglobin concentration post-delivery. Study outcomes were postpartum hemorrhage, hemoglobin drop >2-7 g/dL inclusive, and packed red blood cells transfusion. STATISTICS: descriptive, χ(2) (p 2, 3, or 4 g/dL (OR 1.07; 95 % CI 1.04-1.11, p