Time-Lapse Incubation for Embryo Culture-Morphokinetics and Environmental Stability May Not Be Enough: Results from a Pilot Randomized Controlled Trial.

Background: Does the Time-lapse Incubator (TLI) add value to reproductive outcomes when its two components, undisturbed culturing and morphokinetic embryo grading, are separated. Methods: A prospective pilot, randomized, controlled, double-blinded, single-center study was conducted during the years 2016-2020. In total, 102 patients were randomized into three groups: (1) conventional incubation with morphological evaluation only (n = 34), (2) TLI with both morphological and morphokinetic evaluations (n = 32), and (3) TLI with morphological evaluation only (n = 36). All arms were cultured in ESCO-MIRI® incubators. A total of 1061 injected mature oocytes were evaluated (420 in arm 1, 285 in arm 2, and 356 in arm 3). The primary outcome was live birth rates. Secondary outcomes included clinical and cumulative pregnancy rates as well as embryo quality. Embryos in arm 3 were retrospectively evaluated for their morphokinetic score. Results: No significant difference was found in the live birth rate for single embryo transfer cycles (SET) (35% vs. 31.6% vs. 24%, p = 0.708) or double embryo transfer (DET) cycles (41.7% vs. 38.5% vs. 36.4%, p = 0.966). Comparable pregnancy rates, clinical pregnancy rates, and cumulative pregnancy were found for similar top-quality embryos for days 2, 3, and blastocyst stages across groups. A similar number of embryos were suitable for either transfer or cryopreservation within the different groups. For 62.8% of the embryos in arm 3, the morphokinetic and morphologic evaluations were similar. In only 2/36 (5.6%) treatment cycles, the use of morphokinetic scoring may have helped the patient avoid undergoing an additional treatment cycle. In the other cases, morphokinetic scoring would not have changed the end point of pregnancy. Conclusions: The two components of the TLI system-undisturbed culturing and morphokinetic embryo grading-do not appear to have a significant additional value in reproductive outcome, although these results should be validated by an RCT.

Evaluating the heterogeneous effect of extended culture to blastocyst transfer on the implantation outcome via causal inference in fresh ICSI cycles.

PURPOSE: 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 outcomes are lacking. The purpose of this work is to estimate the causal effect of blastocyst transfer on implantation outcome. METHODS: We fit a causal forest model using a multicenter observational dataset that includes an exogenous source of variability in treatment assignment and has a strong claim for satisfying the assumptions needed for valid causal inference from observational data. RESULTS: We quantified 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 embryos whose implantation potential is predicted to increase via cleavage-stage transfer. CONCLUSION: Relative to the current policy, the proposed embryo transfer policy retrospectively improves implantation rate from 0.2 to 0.27. Our work demonstrates the efficacy of implementing causal inference in reproductive medicine and motivates its utilization in medical disciplines that are dominated by retrospective datasets.

Combined Hormonal Contraception during Breastfeeding-A Survey of Physician's Recommendations.

Until breastfeeding is established, progesterone-only pill (POP) use is preferable over combined hormonal contraception (CHC), as the latter potentially reduces milk production. Yet, POPs are often associated with breakthrough bleeding (BTB), and irregular spotting is often a reason for their cessation. Conversely, CHC is less associated with BTB but is not usually prescribed, even if breastfeeding has been established, despite its verified safety profile. Here, we surveyed physicians' perception of CHC safety during breastfeeding through an online questionnaire (N = 112). Physicians were asked if they would prescribe CHC to a woman three months postpartum, breastfeeding fully, and suffering from BTB while using POPs. Half of the physicians responded they would, 28% would not until six months postpartum, while 14% would not during breastfeeding. Of the physicians that would prescribe CHC, 58% would without any reservation, 24% would only after discussing milk reduction with the patient, 9% would use a pill with a lower hormonal dose, and 9% would only prescribe CHC 3 months postpartum. The main risk associated with CHC during breastfeeding, as perceived by physicians, is a potential decrease in breast milk production (88%). While some physicians consider CHC unsafe during breastfeeding, most health organizations consider CHC compatible with breastfeeding 5-6 weeks after birth. Thus, there is a gap in the attitude and knowledge of physicians about the safety profile of CHC, and only half acknowledge that the risk of BTB justifies the use of CHC instead of POPs while breastfeeding three months postpartum. We highlight the importance of physician's education, advocate CHC breastfeeding compatibility if breastfeeding has been established (i.e., 30 days postpartum), and underline the importance of discussing the option of CHC with patients in case POPs have unwanted side effects.

The importance of gynecological examination in adolescent girls and adult women with Prader-Willi syndrome.

Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020-2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3-39], BMI 30.4 kg/m2 [IQR 23.5-37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16-39. Median spine T score was -1.3 (range between 0.5 and -3.7), and hip T score was -1.2 (range between 0.8 and -3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = -0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.

Delineating the heterogeneity of embryo preimplantation development using automated and accurate morphokinetic annotation.

PURPOSE: Our objective was to design an automated deep learning model that extracts the morphokinetic events of embryos that were recorded by time-lapse incubators. Using automated annotation, we set out to characterize the temporal heterogeneity of preimplantation development across a large number of embryos. METHODS: To perform a retrospective study, we used a dataset of video files of 67,707 embryos from four IVF clinics. A convolutional neural network (CNN) model was trained to assess the developmental states that appear in single frames from 20,253 manually-annotated embryos. Probability-weighted superposition of multiple predicted states was permitted, thus accounting for visual uncertainties. Superimposed embryo states were collapsed onto discrete series of morphokinetic events via monotonic regression of whole-embryo profiles. Unsupervised K-means clustering was applied to define subpopulations of embryos of distinctive morphokinetic profiles. RESULTS: We perform automated assessment of single-frame embryo states with 97% accuracy and demonstrate whole-embryo morphokinetic annotation with R-square 0.994. High quality embryos that had been valid candidates for transfer were clustered into nine subpopulations, as characterized by distinctive developmental dynamics. Retrospective comparative analysis of transfer versus implantation rates reveals differences between embryo clusters as marked by poor synchronization of the third mitotic cell-cleavage cycle. CONCLUSIONS: By demonstrating fully automated, accurate, and standardized morphokinetic annotation of time-lapse embryo recordings from IVF clinics, we provide practical means to overcome current limitations that hinder the implementation of morphokinetic decision-support tools within clinical IVF settings due to inter-observer and intra-observer manual annotation variations and workload constrains. Furthermore, our work provides a platform to address embryo heterogeneity using dimensionality-reduced morphokinetic descriptions of preimplantation development.

Term Idiopathic Polyhydramnios, and Labor Complications.

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 <0.01 in both). Conclusions: The term idiopathic polyhydramnios is independently associated with macrosomia, CD and neonatal complications. The severity of polyhydramnios is also associated with macrosomia and CD.

Neonatal intensive care admission for term neonates and subsequent childhood mortality: a retrospective linkage study.

BACKGROUND: Neonatal intensive care unit (NICU) admission among term neonates is a rare event. The aim of this study was to study the association of the NICU admission of term neonates on the risk of long-term childhood mortality. METHODS: A single-center case-control retrospective study between 2005 and 2019, including all in-hospital ≥ 37 weeks' gestation singleton live-born neonates. The center perinatal database was linked with the birth and death certificate registries of the Israeli Ministry of Internal Affairs. The primary aim of the study was to study the association between NICU admission and childhood mortality throughout a 15-year follow-up period. RESULTS: During the study period, 206,509 births were registered; 192,527 (93.22%) term neonates were included in the study; 5292 (2.75%) were admitted to NICU. Throughout the follow-up period, the mortality risk for term neonates admitted to the NICU remained elevated; hazard ratio (HR), 19.72 [14.66, 26.53], (p < 0.001). For all term neonates, the mortality rate was 0.16% (n = 311); 47.9% (n = 149) of those had records of a NICU admission. The mortality rate by time points (ratio1:10,0000 births) related to the age at death during the follow-up period was as follows: 29, up to 7 days; 20, 7-28 days; 37, 28 days to 6 months; 21, 6 months to 1 year; 19, 1-2 years; 9, 2-3 years; 10, 3-4 years; and 27, 4 years and more. Following the exclusion of congenital malformations and chromosomal abnormalities, NICU admission remained the most significant risk factor associated with mortality of the study population, HRs, 364.4 [145.3; 913.3] for mortality in the first 7 days of life; 19.6 [12.1; 32.0] for mortality from 28 days through 6 months of life and remained markedly elevated after age 4 years; HR, 7.1 [3.0; 17.0]. The mortality risk related to the NICU admission event, adjusted for admission diagnoses remained significant; HR = 8.21 [5.43; 12.4]. CONCLUSIONS: NICU admission for term neonates is a pondering event for the risk of long-term childhood mortality. This group of term neonates may benefit from focused health care.

The Risk of Breakthrough Bleeding Justifies the Use of Combined Hormonal Contraception Over Progesterone-Only Pills While Breastfeeding.

Breakthrough bleeding is a side effect of progesterone-only pills (POPs) in 40% of women, and is reduced to 10% with combined hormonal contraceptives (CHCs). In addition, breakthrough bleeding is reduced if POP is supplemented with norethisterone. As breakthrough bleeding is responsible for a quarter of women stopping the pill, it is vital to realize that CHC is an alternative to POP-even during lactation. CHCs are considered safe during lactation, do not reduce milk production, nor impede infant development. Nevertheless, CHCs are often not prescribed for lactating mothers due to this misconception that they reduce milk production. Among Orthodox Jews, breakthrough bleeding frequently results in stopping POP, as Jewish religious law prohibits any physical contact of the mother with her partner during active bleeding, and for 7 days after bleeding. When such bleeding occurs, not choosing a CHC alternative, results in couples risking discontinuation of POP, and in conceiving within a year of the previous birth, with its increased risk of preterm labor and birth defects. To measure how physicians respond to the presumed dilemma of balancing the risk of breakthrough bleeding versus the concern of reduction of milk production, we conducted a preliminary online survey. Physicians were asked if they would prescribe CHC instead of POP to breastfeeding mothers, 3 months postpartum with breakthrough bleeding. Half of the physicians responded they would prescribe CHC, whereas close to half of the physicians responded that they would not. The main reasons given by the respondents for avoiding CHC was a concern regarding possible milk reduction. These results confirm a significant degree of a lack of updated pharmacological information regarding the options of oral contraceptive use for lactating mothers, particularly for those where breakthrough bleeding has major behavioral and religious consequences. Thus, we contend that the risk of breakthrough bleeding justifies the more routine use of CHC in lieu of POP in lactating mothers.

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.

Embryo classification beyond pregnancy: early prediction of first trimester miscarriage using machine learning.

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.

Noninvasive Pregestational Genetic Testing of Embryos Using Smart Sensors Array.

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.

Clinical outcome of planned oocyte cryopreservation at advanced age.

PURPOSE: To report outcome of planned oocyte cryopreservation (POC) in the first 8 years of this treatment in our center. METHODS: A retrospective study in a university-affiliated medical center. RESULTS: 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. CONCLUSION: 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.

NICU Admission for Term Neonates in a Large Single-Center Population: A Comprehensive Assessment of Risk Factors Using a Tandem Analysis Approach.

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.

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.

Loss of heterochromatin and retrotransposon silencing as determinants in oocyte aging.

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.

Deformability of cord blood vs. newborns' red blood cells: implication for blood transfusion.

AIM: 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. METHODS: We compared the deformability of (1) RBC of PN vs. the PRBC they received, and (2) PN-RBC vs. their autologous CB-RBC. RESULTS: 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. CONCLUSION: 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.

The association between primary cesarean delivery in primipara and subsequent mode of conception, a retrospective study.

OBJECTIVE: To examine the association between primary cesarean delivery and the mode of conception in the subsequent delivery among women without a history of infertility. METHODS: 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. RESULTS: 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 (2.5 vs. 0.8%; p < .01). Those who had fertility treatments were significantly older during both the first and second deliveries, had higher rates of diabetic disorders of pregnancy (pregestational and gestational) at both the first and second deliveries, obesity and morbid obesity at the second delivery, and higher incidence of repeat cesarean delivery. Multivariate analysis revealed that the only factor that correlated significantly with the use of fertility treatments at the second delivery was maternal age at second delivery [aOR 1.2 (1.1-1.3), p < .01]. CONCLUSION: Among women without a history of infertility, cesarean delivery in the first delivery is not independently associated with fertility treatments in the subsequent delivery.