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Objective To study the association among fertility treatments, treatment protocol, and offspring neoplasm risk up to the age of 18 years. Design A population-based retrospective cohort. Setting Soroka University Medical Center (SUMC), the single tertiary medical center and in vitro fertilization (IVF) unit in southern Israel. Patient(s) All offspring born at the SUMC between the years 1995 and 2018 after IVF treatment (the exposed group) and offspring conceived spontaneously (the unexposed group). Intervention(s) The study was performed at the SUMC, the single tertiary medical center and IVF unit in southern Israel. The exposed and unexposed were matched with a ratio of 1:4, based on maternal age and calendar month of delivery. Data collection included a summary of the couple’s medical records, delivery data, and offspring neoplasm diagnoses. Main Outcome Measure(s) Offspring neoplasm of any kind and time to diagnosis in each of the groups. Result(s) A total of 1,583 exposed and 5,874 offspring were included in the study. The incidences of offspring benign neoplasm were 14 (0.9%) versus 21 (0.4%), and the incidences of malignancies were 17 (1.1%) versus 29 (0.5%) among offspring of the IVF and spontaneous groups, respectively. The association between mode of conception and offspring neoplasm risk remained significant after adjusting for confounders, including mode of delivery and pregnancy complications such as hypertensive disorder, gestational diabetes mellitus, and preterm delivery compared with spontaneously conceived offspring. Among the IVF group, the increased risk for neoplasm was found among offspring who were transferred as fresh embryos, at an earlier stage of development (cleavage stage), or after three or more aspirated oocytes. Conclusion(s) IVF treatment is associated with offspring neoplasm risk; specifically, the risk was greater among offspring who were returned as fresh embryos, at an earlier embryotic stage (cleavage stage), or after three or more aspirated oocytes.

Are obstetric and perinatal complications associated with morphokinetic parameters of embryo development?This proof-of-concept pilot study included a retrospective analysis of embryo morphokinetic parameters of 85 live births following day 5 single blastocyst transfer. Kinetic variables included time interval (hours) from time of pronuclei fading (tPNf) to: time of 2 cells (tPNf-t2), 9 cells (tPNf-t9), morula (tPNf-tM), start of blastulation (tPNf-tSB), full blastocyst (tPNf-tB) and expanded blastocyst (tPNf-tEB). Multivariable logistic models were used to calculate the risk of perinatal complications after adjustment for confounders.The mean interval of tPNf-tSB was significantly longer for newborns with congenital anomalies compared with healthy newborns (79.49 ± 5.78 versus 71.7 ± 6.3, respectively, P = 0.01) and for embryos of women who had gestational diabetes mellitus compared with normoglycemic women (76.56 ± 7.55 versus 71.5 ± 6.13, respectively, P = 0.015). The mean interval of tPNf-t9 was significantly longer for low-birthweight newborns compared with normal weight (49.25 ± 5.54 versus 45.47 ± 4.77, respectively, P = 0.01). Preterm delivery was associated with several longer intervals of cell divisions compared with delivery at term (tPNf-t5: 28.76 ± 3.13 versus 26.64 ± 2.40, respectively, P = 0.01; tPNf-t6: 30.10 ± 3.05 versus 27.68 ± 2.30, respectively, P 0.001; tPNf-t7: 32.08 ± 4.11 versus 28.70 ± 2.67, respectively, P 0.001; tPNf-t8: 34.75 ± 4.95 versus 30.70 ± 4.10, respectively, P 0.001; tPNf-t9: 50.23 ± 5.87 versus 45.44 ± 4.67, respectively, P 0.001). For each of the outcomes, the association remained significant after adjusting for confounders.This study indicates that there may be a possible association between adverse perinatal outcomes and morphokinetic parameters. Larger studies are needed to establish this association.

In this study, we investigate if children born following assisted reproduction technologies (ARTs) are at an increased risk for long-term ophthalmic complications. For this purpose, a population-based cohort analysis was conducted which included all deliveries between 1991 and 2014 at a single tertiary medical center. Offspring were classified relative to conception method as ART or spontaneous pregnancies. Offspring hospitalizations up to the age of 18 years involving ophthalmic morbidities were evaluated according to a predefined set of ICD-9 codes. A Kaplan–Meier survival curve was used to compare cumulative hospitalization rates in exposed (ART) and unexposed offspring (spontaneous), and a Cox proportional hazards model was used to control for potential confounders. A total of 243,682 deliveries were included in the study. In that, 1.8% of the deliveries (4364) were of mothers who underwent fertility treatments and 98.2% (239,318) were conceived spontaneously. Offspring born to mothers who underwent fertility treatments had a significantly higher hospitalization rate involving ophthalmic morbidity, as compared to spontaneously conceived offspring (1.2% vs. 1.0%, p = 0.04). The Kaplan–Meier survival curve pointed to a significantly higher cumulative incidence of ophthalmic morbidity following ART (log rank p = 0.02). Cox proportional hazards model was adjusted for maternal age, preterm delivery, maternal hypertensive disorders, diabetes, and mode of delivery which demonstrated ART as an independent risk factor for long-term pediatric ophthalmic morbidity (adjusted hazard ratio = 1.37, CI 1.04–1.80, p-value = 0.02). We concluded that ART is an independent risk factor for long-term ophthalmic morbidity of the offspring.

Sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, is present in the ovarian granulosa cells (GCs) of various species. This study examined the regulation of SIRT1 expression in human granulosa-lutein cells (hGLCs). Two different, structurally unrelated SIRT1 activators, SRT2104 and resveratrol, dose- and time-dependently enhanced SIRT1 (∼2- and 1.5-fold increase at 50 μmol/L for mRNA and protein levels, respectively), whereas EX-527, an inhibitor of SIRT1 deacetylase activity, significantly suppressed SIRT1 protein induced by these activators. Transfecting cells with SIRT1 siRNA molecules efficiently silenced SIRT1 (∼70 % decrease in 48 h post-transfection). Furthermore, the stimulatory effects of SRT2104 on SIRT1 expression observed in non-transfected or in scrambled siRNA-transfected cells were diminished with SIRT1 silencing. The findings described above imply that SIRT1 autoregulates its own expression. Interestingly, SRT2104 elevated cAMP accumulation (1.4-fold) in the culture media of hGLCs which was further augmented in the presence of hCG (2.2-fold); these effects were evident after 12 h of incubation. This additive effect of hCG and SRT2104 on cAMP accumulation may explain the incremental outcome observed on SIRT1 expression (∼3-fold increase from basal level and ∼1.6-fold stimulation for each compound alone) with these two compounds. SIRT1 knockdown diminished SIRT1 induced by forskolin, providing additional evidence that cAMP promotes SIRT1. These findings imply that by activating adenylyl cyclase (hCG or forskolin) and inhibiting phosphodiesterases (SIRT1 activators), these two signals converge to produce an incremental, positive feedback loop on SIRT1 expression. Such a mechanism highlights the importance of maintaining high SIRT1 levels in human luteinized GCs.

To compare pregnancy outcomes between pregnancies following day 2, day 3, and days 5/6 fresh embryo transfer (ET).A retrospective cohort study including all pregnancies following fresh IVF/intracytoplasmic sperm injection (ICSI) ET cycles performed between January 2014 and December 2015 at Fertility andA total of 534 pregnancies following fresh IVF/ICSI ET on day 2 (The common approach of blastocyst transfer, as high quality of the embryo, has not proven beneficial in terms of live birth rate. Moreover, cleavage stage embryos were not associated with adverse perinatal outcomes. The current data suggest maternal age has an independent effect on live birth.

Background This article describes the research trends in sperm DNA fragmentation (SDF) over the past 20 years (1999–2018) using a scientometric approach. Methods A stepwise approach was adopted to retrieve scientometric data (articles per year, authors, affiliations, journals, countries) from Scopus and analyze the publication pattern of SDF with reference to key areas of research in the field of Andrology. Results A total of 2121 articles were retrieved related to SDF. Our data revealed an increasing research trend in SDF (n = 33 to n = 173) over the past 20 years (R2 = 0.894). Most productive country in publications was the USA (n = 450), while Agarwal A. (n = 129) being the most productive author. Most of the articles in SDF were primarily focused on lifestyle (n = 157), asthenozoospermia (n = 135) and varicocele (130). Mechanistic studies on SDF were published twice as much as prognostic/diagnostic studies, with significant emphasis on oxidative stress. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was the most widely used technique to evaluate SDF. Publications on SDF related to assisted reproductive techniques also showed a linear increasing trend (R2 = 0.933). Conclusions Our analysis revealed an increasing trend in SDF publications predominantly investigating lifestyle, asthenozoospermia and varicocele conditions with TUNEL being the most widely used technique. A substantial increase in research is warranted to establish SDF as prognostic/diagnostic parameter to evaluate clinical scenarios and ART outcomes.

OBJECTIVE While the impact of fertility treatments on the perinatal outcome is well established, the long-term effects on offspring are yet to be determined. The current study aimed to investigate the risk of long-term obstructive sleep apnea (OSA) among children born following in vitro fertilization (IVF) and ovulation induction (OI) as compared with spontaneously conceived pregnancies. STUDY DESIGN A retrospective population-based cohort study was performed. Exposure was defined as delivery following pregnancies conceived by IVF or OI. Incidence of OSA related hospitalizations of the offspring, up to the age of 18 years, was evaluated. A Kaplan-Meier survival curve and multivariable Cox regression models were used to assess the association. RESULTS During the study period, 242 187 singleton deliveries met the inclusion criteria; 1.1% were conceived following IVF (n = 2603), and 0.7% following OI (n = 1721). Offspring hospitalization rates, involving OSA (n = 1607), were higher among children conceived following IVF and OI pregnancies as compared with the rate in children conceived spontaneously (1.4% vs 1.2% vs 0.7%, respectively; P

To assess the impact of post-thawing embryo culture on frozen embryo transfer (FET) outcomes.A retrospective cohort study including 678 consecutive FET cycles performed between the years 2004 and 2017 was conducted. Patients older than 45 years old were excluded. FET cycles were stratified as follows: (1) two-day (2d) embryos thawed and cultured to three-day (3d) versus 3d embryos thawed and transferred; (2) 2d or 3d embryos thawed and cultured to blastocysts versus blastocysts thawed and transferred. AMaternal age, BMI, smoking, and basal FSH of the 2d and 3d cultured embryo group (We could not demonstrate that the post-thaw culture had a significant impact on the outcome of FET cycles.

STUDY QUESTION Can a machine-learning-based model trained in clinical and biological variables support the prediction of the presence or absence of sperm in testicular biopsy in non-obstructive azoospermia (NOA) patients? SUMMARY ANSWER Our machine-learning model was able to accurately predict (AUC of 0.8) the presence or absence of spermatozoa in patients with NOA. WHAT IS KNOWN ALREADY Patients with NOA can conceive with their own biological gametes using ICSI in combination with successful testicular sperm extraction (TESE). Testicular sperm retrieval is successful in up to 50% of men with NOA. However, to the best of our knowledge, there is no existing model that can accurately predict the success of sperm retrieval in TESE. Moreover, machine-learning has never been used for this purpose. STUDY DESIGN, SIZE, DURATION A retrospective cohort study of 119 patients who underwent TESE in a single IVF unit between 1995 and 2017 was conducted. All patients with NOA who underwent TESE during their fertility treatments were included. The development of gradient-boosted trees (GBTs) aimed to predict the presence or absence of spermatozoa in patients with NOA. The accuracy of these GBTs was then compared to a similar multivariate logistic regression model (MvLRM). PARTICIPANTS/MATERIALS, SETTING, METHODS We employed univariate and multivariate binary logistic regression models to predict the probability of successful TESE using a dataset from a retrospective cohort. In addition, we examined various ensemble machine-learning models (GBT and random forest) and evaluated their predictive performance using the leave-one-out cross-validation procedure. A cutoff value for successful/unsuccessful TESE was calculated with receiver operating characteristic (ROC) curve analysis. MAIN RESULTS AND THE ROLE OF CHANCE ROC analysis resulted in an AUC of 0.807 ± 0.032 (95% CI 0.743-0.871) for the proposed GBTs and 0.75 ± 0.052 (95% CI 0.65-0.85) for the MvLRM for the prediction of presence or absence of spermatozoa in patients with NOA. The GBT approach and the MvLRM yielded a sensitivity of 91% vs. 97%, respectively, but the GBT approach has a specificity of 51% compared with 25% for the MvLRM. A total of 78 (65.3%) men with NOA experienced successful TESE. FSH, LH, testosterone, semen volume, age, BMI, ethnicity and testicular size on clinical evaluation were included in these models. LIMITATIONS, REASONS FOR CAUTION This study is a retrospective cohort study, with all the associated inherent biases of such studies. This model was used only for TESE, since micro-TESE is not performed at our center. WIDER IMPLICATIONS OF THE FINDINGS Machine-learning models may lay the foundation for a decision support system for clinicians together with their NOA patients concerning TESE. The findings of this study should be confirmed with further larger and prospective studies. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Division of Obstetrics and Gynecology, Soroka University Medical Center, there are no potential conflicts of interest for all authors.

Endothelin-2 (EDN2) expression in granulosa cells was previously shown to be highly dependent on the hypoxic mediator, hypoxia inducible factor 1 alpha (HIF1A). Here, we investigated whether sirtuin-1 (SIRT1), by deacetylating HIF1A and class III histones, modulates EDN2 in human granulosa-lutein cells (hGLCs). We found that HIF1A was markedly suppressed in the presence of resveratrol or a specific SIRT1 activator, SRT2104. In turn, hypoxia reduced SIRT1 levels, implying a mutually inhibitory interaction between hypoxia (HIF1A) and SIRT1. Consistent with reduced HIF1A transcriptional activity, SIRT1 activators, resveratrol, SRT2104, and metformin, each acting via different mechanisms, significantly inhibited EDN2. In support, knockdown of SIRT1 with siRNA markedly elevated EDN2, whereas adding SRT2104 to SIRT1-silenced cells abolished the stimulatory effect of siSIRT1 on EDN2 levels further demonstrating that EDN2 is negatively correlated with SIRT1. Next, we investigated whether SIRT1 can also mediate the repression of the EDN2 promoter via histone modification. Chromatin immunoprecipitation (ChIP) analysis revealed that SIRT1 is indeed bound to the EDN2 promoter and that elevated SIRT1 induced a 40% decrease in the acetylation of histone H3, suggesting that SIRT1 inhibits EDN2 promoter activity by inducing a repressive histone configuration. Importantly, SIRT1 activation, using SRT2104 or resveratrol, decreased the viable numbers of hGLC, and silencing SIRT1 enhanced hGLC viability. This effect may be mediated by reducing HIF1A and EDN2 levels, shown to promote cell survival. Taken together, these findings propose novel, physiologically relevant roles for SIRT1 in downregulating EDN2 and survival of hGLCs.

The present study investigated the association between oocyte zona pellucida shear modulus (ZPSM) and implantation rate (IR). Ninety-three oocytes collected from 38 in-vitro fertilization patients who underwent intracytoplasmic sperm injection were included in this case–control study. The ZP was modeled as an isotropic compressible hyperelastic material with parameter $$C_{10}$$ C 10 , which represents the ZPSM. Computational methodology was used to calculate the mechanical parameters that govern ZP deformation. Fifty-one developed embryos were transferred and divided into two groups—implanted and not implanted. Multivariate logistic regression analysis was performed to identify the association between ZPSM and IR while controlling for confounders. Maternal age and number of embryos per transfer were significantly associated with implantation. The IR of embryos characterized by $$C_{10}$$ C 10 values in the range of 0.20–0.40 kPa was 66.75%, while outside this range it was 6.70%. This range was significantly associated with implantation (p p = 0.001). The present study suggests that ZPSM may improve the classic embryo selection process with the aim of increasing IR.

Male fertility preservation has been steadily increasing over the past two decades. Significant improvements have been achieved in the treatment modalities of cancer and other severe chronic medical conditions, leading to an increase in patient survivorship and the resulting demand for future parenthood. Recognition and proper patient counselling before commencing therapies with a potential gonadotoxic effect are of paramount importance. Similarly, nonmedically indicated fertility preservation is on the rise. Social sperm banking, gender dysphoria prior to affirmation procedures and posthumous reproduction preservation are becoming more common. When timing and logistics are appropriate, sperm cryopreservation is considered the gold standard for fertility preservation. Testicular tissue and spermatogonial stem cell autotransplantation is considered experimental and represents a promising alternative for pre-pubertal patients. The current paper aims to review the recent trends in male fertility preservation, the common indications for sperm cryopreservation, techniques for sperm retrieval and experimental frontiers.

Background Despite the endocrine basis of several infertility etiologies, data on long-term endocrine consequences in offspring conceived following fertility treatments remain limited. Aim To determine the risk of long-term endocrine disorders among children born after in-vitro fertilization (IVF) and ovulation induction (OI) as compared with spontaneous pregnancies. Study design, subjects, and outcome measures A population-based cohort study including all singleton deliveries occurring between 1991 and 2014 at a single tertiary medical center was performed. Hospitalization rates up to the age of 18 years involving endocrine disorders were compared between children delivered following pregnancies achieved by IVF, OI, and spontaneous pregnancies. A Kaplan-Meier survival curve was used to compare cumulative morbidity incidence. A Cox regression model was used to control for confounders. Results During the study period, 242,187 singleton deliveries met the inclusion criteria; 1.0% were following IVF (n = 2603), 0.7% following OI (n = 1721), and the remaining (n = 237,863) were following spontaneous conceptions. Hospitalizations up to the age of 18 years involving endocrine disorders were comparable in children delivered following IVF (0.4%), OI (0.8%) and spontaneous pregnancies (0.5%; p = 0.09). The Kaplan-Meier survival curve demonstrated comparable cumulative incidence of endocrine morbidity following IVF and OI (log-rank p = 0.30). Using the Cox regression model while controlling for confounders, no significant association was noted between IVF (adjusted HR = 0.95, CI 0.51–1.87), or OI (adjusted HR = 1.32, CI 0.78–2.24) conceived pregnancies, and long-term pediatric endocrine morbidity. Conclusions Singletons conceived via fertility treatment do not appear to be at an increased risk for long-term endocrine disorders.

To investigate risk factors and pregnancy outcome of spontaneous vs in-vitro fertilization (IVF) twins complicated with preeclampsia. A retrospective population-based cohort study comparing maternal and neonatal outcome in IVF vs spontaneously conceived twins was conducted. Deliveries occurred in a tertiary medical center between the years 1988 and 2010. Women who conceived after ovulation induction and those with chronic hypertension were excluded from the study. Multiple logistic regression models were used to control for confounders. The study population included 4428 twin pregnancies, of these 314 (7.1%) had preeclampsia; 64 (20.3%) were IVF twins and 250 (79.7%) were spontaneous twins. Preeclampsia was more common in IVF compare to spontaneous twins (13.8 vs 7.6%, OR = 1.81, CI = 1.50–2.17, P

Background Azoospermia is diagnosed when sperm cells are completely absent in the ejaculate even after centrifugation. It is identified in approximately 1% of all men and in 10%–20% of infertile males. Non-obstructive azoospermia (NOA) is characterised by the absence of sperm due to either a Sertoli cell-only pattern, maturation arrest, hypospermatogenesis or mixed patterns. NOA is a severe form of male infertility, with limited treatment options and low fertility success rates. In the majority of patients, the cause for NOA is not known and mutations in only a few genes were shown to be causative. Aim We investigated the cause of maturation arrest in five azoospermic infertile men of a large consanguineous Bedouin family. Methods and results Using whole genome genotyping and exome sequencing we identified a 4 bp deletion frameshift mutation in TDRD9 as the causative mutation with a Lod Score of 3.42. We demonstrate that the mutation results in a frameshift as well as exon skipping. Immunofluorescent staining with anti-TDRD9 antibody directed towards the N terminus demonstrated the presence of the protein in testicular biopsies of patients with an intracellular distribution comparable to a control biopsy. The mutation does not cause female infertility. Conclusion This is the first report of a recessive deleterious mutation in TDRD9 in humans. The clinical phenotype recapitulates that observed in the Tdrd9 knockout mice where this gene was demonstrated to participate in long interspersed element-1 retrotransposon silencing. If this function is preserved in human, our data underscore the importance of maintaining DNA stability in the human male germ line.

Background Prevalence of pregnancies conceived following fertility treatments is high worldwide. While the impact of fertility treatments on short-term perinatal outcome is well established, long-term consequences are yet to be determined. Objective To study the association between mode of conception and long-term gastrointestinal morbidity among children born following fertility treatments. Study design A population-based cohort analysis including all singleton deliveries occurring between 1991 and 2014 at a single regional tertiary medical center was performed. Fetuses with congenital malformations were excluded. A comparison was performed between children delivered following IVF, OI and spontaneous pregnancies. Hospitalizations up to the age of 18 years involving gastrointestinal morbidity were evaluated. Kaplan-Meier survival curve was used to compare cumulative morbidity incidence. A Cox regression model was used to control for confounders. Results During the study period 242,187 singleton deliveries met the inclusion criteria; 1.1% following IVF (n = 2603), and 0.7% following OI (n = 1721). Hospitalization rates involving gastrointestinal morbidity were significantly higher in children conceived following IVF and OI (5.7%, 7.1% respectively) as compared with children conceived spontaneously (5.4%; p = 0.005). The Kaplan-Meier survival curve demonstrated a significantly higher cumulative incidence of gastrointestinal morbidity following IVF and OI (log rank p = 0.001). Using a Cox proportional hazards model, controlling for maternal age, preterm delivery, birthweight, maternal diabetes and hypertensive disorders in pregnancy, IVF (adjusted HR = 1.27, CI 1.08–1.50, p = 0.004), was noted as an independent risk factor for long-term pediatric gastrointestinal morbidity. Conclusion Singletons conceived by IVF appear to be at an increased risk for long-term gastrointestinal morbidity.

This study aimed to assess the association between maternal-isolated oligohydramnios (IO) and offspring long-term neurological complications. A population-based retrospective cohort study was conducted, including all births at a single tertiary medical center in Israel between the years 1991 and 2014. Multiple pregnancies and potential pregnancy complications associated with oligohydramnios were excluded. The computerized obstetrical database was linked with the computerized dataset of all pediatric hospitalizations of the same medical center. Evaluation of cumulative neurological-associated hospitalizations rate over time was compared using a Kaplan–Meier survival curve. The Weibull survival parametric model was conducted to assess the neurological-associated hospitalization risk in the presence of IO, while accounting for potential confounders. A total of 190,259 pregnancies were included in the study, of which 4063 (2.13%) pregnancies were complicated with IO. Total neurological-related hospitalizations were significantly more common in the IO group (3.7% in the IO group and 3.0% in the comparison group,p = 0.005). Pervasive developmental disorder, movement disorders, developmental disorders, and degenerative and demyelization disorders were all specific neurological diagnoses significantly more common in the exposed group. The survival curve demonstrated a significantly higher cumulative hospitalization rate in the exposed group (log-rankp= 0.001). Using a multivariate model adjusting for gestational age, maternal age, and labor induction, an independent association between IO and long-term neurological morbidity of the offspring was observed (adjusted hazard ratio 1.203; 95% CI 1.02–1.42). In summary, a significant association was found between pregnancies complicated by IO and long-term neurological morbidity of the offspring.

Endometrial scratching (ES) using a biopsy catheter prior to the IVF cycle in the repeated implantation failure (RIF) population has been suggested, but no convincing evidence of its benefit has been presented until now. A retrospective mono-center study among 300 consecutive IVF-RIF cycles following evaluation of the ovarian reserve, hysterosalpingography or hysteroscopy, pelvic ultrasound, thrombophilia evaluation, karyotyping and assessment of male sperm parametrs. The findings within normal limits. All the patients offered ES, 78 consented and underwent ES prior to their next IVF cycle. A comparison of treatment outcomes between the post-ES cycles (n = 78) and the non-ES cycles (222) demonstrated the following: 34 (43.5%) versus 14 (6.3%) conceptions, respectively (p = 0.001) and 30 (38.4%) versus 2 (0.9%) clinical pregnancies, respectively (p

Objective To study the association between mode of conception and offspring infectious morbidity risk. Design Population-based cohort study. Setting Regional university medical center. Patient(s) All singleton infants born between the years 1991 and 2014 and discharged alive from the hospital. Intervention(s) Follow-up time in the study was calculated from birth to an event, defined as the first offspring hospitalization with any infectious morbidity. All infectious diagnoses were compared between the study groups, and a multivariable survival model was created to study the association between mode of conception and offspring pediatric hospitalization with infectious morbidity, and adjusting for confounding or clinically significant variables. Main Outcome Measure(s) First offspring pediatric hospitalization with infectious morbidity. Result(s) During the study period, 242,187 newborns met the inclusion criteria: 2,603 (1.1%) of which were conceived after undergoing IVF, 1,172 (0.7%) after ovulation induction (OI), and 237,863 (98.3%) were conceived spontaneously. Mothers receiving fertility treatments were older and with higher rates of preterm births and low birthweights. The hospitalizations rates per 1,000 person years of follow-up were 16.34/1,000 person years, 11.61/1,000 person years, and 10.19/1,000 person years, among the IVF, OI, and spontaneously conceived offspring, respectively. The adjusted hazard ratios were 1.26 (95% confidence interval 1.13–1.42) and 1.14 (95% confidence interval 1.00–1.38), for the IVF and OI compared with the spontaneously conceived offspring, respectively. The model adjusted for preterm delivery, birthweight, maternal age, hypertension, diabetes, and cesarean section. Conclusion(s) Higher risk for infectious morbidity was found among offspring conceived after fertility treatments compared with spontaneously conceived offspring.

Granulosa-lutein cells (GLCs) from PCOS women display reduced HIF-1α and EDN2 levels, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in aberrant EDN2 expression in PCOS, and its association with HIF-1α. Various HIF-1α-dependent factors were studied in GLCs from PCOS and compared to normally ovulating women. MicroRNA-210 (miR-210), its target genes (SDHD and GPD1L), and HIF-1α-responsive genes (EDN2 and VEGFA) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210—designated hypoxiamiR—and EDN2 were reduced in the PCOS GLCs, concomitantly, GPD1L and SDHD levels were elevated. Cultured GLCs retained low EDN2 expression and had low HIF-1α levels, providing evidence for a disrupted hypoxic response in the PCOS GLCs. However, VEGFA expression was elevated in these cells. Next, miR-210 levels were manipulated. miR-210-mimic stimulated EDN2 twice as much as the miR-NC-transfected cells, whereas miR-210-inhibitor diminished EDN2, emphasizing the importance of hypoxiamiR for EDN2 induction. Intriguingly, VEGFA transcripts were reduced by both miR-210-mimic and -inhibitor, demonstrating that EDN2 and VEGFA are distinctly regulated. Disrupted hypoxic response in the GLCs of periovulatory follicles in PCOS women may play a role in ovulation failure, and in the reduced fertility prevalent in this syndrome.

Objective Approximately 37% of men of reproductive age smoke cigarettes, with Europe having the highest tobacco use among all the World Health Organization (WHO) regions. Toxins from tobacco smoking can potentially affect sperm development and function, with a negative effect on semen parameters. Given the high prevalence of smoking and recent changes in the WHO laboratory methods for the examination of human semen, the role of this exposure in face of new WHO methods needs to be clarified. Evidence acquisition We conducted a systematic review, followed by a meta-analysis, to determine whether cigarette smoking affects human semen parameters. PubMed, Saint Joseph's University Discover, and Google Scholar were used to identify relevant studies published after release of the latest WHO methods for laboratory evaluation of human semen. Participants were from fertility/urologic clinics and andrology laboratories. The outcome measures were semen volume, sperm concentration, motility, and morphology, the parameters usually used in clinical settings to assess fertility. Evidence synthesis Twenty studies with 5865 participants were included in the meta-analysis. Exposure to cigarette smoking was associated with reduced sperm count (mean difference [MD]: −9.72×10 6 /ml; 95% confidence interval [CI], −13.32 to −6.12), motility (MD: −3.48%; 95% CI, −5.53 to −1.44), and morphology (MD: −1.37%; 95% CI, −2.63 to −0.11). Subgroup analyses indicated that effect size was higher in infertile men than in the general population and in moderate/heavy smokers than in mild smokers. The overall effect size on semen volume, sperm count, and motility remained similar when 2010 and earlier WHO manuals were used for semen analysis but was lower with regard to sperm morphology. Conclusions Our results suggest that cigarette smoking has an overall negative effect on semen parameters. The latest WHO laboratory methods for the examination of human semen had a minimal impact on the magnitude of effect size, thus confirming the observed negative effect of smoking on conventional semen parameters. Patient summary A new systematic review and meta-analysis comprising 5865 men shows that cigarette smoking is associated with reduced sperm count and motility. Deterioration of semen quality is more pronounced in moderate and heavy smokers.

Uterine fibroids are a common morbidity in women and its prevalence is increasing with age. As maternal age rises, fibroids become more prevalent during pregnancy.To assess perinatal outcome and long-term health of children to mothers with uterine fibroids during pregnancy.A population-based cohort analysis assessing long-term hospitalizations of offspring, up to the age of 18 years, due to gastrointestinal, neurological, cardiovascular, endocrine, and respiratory morbidity, following pregnancies diagnosed with and without a fibroid uterus. Multivariable generalized estimating equation (GEE) analysis adjusted for maternal clusters and other possible confounders was performed. Kaplan-Meier survival curves and Cox survival regression models were used to compare cumulative morbidity incidence and control for confounders.All singleton deliveries occurring between 1991 and 2014.Perinatal outcome and long-term pediatric morbidity.A total of 242,445 singleton deliveries were included; 0.5% of which were diagnosed with uterine fibroids (n = 1237). In the GEE multivariable analyses, advanced maternal age, hypertensive disorder and diabetes mellitus, fetal growth restriction, low birthweight (2500 g), and small for gestational age newborns, were all independently associated with uterine fibroids during pregnancy. Hospitalizations up to the age of 18 years in the different health categories were comparable between the groups, using Cox regression models, controlled for clinically significant confounders in the long-term outcomes.Maternal uterine fibroids appear to negatively impact perinatal outcome, mainly fetal growth. However, no independent major impact on future health of the offspring can be detected.

Objective: We aimed to evaluate the association between advanced maternal age and the long-term health of the offspring. Methods: In this population-based cohort study, hospitalizations of offspring up to the age of 18 years were compared according to maternal age. The incidence of long-term hospitalizations of the offspring due to cardiovascular, endocrine, neurological, hematological, respiratory and gastro­intestinal morbidities was evaluated. Deliveries occurred between the years 1991 and 2014 in a tertiary medical center. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence. Cox regression models were performed to control for confounders. Results: During the study period, 202,709 deliveries were included, of which 26,287 (12.9%) were in women aged 35–39 years, and 6,718 (3.3%) in women aged 40–50 years. Children born to older mothers did not have a significantly different cumulative incidence of long-term pediatric morbidities evaluated, as compared with the comparison group, using Kaplan-Meier survival analyses. In the Cox regression analyses, advanced maternal age did not exhibit an independent association with long-term morbidities of the offspring. Conclusion: Despite the association of advanced maternal age with adverse maternal and immediate neonatal outcomes, there does not seem to be an association with the long-term morbidity of the offspring.

Research question To assess the perinatal and obstetric outcomes of twin pregnancies resulting from IVF frozen embryo transfer (FET) in comparison with fresh embryo transfer. Design A retrospective cohort study of 773 twin pregnancies conceived via IVF treatment. Data were collected from the records of two outpatient fertility IVF clinics of cycles conducted between 2006 and 2016. Results A total of 773 pregnancies were evaluated: 614 (79.4%) following FET and 159 (20.6%) following fresh embryo transfer. The FET group had a significantly higher mean birthweight (P = 0.002), and lower rates of small for gestational age (P = 0.003), low (P = 0.003) and very low birthweight (P = 0.006) infants. Also, a significantly lower rate of spontaneous second trimester miscarriage compared with the fresh embryo transfer group was observed (P = 0.001). No significant difference was found between groups regarding gestational age at delivery, term birth (after 37 weeks of gestation), twin discordancy rate, fetal major malformation rate, and hospitalization duration. Conclusion In twin pregnancies, FET might have better perinatal outcomes compared with fresh embryo transfer in regards to birthweight and spontaneous second trimester miscarriages. Further research is needed to evaluate these results.

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, Traditionally, the success of a researcher is assessed by the number of publications he or she publishes in peer-reviewed, indexed, high impact journals. This essential yardstick, often referred to as the impact of a specific researcher, is assessed through the use of various metrics. While researchers may be acquainted with such matrices, many do not know how to use them to enhance their careers. In addition to these metrics, a number of other factors should be taken into consideration to objectively evaluate a scientist′s profile as a researcher and academician. Moreover, each metric has its own limitations that need to be considered when selecting an appropriate metric for evaluation. This paper provides a broad overview of the wide array of metrics currently in use in academia and research. Popular metrics are discussed and defined, including traditional metrics and article-level metrics, some of which are applied to researchers for a greater understanding of a particular concept, including varicocele that is the thematic area of this Special Issue of Asian Journal of Andrology. We recommend the combined use of quantitative and qualitative evaluation using judiciously selected metrics for a more objective assessment of scholarly output and research impact

This study investigated the effects of varicocele on semen parameters in infertile men based on the new 2010 World Health Organization laboratory manual for the examination of human semen. Semen analysis results (volume, sperm count, motility, and morphology) were the primary outcomes. An electronic search to collect the data was conducted using the Medline/PubMed, SJU discover, and Google Scholar databases. We searched articles published from 2010 to August 2015, i.e., after the publication of the 2010 WHO manual. We included only those studies that reported the actual semen parameters of adult infertile men diagnosed with clinical varicocele and contained a control group of either fertile men or normozoospermic men who were not diagnosed with varicocele. Ten studies were included in the meta-analysis, involving 1232 men. Varicocele was associated with reduced sperm count (mean difference: −44.48 × 10 [6] ml−1 ; 95% CI: −61.45, −27.51 × 10 [6] ml−1 ; P < 0.001), motility (mean difference: −26.67%; 95% CI: −34.27, −19.08; P < 0.001), and morphology (mean difference: −19.68%; 95% CI: −29.28, −10.07; P < 0.001) but not semen volume (mean difference: −0.23 ml; 95% CI: −0.64, 0.17). Subgroup analyses indicated that the magnitude of effect was influenced by control subtype but not WHO laboratory manual edition used for semen assessment. We conclude that varicocele is a significant risk factor that negatively affects semen quality, but the observed pooled effect size on semen parameters does not seem to be affected by the WHO laboratory manual edition. Given most of the studies published after 2010 still utilized the 1999 manual for semen analysis, further research is required to fully understand the clinical implication of the 2010 WHO laboratory manual on the association between varicocele and semen parameters.

Background Although concerns have been raised regarding the long-term health risks of offspring conceived following fertility treatments, limited information is available regarding their health status beyond the neonatal period. We aimed to evaluate the risk of long-term eruptive dermatological morbidity among children born following fertility treatments as compared to those conceived spontaneously. Methods A population-based cohort study was conducted, including all singleton deliveries occurring between the years 1991 and 2014 at a single tertiary medical center. Fetuses with congenital malformations and multiple gestations were excluded. Children delivered following fertility treatment pregnancies and spontaneous pregnancies were compared. Hospitalizations of the offspring up to the age of 18 years involving cutaneous eruptions were evaluated. A Kaplan-Meier survival curve was used to compare cumulative morbidity incidence and a Cox regression model to control for confounders. Results During the study period, 242,187 singleton deliveries met the inclusion criteria, 1.8% of which were following fertility treatments (n = 4324). Eruptive dermatological morbidity of the offspring up to the age of 18 years was significantly more common in the fertility treatment group (1.5%) as compared to spontaneous pregnancies (1.1%; P = 0.023). The Kaplan-Meier survival curve demonstrated a significantly higher cumulative incidence of eruptive dermatological morbidity following fertility treatments (log-rank P = 0.007). Using the Cox regression model, while controlling for multiple confounders, fertility treatment was noted as an independent risk factor for long-term pediatric eruptive dermatological morbidity (adjusted HR = 1.43, CI 1.12-1.83, P = 0.004). Conclusion Singletons conceived via fertility treatments appear to be at an increased risk for long-term eruptive dermatological morbidity.

Objective To compare perinatal outcomes between spontaneous conception and assisted reproductive technologies (ART) among patients of advanced maternal age. Methods The present retrospective study included data from singleton pregnancies of women aged at least 40 years who delivered between January 1, 1991, and December 31, 2013, at Soroka University Medical Center, Beer Sheva, Israel. Demographic, obstetric, and perinatal data were compared between pregnancies conceived with ART (in vitro fertilization [IVF] or ovulation induction) and those conceived spontaneously. Multiple regression models were used to define independent predictors of adverse outcomes. Results A total of 8244 singleton pregnancies were included; 229 (2.8%) following IVF, 86 (1.0%) following ovulation induction, and 7929 (96.2%) were spontaneous. Preterm delivery (P

To investigate risk factors for postpartum hemorrhage (PPH) in vaginal deliveries and the influence of previous PPH on the subsequent pregnancy.A retrospective cohort study including first singleton deliveries between the years 1988 and 2012 was performed comparing deliveries with and without PPH. In addition, perinatal outcomes of the subsequent pregnancy were evaluated. Multivariable analysis was performed to control for confounders.PPH complicated 0.8% of all first vaginal deliveries. Significant risk factors for PPH in vaginal delivery, using a multiple logistic regression model, were: post-term pregnancy, fertility treatments, hypertensive disorders, labor dystocia during the 2nd, and perineal tears grade 2 and 3, respectively. Previous PPH was found to be an independent risk factor for PPH in the subsequent pregnancy. Moreover, previous PPH was found to be a significant risk factor for cesarean section (CS) deliver, to complicate delivery with revision of uterus cavity, anemia, and to require blood transfusion.Previous PPH poses a risk for recurrent PPH in subsequent delivery and an increased risk for CS. As PPH remains one of the major causes of maternal morbidity, this study strengthens the need for a comprehensive evaluation of prior PPH as a major risk factor for PPH recurrence.

To investigate pregnancy outcome in patient who conceived by assisted reproductive techniques.A retrospective population-based study was conducted, comparing obstetrical complications and neonatal outcomes of singleton pregnancies conceived by in vitro fertilization (IVF; n = 1296) and ovulation induction (n = 1988) as compared to singleton pregnancies conceived spontaneously (n = 172 288). Multivariable models were constructed to control for confounders.A significant linear association (using the chi-square test for trends) was documented among the three groups in adverse outcomes such as gestational diabetes mellitus (17.3% in the IVF, 14.2% in the ovulation induction, 6.6% in the comparison group, p 0.001), severe preeclampsia (2.7% in the IVF, 1.8% in the ovulation induction, 1.1% in the comparison group, p 0.001) and perinatal mortality (3.3% in the IVF, 2.1% in the ovulation induction, 1.3% in the comparison group, p 0.001). In vitro fertilization and ovulation induction treatments were found to be independent risk factors for gestational diabetes mellitus, using two different multiple logistic regression models controlling for confounders such as maternal age (adjusted OR = 1.77, 95% CI:1.52-2.07, p 0.001 and adjusted OR = 1.93, 95% CI:1.69-2.21, p 0.001; respectively).Pregnancies conceiving following assisted reproductive techniques are at an increased risk for adverse obstetrics outcomes. The risk is higher for pregnancies following IVF compared with these conceived following ovulation induction.

To examine if, as in obesity, pregnancies complicated by gestational diabetes mellitus (GDM) exhibit increased macrophage infiltration and activated MAP-kinases in omental adipose tissue.Paired omental (OM) and abdominal subcutaneous (SC) fat samples were collected from 11 GDM and 20 normal pregnancies during cesarean delivery. Tissues were stained to detect macrophages, and analyzed to assess MAP-kinases.OM had higher macrophage counts than SC in GDM (6.10 ± 2.20 versus 2.53 ± 1.45, p = 0.04), but not in normal pregnancies (p = 0.346). GDM pregnancies had more macrophages than normal pregnancies in OM (6.10 ± 2.20 versus 1.29 ± 0.55, p = 0.01), while only a trend was observed in SC fat (p = 0.08). Significant correlation (R = 0.619, p = 0.005) was observed between OM-macrophage infiltration and insulin resistance. Using multivariate analysis, only obesity independently associated with GDM. Expression of total p38MAP-kinase was higher in OM versus SC in both normal and GDM pregnancies, without significant differences between these groups. However, expression of activated p-p38MAP-kinase, and its upstream kinase MKK4, was comparable between fat depots.GDM pregnancies demonstrate increased macrophage infiltration to OM fat, correlating with higher insulin resistance. As in non-pregnant-patients obesity and OM macrophage infiltration may be on the same causal pathway, leading to GDM. Yet, this occurs without activation of p38MAP-kinase signaling.

To address risk factors and perinatal outcomes after vacuum-assisted delivery (VAD) due to non-progressive labor (NPL) 2nd stage, and to assess its impact on the subsequent delivery. A retrospective, population-based cohort study was conducted in a tertiary medical center. Maternal characteristics, and maternal and neonatal outcomes of singleton pregnancies that resulted in VAD due to NPL 2nd stage were compared to those that resulted in VAD due to other indications. Multiple logistic regression models were constructed. Out of 202,462 singleton deliveries, 3.4% were delivered using VAD. Of these, 1928 VAD due to NPL 2nd stage and 4985 VAD due to other indications were identified. Independent risk factors for VAD due to NPL 2nd stage were identified: advanced gestational age, pre-eclampsia, and labor induction. VAD due to NPL 2nd stage in the index pregnancy was noted as an independent risk factor for NPL 1st stage and NPL 2nd stage during the subsequent pregnancy. VAD due to NPL 2nd stage results in adverse perinatal outcome in the index and subsequent pregnancies. VAD due to NPL 2nd stage in the index pregnancy is an independent risk factor for NPL 1st stage and NPL 2nd stage during the subsequent pregnancy.

Background: Different etiologies for recurrent pregnancy loss have been identified, among them are: anatomical, endocrine, genetic, chromosomal and thrombophilia pathologies. Aims: To assess medical and obstetric characteristics, and pregnancy outcomes, among women with uterine abnormalities and recurrent pregnancy loss (RPL). This study also aims to assess the impact of uterine anatomic surgical correction on pregnancy outcomes. Methods: A retrospective case control study of 313 patients with two or more consecutive pregnancy losses followed by a subsequent (index) pregnancy. Anatomic abnormalities were detected in 80 patients. All patients were evaluated and treated in the RPL clinic at Soroka University Medical Center. Out of 80 patients with uterine anatomic abnormalities, 19 underwent surgical correction, 32 did not and 29 had no clear record of surgical intervention, and thus were excluded from this study. Results: Women with anatomic abnormalities had a higher rate of previous cesarean section (18.8% vs. 8.6%, P=0.022), tended to have a lower number of previous live births (1.05 vs. 1.37, P=0.07), and a higher rate of preterm delivery (22.9% vs. 10%, P=0.037). Using multivariate logistic regression analysis, anatomic abnormality was identified as an independent risk factor for RPL in patients with previous cesarean section after controlling for place of residence, positive genetic/autoimmune/endocrine workup, and fertility problems (OR 7.22; 95% CI 1.17–44.54, P=0.03). Women suffering from anatomic abnormalities tended to have a higher rate of pregnancy loss compared to those without anatomic abnormalities (40% vs. 30.9%, P=0.2). The difference in pregnancy loss rate among women who underwent surgical correction compared to those who did not was not statistically significant. Conclusion: In patients with previous cesarean section, uterine abnormality is an independent risk factor for pregnancy loss. Surgical correction of uterine abnormalities among RPL patients might have the potential to improve live birth rate.

Background: Recurrent pregnancy loss (RPL) is defined by two or more failed clinical pregnancies. Three to four percent of the couples with RPL have chromosomal aberrations (CA) in at least one partner. The parent’s structural chromosomal abnormalities may cause an unbalanced karyotype in the conceptus which could lead to implantation failure, early or late pregnancy loss, or delivery of a child with severe physical and/or mental disabilities. Objective: To compare live birth rates of couples with CA to couples with normal karyotypes and to investigate medical and obstetric characteristics and pregnancy outcomes of couples with CA and RPL who attend an RPL clinic at a tertiary hospital. Methods: A retrospective cohort study, including 349 patients with two or more consecutive pregnancy losses. The study group consisted of 52 patients with CA, and the control group consisted of 297 couples with normal karyotype. All patients were evaluated and treated in the RPL clinic at Soroka University Medical Center and had at least one subsequent spontaneous pregnancy. Results: The demographic and clinical characteristics were not found to be statistically different between the two groups. The group of carriers of CA had 28/52 (53.8%) live births in their index pregnancy vs. the normal 202/297 (68%) (P=0.067, CI 95%) in the control group. No statistically significant etiology was found between the study group and the control group. A statistically significant difference in live birth rates was found when comparing the total amount of pregnancies [index pregnancy (IP)+post index pregnancy (PIP)] between the study group and the control group (54.16% vs. 67.82%, respectively, P=0.0328). Conclusion: Patients with RPL and CA who have spontaneous pregnancies, have a good prognosis (63.4%) of a successful pregnancy with at least one of the pregnancies (index or post index) resulting in a live birth.

Studies have questioned the long-term health effects of offspring conceived after fertility treatments.We aimed to evaluate whether an association exists between mode of conception (in vitro fertilization, ovulation induction, or spontaneous pregnancy) and neoplasm risk (both benign and malignant tumors) among the offspring; we observed the offspring for up to 18 years.A population-based cohort analysis was performed that compared the risk for neoplasms among children (up to the age of 18 years) based on mode of conception. Neoplasm diagnoses were based on hospital records of the same single tertiary center in the region. All singletons born during from 1991-2013 and discharged alive were included in the study. Offspring with congenital malformations were excluded from the analysis. Kaplan-Meier survival curves were constructed to compare cumulative neoplasms incidence; multivariable survival analyses were used to control for confounders that included gestational age, pregnancy complications, and maternal factors.During the study period, 242,187 newborn infants met the inclusion criteria: 2603 (1.1%) were conceived after in vitro fertilization; 1721 (0.7%) were conceived after ovulation induction treatments, and 237,863 (98.3%) were conceived spontaneously. During the follow-up period (median, 10.55 years), 1498 neoplasms(0.6%) were diagnosed. Incidence density rate for neoplasms was higher among children conceived either after in vitro fertilization (1.5/1000 person years) or ovulation induction treatments (1.0/1000 person years), as compared with naturally conceived children (0.59/1000 person years; Kaplan-Meier log rank, P.001). The association between in vitro fertilization and total pediatric neoplasms and the association between any fertility treatments and malignancies remained significant; we controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age (adjusted hazard ratio, 2.48; 95% confidence interval, 1.71-3.50; and adjusted hazard ratio, 1.96; 95% confidence interval, 1.14-3.36, for all neoplasms and all malignancies, respectively).Children conceived after fertility treatments are at an increased risk for pediatric neoplasms.

Fertility preservation consideration prior to gonadotoxic aggressive treatment is now mandatory. Nevertheless, while cryopreservation of mature sperm cells is a well-established technique, preserving fertitity from testicular tissue of pre-pubertal male children in whom only spermatogonial stem cells are avaitable is still under investigation. In rodents, our group was able to demonstrate in-vitro maturation of spermatogonial stem cells to a mature sperm cell which undergoes acrosome reaction.To culture, expand and preserve spermatogonial stem cells in-vitro in order to allow future fertility to pre-pubertal male children undergoing aggressive gondotoxic treatment.Pre-pubertal male children scheduled for aggressive gonadotoxic treatment were referred to the Soroka University Medical Center. Testicular biopsy was performed from one testicle. Most of the tissue was cryopreserved for future fertility. A minor part of the tissue was transferred to the research laboratory for culturing and further growth and differentiation. Testicular cells were isolated by enzymatic digestion.This is a first published account in humans of cells from testicular tissue that were cultured for more than two months. In this culture, isolated and groups of cells were observed. Some of the cells expressed pre-meiotic markers, while meiotic markers were expressed by other cells after culture.Preliminary results indicate a possible culturing technique from human testicular tissue in-vitro. Furthermore, meiotic activity may indicate the beginning of differentiation. Further studies are required to develop growth and differentiation techniques and for examining the cell for possible genetic and epigenetic changes before injecting them to mature oocytes for the purpose of fertilization and embryo development.

A B S T R A C T Objective: To assess pregnancy outcome in women who initially refused medically indicated caesarean delivery (CD) in cases of non-reassuring fetal heart rate (FHR) patterns. Study design: A retrospective cohort study, comparing patients who refused and did not refuse caesarean delivery (CD) due to non-reassuring FHR tracings, was conducted. Deliveries occurred between the years 1988 and 2009 in a tertiary medical center. Multivariate analysis was performed to control for confounders. Results: Out of 10,944 women who were advised to undergo CD due to non-reassuring FHR patterns, 203 women initially refused CD. Women refusing medical intervention tended to be older (30.6 6.9 vs. 28.29 6.1, P < 0.001) and of higher parity (46.8% vs. 19.9% had more than 5 deliveries; P < 0.001) as compared to the comparison group. Refusal of CD was significantly associated with adverse perinatal outcome. Using a multiple logistic regression model controlling for confounders such as maternal age, refusal of treatment was found as an independent risk factor for perinatal mortality (adjusted OR = 3.3, C.I. 95% 1.8– 5.9, P < 0.001). A non-significant trend towards higher rates of adverse perinatal outcome was found when refusal latency time was longer than 20 min (OR = 2, 95% CI 0.36–11.95; P = 0.29). Conclusion: Refusal of CD in cases of non-reassuring FHR tracings is an independent risk factor for perinatal mortality.

Objective To determine the risk of long-term cardiovascular disease (CVD) among children born following in vitro fertilization (IVF) and compared with spontaneous pregnancies. Study design A population-based cohort study including all singleton deliveries occurring between 1991and 2014 at a tertiary medical center was performed. Hospitalizations up to the age of 18 years involving CVD were evaluated in children delivered following IVF, ovulation induction, and spontaneous pregnancies. CVD included valvular disorders, hypertension, arrhythmias, rheumatic disease, cardiomyopathy, ischemic heart disease, and heart failure. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence, and a Cox regression model controlled for confounders. Results During the study period, 242 187 singleton deliveries met the inclusion criteria; 1.1% following IVF (n = 2603), and 0.7% following ovulation induction (n = 1721). Hospitalizations up to the age of 18 years involving CVD (n = 1503) were comparable in children delivered following IVF (0.6%), ovulation induction (0.7%), and spontaneous pregnancies (0.6%; P = .884). No significant difference in the cumulative incidence of CVD was noted between the groups (log rank P = .781). Controlling for maternal age, gestational age, birthweight, maternal diabetes, and hypertensive disorders in pregnancy, fertility treatment was not noted as a risk factor for long-term pediatric CVD (IVF adjusted hazard ratio 1.05, 95% CI 0.63-1.74, P = .86; ovulation induction adjusted hazard ratio 0.97, CI 95% 0.55-1.71, P = .92). Conclusions Singletons conceived via fertility treatments do not appear to be at an increased risk of long-term pediatric CVD.

To investigate pregnancy outcome in women suffering from idiopathic vaginal bleeding (IVB) during the second half of pregnancy.A comparison between patients admitted to the hospital due to bleeding during the second half of pregnancy and patients without bleeding was performed. Patients lacking prenatal care as well as multiple gestations were excluded from the analysis. Stratified analyses using the Mantel-Haenszel technique and a multiple logistic regression model were performed to control for confounders.During the study period, 173,621 singleton deliveries occurred at our institute. Of these, 2077 (1.19%) were complicated with bleeding upon admission during the second half of pregnancy. After excluding cases with bleeding due to placental abruption, placenta previa, cervical problems, etc., 67 patients were classified as having IVB (0.038%). Independent risk factors associated with IVB, using a backward, stepwise multivariable analysis were oligohydramnios (OR=6.2; 95% CI 3.1-12.7; p0.001), premature rupture of membranes (OR=3.4; 95% CI 1.8-6.2; p0.001), intrauterine growth restriction (IUGR, OR 5.6; 95% CI 2.5-12.2; p0.001), and Jewish ethnicity (OR=1.9; 95% CI 1.0-3.5; p=0.036). These patients subsequently were more likely to deliver preterm (37 weeks, 56.7% vs. 7.3%; mean gestational age of 33.6+/-5.7 weeks vs. 39.2+/-2.1 weeks; p0.001) and by cesarean delivery (CD, 35.8% vs. 12.1%, OR=4.0; 95% CI 2.4-6.6; p0.001). Higher rates of low Apgar scores (7) at 1 and 5 minutes were noted in these patients (OR=10.3; 95% CI 5.9-17.8; p0.001 and OR=17.8; 95% CI 7.1-44.5; p0.001, respectively). Moreover, perinatal mortality rate among patients admitted due to idiopathic bleeding was significantly higher as compared to patients without bleeding (9.6% vs. 1.2%, OR=8.4; 95% CI 3.3-21.2; p0.001). However, when controlling for preterm delivery, using the Mantel-Haenszel technique, the association lost its significance.Idiopathic vaginal bleeding during the second half of pregnancy is a risk factor for adverse perinatal outcome, mostly due to its significant association with preterm delivery. Careful surveillance, including fetal monitoring, is suggested in these cases in order to reduce the adverse perinatal outcome.

Oxidative stress is induced by reactive oxygen substances (ROS) that are known to affect male fertility. The aims of this study were to prospectively investigate and characterize total antioxidant and specifically polyphenols concentrations and their relations to sperm quality and fertility treatment success. During their infertility treatment, sixty-seven males were prospectively recruited to this study. After separation of the sperm from the semen sample, the semen fluid samples antioxidants and polyphenols concentrations were determined. Antioxidant concentration was significantly associated with sperm concentration and total motile count. Antioxidants concentration in the group of male with sperm concentration ≥ 15 × 106was significantly higher than in the group of male with antioxidants concentration < 15 × 106(830.3 ± 350 μM and 268.3 ± 220 μM, resp.,p<0.001). Polyphenols concentration did not differ between the groups of sperm concentration above and below 15 × 106(178.7 ± 121 μM and 161.7 ± 61 μM, resp.,p-NS). No difference was found between fertilization rates and antioxidants or polyphenols concentrations. This is the first study that reports on polyphenols concentration within semen fluid. More studies are needed in order to investigate polyphenols role in male fertility.

To examine whether a pre-gestational diagnosis of depression is a risk factor for adverse obstetric and neonatal outcome.A retrospective cohort study investigating maternal characteristics, obstetrical and perinatal outcomes in singleton pregnancies of women with and without a diagnosis of depression was conducted. A pre-gestational diagnosis of depression was made by a psychiatrist or family physician and was recorded in the patients' chart. Multiple logistic regression models were used to control for possible confounders.During the study period, 256 312 deliveries occurred. Of which, 221 women (0.1%) had a pre-gestational diagnosis of depression. When examining obstetric outcomes, women with a diagnosis of depression were older (32.05 ± 5.772 versus 28.56 ± 5.851) and smokers (7.2% versus 1.1%), had a higher rate of preterm deliveries (37.99 ± 2.989 versus 39.02 ± 2.249) and cesarean sections (CS; 28.5% versus 13.6%) in comparison to the control group. When examining neonatal outcomes, neonates of women diagnosed with depression had a lower birth mean weight (3.038.47 ± 649.6 versus 3183.44 ± 551.8) and increased rates of perinatal mortality (3.2% versus 1.3%). Using a multiple logistic regression model, with perinatal mortality as the outcome variable to control for cofounders such as maternal age, preterm birth, chronic hypertension and gestational diabetes mellitus, a diagnosis of depression was not found to be an independent risk factor for perinatal mortality. Another multiple logistic regression model found advanced maternal age, smoking, preterm birth and labor induction to be associated with a diagnosis of depression.Pregnant women diagnosed with depression are at an increased risk for preterm birth, low birth weight, and CSs. However, it was not associated with increased rates of perinatal mortality.

To determine the reproductive outcome following hysteroscopic septum resection in women with a septated uterus and a history of spontaneous miscarriages or premature deliveries.A retrospective, cohort study investigating reproductive outcomes following septum resection was conducted. Patients who had no other apparent cause for spontaneous miscarriage or preterm delivery were included in the study. Reproductive outcomes were compared between pregnancies prior to and after the septum resection. Multiple pregnancies were excluded.Twenty-eight patients met the inclusion criteria with a total of 85 pregnancies, 45 prior and 40 after septectomy. The mean gestational age increased from 33.73 ± 6.27 (weeks) prior to the resection to 38.47 ± 1.71 (weeks) after it (p 0.05). The mean birth weight increased from 2520 ± 764.4 (g) to 3202.6 ± 630.2 (g) after the resection. Spontaneous miscarriage rate dropped from 63.6% to 12.5%. Multivariate analysis models showed uterine septectomy to be independently associated with increased gestational age at delivery (β = 0.606, Adjusted R(2 )= 0.328, CI 10.647-20.612, p 0.01), increased birth weight (β = 0.424, Adjusted R(2 )= 0.129, CI 202.097-1210.287, p 0.01) and with lower risk for preterm delivery (OR = 0.073, CI 0.16-0.327, p 0.01).Hysetroscopic resection of a uterine septum improves reproductive outcomes in women with a septated uterus and a history of spontaneous miscarriages or premature deliveries.

Objective To evaluate whether vanishing twin syndrome (VTS) is associated with adverse perinatal outcome. Design A retrospective cohort study investigating the impact of VTS on perinatal outcome was conducted. Parturients were classified into three groups: those pregnancies that started with double fetal sacs and spontaneously reduced into one (VTS), those with dichorionic twins, and those with singleton pregnancies. Statistical analysis included multiple logistic regression models to control for possible confounders. Setting Tertiary university medical center. Patient(s) The study involved 252,994 singleton deliveries between the years 1988 and 2012. Intervention(s) None. Main Outcome Measure(s) The impact of VTS on perinatal outcome. Result(s) During the study period, 278 pregnancies with VTS were compared with 1,801 pregnancies of dichorionic twins and 252,994 pregnancies of singletons. A significant linear association was documented among the three groups and various adverse outcomes, including gestational diabetes mellitus (GDM), intrauterine growth restriction (IUGR), very low birth weight (VLBW), and perinatal mortality. The higher risk was noted in the VTS group, and the lowest in singletons. Using multivariable logistic regression models, while controlling for confounders such as fertility treatment and maternal age, VTS (as compared with singletons) was found to be an independent risk factor for several adverse perinatal outcomes including GDM, IUGR, VLBW, low Apgar scores, and perinatal mortality (adjusted odds ratios with their respective 95% confidence intervals, 1.4 [1.01–2.0], 2.7 [1.7–4.3], 6.9 [4.7–10.2], 1.9 [1.1–3.3], 2.4 [1.2–4.5]). Conclusion(s) Pregnancies with VTS are associated with an adverse perinatal outcome, even after controlling for confounders such as fertility treatment and maternal age.

To establish whether failure to progress during labor poses a risk factor for another non-progressive labor (NPL) during the subsequent delivery.A retrospective cohort study including singleton pregnancies that failed to progress during the previous labor and resulted in a cesarean section (CS) was conducted. Parturients were classified into three groups for both previous and subsequent labors: CS due to NPL stage I, stage II and an elective CS as a comparison group.Of 202 462 deliveries, 10 654 women met the inclusion criteria: 3068 women were operated due to NPL stage I and 1218 due to NPL stage II. The comparison group included 6368 women. Using a multivariable logistic regression models, NPL stage I during the previous delivery was found as an independent risk factor for another NPL stage I in the subsequent labor (adjusted odds ratio [OR] = 2.9; 95% confidence interval [CI] = 2.4-3.7; p 0.001). Similarly, NPL at stage I or II was found to be an independent risk factor for a NPL stage II during the subsequent labor (adjusted OR = 1.4; 95% CI = 1.1-2.1; p = 0.033; adjusted OR = 5.3; 95% CI = 3.7-7.5; p 0.001; respectively).A previous CS due to a NPL is an independent risk factor for another NPL in the subsequent pregnancy and for recurrent cesarean delivery.

To compare pregnancy outcomes of two consecutive pregnancies in a cohort of women with recurrent pregnancy loss (RPL), in order to determine the long-term prognosis of women with RPL managed in a dedicated RPL clinic.A retrospective cohort study including 262 patients with two or more consecutive pregnancy losses followed by two subsequent pregnancies--index pregnancy (IP) and post-index pregnancy (PIP). All patients were evaluated and treated in the RPL clinic in the Soroka University Medical Center.Comparing IP with PIP, no significant difference in perinatal outcome was observed. The perinatal outcome remained encouraging with approximately 73% birth rate (73.7% versus 72.5%; p=0.83). Only 11% of the women with RPL continued to experience pregnancy losses for two subsequent pregnancies. In a multivariate logistic regression analysis, number of miscarriages pre-Index was the only factor independently associated with birth in the PIP.There is no significant difference between IP and PIP regarding perinatal outcome. Appropriate management in the RPL clinic conferred a significant beneficial effect on long-term pregnancy outcome of a cohort of women with RPL.

Objective: To determine whether perineal massage during the second stage of labor using oil enriched with vitamins, increases the chances of delivering with an intact perineum as compared to perineal massage using pure liquid wax. Method: A prospective, randomized, double-blind study was conducted. Women were assigned to liquid wax (jojoba oil) versus purified formula of almond and olive oil, enriched with vitamin B1, B2, B6, E and fatty acids. The caregivers used the oils during the second stage of labor. Results: A total of 164 women undergoing vaginal delivery were recruited. No significant differences regarding perineal lacerations, number of sutures and length of suturing were noted between the two groups. Likewise, while analyzing separately nulliparous and multiparous women, no significant differences were noted. Controlling for birth weight 44000 g, using the Mantel–Haenszel technique, no association was noted between perineal lacerations and the type of oil used (weighted OR ¼ 0.9, 95% CI 0.3–2.4; p ¼ 0.818). Conclusion: The type of the oil used during the second stage of labor for prevention of perineal tears has no effect on the integrity of the perineum. Accordingly, it seems that there is no perfect oil.

To establish whether postterm pregnancies are associated with adverse perinatal outcomes in a linear fashion.A retrospective cohort study investigating perinatal outcomes in singleton term (≥ 37 weeks gestation) and postterm pregnancies was conducted. Deliveries occurred between the years 1988 and 2010. Parturients were classified into three groups according to their gestational age: 37-39 + 6, 40-41 + 6 and over 42 weeks' gestation (postterm). Statistical analysis included multiple logistic regression model to control for possible confounders.Out of 202,462 deliveries, meeting the inclusion criteria, during the study period, 47.7% occurred at 37-39 + 6 weeks, 47.4% occurred at 40-41 + 6 weeks and 4.9% were postterm. Fertility treatments, diabetes mellitus, hypertensive disorders, intrauterine growth restriction (IUGR) and premature rupture of membranes (PROM) were less likely to be associated with postterm pregnancies. However, postterm was found as a significant risk factor for labor complications and adverse perinatal outcome including perinatal mortality. Using a multivariable logistic regression model, controlling for confounders such as maternal age and macrosomia, postterm was found to be an independent risk factor for perinatal mortality (adjusted OR = 1.5; 95% CI = 1.20-2.0; p0.001).Although postterm pregnancies were less likely to be associated with obstetrical risk factors and complications such as fertility treatments, diabetes mellitus, hypertensive disorders, IUGR and PROM, postterm is an independent risk factor for perinatal mortality.

Objective The objective of the study was to determine whether 1 previous miscarriage is associated with an increased rate of adverse pregnancy outcomes in the following pregnancy. Study Design Second pregnancies of women with and without a miscarriage in their initial pregnancy were compared. Multivariable logistic regression models were constructed to control for confounders. Results Of 35,125 singleton deliveries in the second pregnancy, 5777 (16.4%) were of patients with an initial miscarriage. Multivariable analysis showed a significant association between a previous miscarriage and the following adverse pregnancy outcomes including premature rupture of membranes (odds ratio [OR], 2.22; 95% confidence interval [CI], 2.01–2.44), preterm delivery (OR, 1.34; 95% CI, 1.21–1.48), intrauterine growth restriction (OR, 1.24; 95% CI, 1.04–1.47), hypertensive disorders (OR 1.41; 95% CI 1.07–1.85), preeclampsia (OR, 1.63; 95% CI, 1.22–2.18), and cesarean delivery (OR, 1.59; 95% CI, 1.46–1.73). Perinatal mortality was significantly higher among women with an initial miscarriage (1.6% vs 1.0%; P Conclusion An initial miscarriage is independently associated with adverse pregnancy outcomes.