The Association between Ovarian Hyperstimulation Syndrome and Pregnancy Complications following Fertility Treatments.

OBJECTIVE: This study was aimed to assess the association between ovarian hyperstimulation syndrome (OHSS) and pregnancy complications among women who conceived following fertility treatment. STUDY DESIGN: A retrospective population-based cohort study, including all singleton deliveries of patients conceived following ovulation induction (OI) or in vitro fertilization (IVF) between 1988 and 2016, was conducted. All births occurred in a single tertiary medical center. A comparison was performed between deliveries of women who had experienced OHSS at early gestation and subsequently had a pregnancy and women without OHSS. Women lacking prenatal care, multiple gestations, and stillbirths were excluded from the analyses. A multivariable logistic regression model was used to control for confounders. RESULTS: During the study period, 351,373 deliveries met the inclusion criteria, of which 6,748 were deliveries of infants who were conceived by either IVF or OI. Of this study population, 105 cases (1.6%) composed the exposed group, that is, women who had experienced OHSS with a subsequent live birth. In the multivariate analyses, after controlling for confounders, OHSS was not found as an independent risk factor for preeclampsia, gestational diabetes mellitus (GDM), intrauterine growth restriction (IUGR), preterm delivery (both <37 and <34 weeks), low birth weight (LBW), very LBW (VLBW), small for gestational age (SGA), and caesarean delivery. In a subanalysis conducted solely on the IVF population, similar results were found, aside from the association between OHSS and preterm delivery before 34 weeks of gestation which was statistically significant (adjusted odds ratio [AOR] = 2.3 95% confidence interval [CI]: 1.0-5.3, p = 0.049). CONCLUSION: In our population, OHSS was not found as a risk factor for adverse pregnancy and perinatal outcome. In IVF patients, OHSS is a risk factor for preterm delivery before 34 weeks of gestation. KEY POINTS: · OHSS is not a risk factor for pregnancy complications.. · Complications investigated were preeclampsia, GDM, prematurity, and others.. · In IVF patients, OHSS is a risk factor for preterm delivery..

Sirtuin-1 inhibits endothelin-2 expression in human granulosa-lutein cells via hypoxia inducible factor 1 alpha and epigenetic modifications†.

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.

Are morphokinetic parameters of embryo development associated with adverse perinatal outcomes following fresh blastocyst transfer?

RESEARCH QUESTION: Are obstetric and perinatal complications associated with morphokinetic parameters of embryo development? DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Mutation in CATIP (C2orf62) causes oligoteratoasthenozoospermia by affecting actin dynamics.

BACKGROUND: Oligoteratoasthenozoospermia (OTA) combines deteriorated quantity, morphology and motility of the sperm, resulting in male factor infertility. METHODS: We used whole genome genotyping and exome sequencing to identify the mutation causing OTA in four men in a consanguineous Bedouin family. We expressed the normal and mutated proteins tagged with c-Myc at the carboxy termini by transfection with pCDNA3.1 plasmid constructs to evaluate the effects on protein stability in HEK293 cells and on the kinetics of actin repolymerisation in retinal pigment epithelium cells. Patients' sperm samples were visualised by transmission electron microscopy to determine axoneme structures and were stained with fluorescent phalloidin to visualise the fibrillar (F)-actin. RESULTS: A homozygous missense mutation in Ciliogenesis Associated TTC17 Interacting Protein (CATIP): c. T103A, p. Phe35Ile, a gene encoding a protein important in actin organisation and ciliogenesis, was identified as the causative mutation with a LOD score of 3.25. The mutation reduces the protein stability compared with the normal protein. Furthermore, overexpression of the normal protein, but not the mutated protein, inhibits repolymerisation of actin after disruption with cytochalasin D. A high percentage of spermatozoa axonemes from patients have abnormalities, as well as disturbances in the distribution of F-actin. CONCLUSION: This is the first report of a recessive mutation in CATIP in humans. The identified mutation may contribute to asthenozoospermia by its involvement in actin polymerisation and on the actin cytoskeleton. A mouse knockout homozygote for CATIP was reported to demonstrate male infertility as the sole phenotype.

Male fertility preservation-Methods, indications and challenges.

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.

Does methylphenidate use affect sperm parameters in patients undergoing infertility investigation? A retrospective analysis of 9769 semen samples.

OBJECTIVES: Methylphenidate (MPH) is the most widely prescribed therapy for attention deficit hyperactivity disorder. Animal studies have shown a potential adverse effect of MPH exposure on male fertility. We examined the impact of MPH on human male sperm parameters. DESIGN: Sperm parameters of 9769 samples from patients 18 years of age or older, collected as part of the basic evaluation of couples referred to the Infertility Clinic were analyzed retrospectively. We divided the study population into three groups according to MPH purchasing information: MPH purchased ≤ 90 days prior to sperm analysis-current users (n = 83), MPH purchased > 90 days prior to sperm analysis-past users (n = 293), and MPH-naïve patients (n = 9393). METHODS: All sperm samples were analyzed by the same laboratory technician team for the following routine parameters: semen volume, sperm concentration, percentage of motile sperm, and percentage of normal morphology according to World Health Organization. The analysis of the samples was completed by evaluation of total sperm count, total sperm motility, and percentage of fast and slow motile cells. Sperm morphology was evaluated by a laboratory technician using methodological examination according to the strict Kruger-Tygerberg criteria. RESULTS: Methylphenidate exposure did not affect sperm morphology but was associated with increased sperm concentration as well as increased total sperm count and total sperm motility among current and past users compared with MPH-naïve patients. In particular, progressive motility and total motile sperm count were significantly increased following MPH use. A multivariate analysis adjusting for age and current smoking was conducted, further supporting a positive correlation between current MPH use and increased values of total sperm count and total sperm motility. LIMITATIONS: Our study has several inherent weaknesses, foremost of which is its retrospective nature. Another notable weakness is that medication purchasing data may not accurately reflect MPH exposure in the study population. Patients may be purchasing MPH and not taking it as prescribed. CONCLUSIONS: In the present study, we could not demonstrate a negative impact of methylphenidate treatment on sperm parameters in adults with ADHD. Hence, we may assume that methylphenidate does not negatively affect male fertility.

Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women.

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.

Recurrent implantation failure: which patients benefit from endometrial scratching prior to IVF?

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001%), emphasizing an extremely high biochemical pregnancy rate among the non-ES cycles. Implantation rate was 19.7% versus 0.4%, respectively (p < 0.001) and live birth rate was 33.33% (26 newborns) versus 0.45% (1 newborn), respectively (p < 0.001). Since there were more embryos available for transfer and more top-quality embryos in the post-ES-IVF conception cycles, the role of ES became questionable. A multivariate analysis that included ES and the percentage of top-quality embryos demonstrated that ES was an independent factor highly correlated with conception in this particular RIF population. CONCLUSIONS: ES proved to be an efficient tool in a particular subgroup of RIF patients with fertility investigation results within normal limits, an optimal ovarian response to gonadotropins, and a high percentage of top-quality embryos. Nevertheless, the results should not be overestimated, since the study has limitations related to its retrospective model.

Long-Term Cardiovascular Morbidity in Children Born Following Fertility Treatment.

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.

Tracking research trends and hotspots in sperm DNA fragmentation testing for the evaluation of male infertility: a scientometric analysis.

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.

Twin pregnancies and perinatal outcomes: a comparison between fresh and frozen embryo transfer: a two-centre study.

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.

Infertility Treatments and Long-Term Neurologic Morbidity of the Offspring.

OBJECTIVE: To determine the risk of long-term neurologic morbidity among children (up to 18 years) born following in vitro fertilization (IVF) or ovulation induction (OI) treatments as compared with spontaneously conceived. STUDY DESIGN: A population-based cohort analysis was performed, including data from the perinatal computerized database on all singleton infants born at the Soroka University Medical Center (SUMC) between the years 1991 and 2014. This perinatal database was linked and cross-matched with the SUMC computerized dataset of all pediatric hospitalizations. RESULTS: Neurologic morbidity was significantly more common in IVF (3.7%) and OI (4.1%) offspring as compared with those following spontaneous pregnancies (3.1%; p = 0.017). In particular, attention deficit/hyperactivity disorders and headaches were more common in the OI group and sleep disorders in the IVF group, whereas autism and cerebral palsy were comparable between the groups. In the Weibull multivariable analysis, while controlling for maternal age, preterm delivery, birthweight centile, maternal diabetes, and hypertensive disorders, IVF (adjusted hazard ratio [HR]: 1.40; 95% confidence interval [CI]: 1.14-1.71; p = 0.001), but not OI (adjusted HR: 1.17' 95% CI: 0.92-1.48; p = 0.196), was noted as an independent risk factor for long-term pediatric neurologic morbidity. CONCLUSION: IVF offspring appear to be at an increased risk of long-term neurologic morbidity up to 18 years of age.

Advanced Maternal Age and the Future Health of the Offspring.

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 gastro-intestinal 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.

Mutation in TDRD9 causes non-obstructive azoospermia in infertile men.

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.

Preeclampsia acts differently in in vitro fertilization versus spontaneous twins.

OBJECTIVE: To investigate risk factors and pregnancy outcome of spontaneous vs in-vitro fertilization (IVF) twins complicated with preeclampsia. STUDY DESIGN: 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. RESULTS: 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 < 0.001). The mothers of IVF twins were significantly older, and were more likely to be nulliparous. The rate of cesarean delivery was higher among IVF twins. The mean gestational age at delivery and the mean birth weight were significantly lower in IVF twins. While controlling for confounders using a multivariate analysis, IVF was found as an independent risk factor for preterm delivery in twin pregnancies with preeclampsia. However, there was no difference in the perinatal mortality or 5 min Apgar scores < 7 between the two groups. CONCLUSION: Preeclampsia is more common in IVF twins compared to spontaneous twin pregnancies. IVF twins with preeclampsia are at an increased risk for cesarean delivery, preterm delivery and low birth weight.

Fertility treatments and pediatric neoplasms of the offspring: results of a population-based cohort with a median follow-up of 10 years.

OBJECTIVE: Studies have questioned the long-term health effects of offspring conceived after fertility treatments. METHODS: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: Children conceived after fertility treatments are at an increased risk for pediatric neoplasms.

Non-progressive labor in the second stage leading to vacuum extraction is a risk factor for recurrent non-progressive labor.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[FERTILITY PRESERVATION BY CRYOPRESERVATION OF TESTICULAR TISSUE FROM PRE-PUBERTAL BOYS UNDERGOING GONADOTOXIC TREATMENT - PRELIMINARY RESULTS].

INTRODUCTION: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.