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..

Pregnancy outcomes of fresh IVF conceived pregnancies after embryo transfer at different stages of early embryonic development.

OBJECTIVE: To compare pregnancy outcomes between pregnancies following day 2, day 3, and days 5/6 fresh embryo transfer (ET). METHODS: 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 and In Vitro Fertilization (IVF) Unit of the tertiary Soroka University Medical Center. The study groups consisted of 48, 72, 120, and 144 hours embryos. Pregnancies were confirmed by a serum beta-human chorionic gonadotropin measurement. Data regarding patients' medical history, infertility workup, fertility treatment characteristics, and outcome, as well as obstetrical outcome, were collected from patients' medical records and IVF Laboratory database. Multiple regression models were constructed to control for confounders. Patients who underwent fertility preservation treatment, cycles of oocyte donation or in vitro maturation oocytes, and cases of preimplantation genetic testing were excluded. RESULTS: A total of 534 pregnancies following fresh IVF/ICSI ET on day 2 (n = 189, 35.4%), day 3 (n = 200, 37.5%), and days 5 or 6 (n = 145, 27.2%) were included. Live birth rate demonstrated a linear association to the developmental stage at ET with the highest rates in blastocysts and gradually lower in day 3 and day 2 ET (79.2, 65.8, and 60.6%, respectively, p = .001). A positive linear association was also observed between ET age and clinical pregnancy rate (77.3, 87.5, and 90.3% for days 2, 3, and 5/6, respectively, p = .002), as well as with combined pregnancy complication rate (29, 37.3, and 43.3%, p = .026). However, using multivariate logistic regression model controlling for ET age, maternal age, smoking, obesity, initial HCG level and peak E2 level, live birth rate was comparable between the study groups regardless of ET age. Pregnancy complications were comparable between the groups; however, a composite pregnancy complications variable was higher in the blastocyst pregnancies compared to cleavage embryos pregnancies. CONCLUSIONS: 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.

Effects of nifedipine on endothelial function, assessed by flow-mediated vasodilatation in pregnant patients.

OBJECTIVES: To evaluate the endothelial function, through flow-mediated vasodilation parameters from brachial artery test in women receiving nifedipine for acute tocolysis with threatened preterm delivery. METHODS: In a prospective study in a university-affiliated hospital, each participant served as herself control. We evaluated various parameters of endothelial function in 22 patients between 27 and 33 weeks of gestation with a diagnosis of threatened preterm delivery (TPTD) before and after 48 h of nifedipine treatment. Each patient received 80 mg nifedipine per day. The assessment tool was Brachial artery reactivity test (BART). Primary outcome was flow mediated vasodilation (FMD). RESULTS: The average participant's age was 27 ± 4.5 years, median gestational age of 28.5 weeks, BMI, kg/m2 (mean ± SD) 28.4 ± 3.3. Systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) decreased from 108 ± 6 to 104 ± 5, p < .001 and from 66 ± 4 to 63 ± 4, p < .001, respectively. FMD (%) significantly decrease from 10.8 ± 6.1 to 7.2 ± 4.7, p = .03 prior to and after nifedipine treatment. The basal brachial artery diameter (mm) at rest was (3.19 ± 0.38 versus 3.39 ± 0.49, p = .28) before versus after nifedipine. The largest brachial artery diameter (mm) was (3.54 ± 0.35 versus 3.58 ± 0.44, p = .76) before versus after nifedipine. CONCLUSIONS: Our results suggest unfavorable changes in FMD probably as a result of nifedipine used for acute tocolysis. Future prospective studies should try to evaluate the safety of acute and maintenance tocolytic therapy with nifedipine on endothelial function in pregnant women.

Post-thaw culture has no beneficial effect on frozen embryos transfer outcomes comparing to same embryonal age non-cultured frozen-thawed embryos.

PURPOSE: To assess the impact of post-thawing embryo culture on frozen embryo transfer (FET) outcomes. METHODS: 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. A p-value <.05 was considered statistically significant. RESULTS: Maternal age, BMI, smoking, and basal FSH of the 2d and 3d cultured embryo group (n = 110) and the 3d non-cultured embryo group (n = 189) were comparable. Endometrium preparation protocols and the achieved endometrial thickness did not differ between groups. Pregnancy rate, implantation rate, clinical pregnancy, live birth rate, abortions, multiple pregnancies, perinatal outcomes, and birth weight were comparable.The 2d and 3d embryos cultured to blastocyst (n = 41) compared to non-cultured blastocyst (n = 338) showed that the non-cultured blastocyst patients had higher smoking rates and longer follicular phase. Endometrial thickness was comparable. The 2d and 3d embryos cultured to blastocyst stage had higher multiple pregnancies rate compared to the blastocyst non-cultured group, whereas pregnancy rate, implantation rate, live birth rate, miscarriages, perinatal outcomes, and birth weight were comparable. CONCLUSION: We could not demonstrate that the post-thaw culture had a significant impact on the outcome of FET cycles.

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.

Possible association between in vitro fertilization technologies and offspring neoplasm.

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.

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.

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.

Assisted reproductive technology and long-term ophthalmic morbidity of the offspring.

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.

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.

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.

The cAMP pathway promotes sirtuin-1 expression in human granulosa-lutein cells.

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.

Zona pellucida shear modulus, a possible novel non-invasive method to assist in embryo selection during in-vitro fertilization treatment.

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 [Formula: see text], 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 [Formula: see text] 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 < 0.001). Geometric properties were not associated with implantation. Multivariate logistic regression analysis that controlled for relevant confounders indicated that this range was independently associated with implantation (adjusted OR 38.03, 95% confidence interval 4.67-309.36, p = 0.001). The present study suggests that ZPSM may improve the classic embryo selection process with the aim of increasing IR.

Long-term endocrine disorders in children born from pregnancies conceived following fertility treatments.

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.

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.

Fertility treatments and gastrointestinal morbidity of the offspring.

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.

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.

Ritalinic Acid Stimulates Human Sperm Motility and Maintains Vitality In Vitro.

PURPOSE: To evaluate the in vitro impact of ritalinic acid (RA), a major metabolite of methylphenidate (drug to treat attention-deficit hyperactivity disorder), on sperm motility, vitality and oxidative stress. MATERIALS AND METHODS: Semen samples (n=13) were collected from healthy donors and a semen analysis was performed according to World Health Organization. Density gradient centrifugation was performed to isolate motile sperm. Samples were incubated with different concentrations (0, 1, 10, 100, and 1,000 ng/mL) of RA. The non-exposed group (0 ng/mL) was defined as the control group. Samples were analyzed for motility at different time points (0, 60, 150, 240, and 300 minutes) and for vitality and oxidation reduction potential (ORP) (at 0, 240, and 300 minutes). Sperm motility was assessed manually and motion kinetic parameters were recorded by computer aided semen analysis. RESULTS: RA at any tested concentration significantly increased sperm motility compared to the control in a time-dependent manner with a maximum increase after 240 minutes. Motion kinetic parameters were not comparable. For sperm vitality, supplementation with RA significantly maintained survival at higher levels, while non-treated sperm gradually died. These higher levels of vitality were maintained with rising RA concentrations of up to 1,000 ng/mL. A non-significant trend of increased ORP was observed in all study groups. CONCLUSIONS: RA increases sperm motility and maintains vitality at any concentration tested. Therefore, RA might be utilized to improve sperm quality in asthenozoospermic specimens. However, further investigation is ongoing to evaluate the effect of RA on other sperm parameters.

Isolated oligohydramnios and long-term neurological morbidity of the offspring.

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-rank p = 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.

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.