Dysregulation in Multiple Transcriptomic Endometrial Pathways Is Associated with Recurrent Implantation Failure and Recurrent Early Pregnancy Loss.

Overlapping disease aetiologies associated with multiple altered biological processes have been identified that change the endometrial function leading to recurrent implantation failure (RIF) and recurrent early pregnancy loss (REPL). We aimed to provide a detailed insight into the nature of the biological malfunction and related pathways of differentially expressed genes in RIF and REPL. Endometrial biopsies were obtained from 9 women experiencing RIF, REPL and control groups. Affymetrix microarray analysis was performed to measure the gene expression level of the endometrial biopsies. Unsupervised clustering of endometrial samples shows scattered distribution of gene expression between the RIF, REPL and control groups. 2556 and 1174 genes (p value < 0.05, Fold change > 1.2) were significantly altered in the endometria of RIF and REPL patients' group, respectively compared to the control group. Downregulation in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the differentially expressed genes (DEGs) in RIF and REPL including ribosome and oxidative phosphorylation pathways. Gene Ontology (GO) analysis revealed ribosomes and mitochondria inner membrane as the most significantly downregulated cellular component (CC) affected in RIF and REPL. Determination of the dysregulated genes and related biological pathways in RIF and REPL will be key in understanding their molecular pathology and of major importance in addressing diagnosis, prognosis, and treatment issues

Does hysteroscopic resection of uterine septum improve reproductive outcomes: a systematic review and meta-analysis.

PURPOSE: Uterine septum in women with subfertility or previous poor reproductive outcomes presents a clinical dilemma. Hysteroscopic septum resection has been previously associated with adverse reproductive outcomes but the evidence remains inconclusive. We aimed to thoroughly and systematically appraise relevant evidence on the impact of hysteroscopically resecting the uterine septum on this cohort of women. METHODS: AMED, BNI, CINAHL, EMBASE, EMCARE, Medline, PsychInfo, PubMed, Cochrane register of controlled trials, Cochrane database of systematic reviews and CINAHL were assessed to April 2020, with no language restriction. Only randomised control trials and comparative studies which evaluated outcomes in women with uterine septum and a history of subfertility and/or poor reproductive outcomes treated by hysteroscopic septum resection against control were included. The primary endpoint was live birth rate, whereas clinical pregnancy, miscarriage, preterm birth and malpresentation rates were secondary outcomes. RESULTS: Seven studies involving 407 women with hysteroscopic septum resection and 252 with conservative management were included in the meta-analysis. Hysteroscopic septum resection was associated with a lower rate of miscarriage (OR 0.25, 95% CI 0.07-0.88) compared with untreated women. No significant effect was seen on live birth, clinical pregnancy rate or preterm delivery. However, there were fewer malpresentations during labour in the treated group (OR 0.22, 95% CI 0.06-0.73). CONCLUSION: Our review found no significant effect of hysteroscopic resection on live birth. However, given the limited evidence available, high-quality randomised controlled trials are recommended before any conclusive clinical guidance can be drawn.

Epigenetic Influences During the Periconception Period and Assisted Reproduction.

The periconception period starts 6 months before conception and lasts until the tenth week of gestation. In this chapter, we will focus on epigenetic modifications to DNA and gene expression within this period and during assisted reproduction. There are two critical times during the periconception window when significant epigenetic 'reprogramming' occur: one during gametogenesis and another during the pre-implantation embryonic stage. Furthermore, assisted conception treatments, laboratory protocols and culture media can affect the embryo development and birth weights in laboratory animals. There is, however, an ongoing debate as to whether epigenetic changes in humans, causing embryo mal-development, placenta dysfunction and birth defects, result from assisted reproductive technologies or are consequences of pre-existing medical and/or genetic conditions in the parents. The periconception period starts from ovarian folliculogenesis, through resumption of oogenesis, fertilisation, peri-implantation embryo development, embryogenesis until the end of organogenesis. In men, it is the period from spermatogenesis to epididymal sperm storage and fertilisation. Gametes and developing embryos are sensitive to environmental factors during this period, and epigenetic modifications can occur in response to adverse lifestyles and environmental factors. We now know that lifestyle factors such as advanced parentage age, obesity or undernutrition, smoking, excessive alcohol and caffeine intake and recreational drugs used during gamete production and embryogenesis could induce epigenetic alterations, which could impact adversely on pregnancy outcomes and health of the offspring. Furthermore, these can also result in a permanent and irreversible effect in a dose-dependent manner, which can be passed on to the future generations.

Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis.

OBJECTIVE: The objective of this review was to provide pooled estimates of randomized controlled trials comparing the effects of oral hypoglycemic agents with insulin in achieving glycemic control and to study the maternal and perinatal outcomes in gestational diabetes mellitus. STUDY DESIGN: A protocol for the study was developed. All metaanalyses were performed using Stats Direct statistical software (Stats Direct Ltd, Cheshire, UK). RESULTS: Six studies comprising 1388 subjects were analyzed. No significant differences were found in maternal fasting (weighted mean difference [WMD], 1.31; 95% confidence interval [CI], 0.81-3.43) or postprandial (WMD, 0.80; 95% CI, -3.26 to 4.87) glycemic control. Use of oral hypoglycemic agents (OHAs) was not associated with risk of neonatal hypoglycemia (odds ratio [OR], 1.59; 95% CI, 0.70-3.62), increased birthweight (WMD, 56.11; 95% CI, -42.62 to 154.84), incidence of caesarean section (OR, 0.91; 95% CI, -0.68 to 1.22), or incidence of large-for-gestational-age babies (OR, 1.01; 95% CI, 0.61-1.68). CONCLUSION: Our study demonstrates that there are no differences in glycemic control or pregnancy outcomes when OHAs were compared with insulin.

The expression of inducible nitric oxide synthase in the human fallopian tube during the menstrual cycle and in ectopic pregnancy.

OBJECTIVE: To investigate the production of inducible nitric oxide synthase (iNOS) in the fallopian tube (FT) during the menstrual cycle and whether epithelia from FTs bearing an ectopic pregnancy differ from healthy tubes in iNOS expression. DESIGN: Prospective study. SETTING: Academic unit of reproductive and developmental medicine. PATIENT(S): Fallopian tubes from the different stages of the menstrual cycle (n=12), FTs bearing an ectopic pregnancy (n=15), and FTs from pseudopregnant women (n=6) were collected. INTERVENTION(S): In the pseudopregnant group, patients were injected with hCG in the days leading up to hysterectomy. Samples were processed for immunohistochemistry staining and quantitative reverse transcriptase polymerase chain reaction. MAIN OUTCOME MEASURE(S): To compare iNOS protein and messenger RNA expression between the different groups. RESULT(S): This is the first report on cyclicity in iNOS production by human fallopian tube during the menstrual cycle. The intensity of expression of iNOS was higher in the ectopic pregnancy group compared with the pseudopregnant group (P<0.05). CONCLUSION(S): The cyclicity in iNOS expression by the tube suggests its involvement in fertilization and early embryonic development. Pathologic generation of nitric oxide through increase iNOS production may decrease tubal ciliary beats and smooth muscle contractions and thus affect embryo transport, which may consequently result in ectopic pregnancy.

Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial.

BACKGROUND: Hydrosalpinges have adverse effects on IVF outcomes. Salpingectomy is effective in improving outcomes, but it is not always practical or safe. Ultrasound-guided aspiration of hydrosalpinges at oocyte collection is an option for those who develop hydrosalpinges during controlled ovarian stimulation; however, there is no randomized evidence to show whether this practice is effective. METHODS: Between October 1999 and June 2003, consenting women of age

The expression of activin-betaA- and -betaB-subunits, follistatin, and activin type II receptors in fallopian tubes bearing an ectopic pregnancy.

CONTEXT: Ectopic pregnancy is a major cause of maternal morbidity and mortality with increasing incidence worldwide. OBJECTIVE: We investigated whether epithelia from Fallopian tubes (FTs) bearing an ectopic pregnancy differ from normal tubes in expression of TGF-beta family and related proteins and their receptors. METHODOLOGY: Because it is not possible to collect FTs from women carrying a healthy pregnancy, we studied tissue collected at the time of hysterectomy for benign disease. Women were injected with human chorionic gonadotropin in the days leading up to hysterectomy to produce a state of pseudopregnancy. Pseudopregnancy status was confirmed by the presence of high serum progesterone levels and the decidualization of the endometrium. Fifteen FTs bearing ectopic pregnancy and six pseudopregnant tubes were collected and examined using immunohistochemistry and quantitative RT-PCR. RESULTS: Immunohistochemistry demonstrated clear staining for the betaA- and betaB-subunits, type II receptor group comprising the activin type IIA and type IIB receptors, and follistatin, which increased in intensity from the isthmus to the ampulla in both models. However, the intensity of expression of these molecules was stronger in the ectopic pregnancy group when compared with the pseudopregnant group. Quantitative RT-PCR showed significant decrease in mRNA levels of betaA-subunit, activin type IIA and IIB receptors, and follistatin in ectopic group (P < 0.05) but no changes in betaB-subunit (P > 0.05). Overall, there was an apparent paradox of high concentration of protein but low mRNA expression. CONCLUSION: Activin-A may stimulate tubal decidualization and trophoblast invasion. A better understanding of the mechanism by which an embryo implants in the tubal epithelium may lead to improved methods for early diagnosis and/or management of ectopic pregnancy.

Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and metaanalysis of randomized, controlled trials.

The objective of the study was to study the effects of continuous subcutaneous insulin infusion (CSII) vs multiple-dose insulin (MDI) therapy on glycemic control and pregnancy outcome in diabetic women. Randomized, controlled trials comparing CSII vs MDI in pregnant diabetic women were included after an electronic database search. Studies were rated for quality independently by 2 reviewers in accordance with the Quality of Reporting of Metaanalyses statement. Summary weighted mean difference and odds ratio were estimated for insulin dose, birthweight, gestational age, mode of delivery, hypoglycemic/ketotic episodes, worsening retinopathy, neonatal hypoglycemia, and rates of intrauterine fetal death. Six randomized clinical trials met the inclusion criteria. Pregnancy outcomes and glycemic control were not significantly different among treatment groups. Higher number of ketoacidotic episodes and diabetic retinopathy found in the CSII group did not reach statistical significance. This systematic review does not show any advantage or disadvantage of using CSII over MDI in pregnant diabetic women. Large multicenter, randomized, controlled trials addressing the quality of life/cost effectiveness are required.

Implantation failure following in-vitro fertilization.

PURPOSE OF REVIEW: Embryo implantation remains the rate-limiting step in assisted conception programmes. Factors affecting the interactions between blastocyst and endometrium are subjects of current research and, sadly, have also been the subjects of much confusion. This review aims to present current thinking on factors affecting embryo development, endometrial receptivity during and around the implantation window and the evidence for and against various proposed treatment options RECENT FINDINGS: Age-related aneuploidies of the sex chromosomes and several other autosomes are now thought to adversely affect oocyte and embryo quality, leading to repeat in-vitro fertilization failures. Several small controlled trials have suggested improvements in clinical outcomes following preimplantation screening and blastocyst transfer for aneuploidy in older women. These are, however, very costly, wasteful of embryos and do not appear beneficial after the age of 40 years. Factors influencing endometrial receptivity remain largely unresolved. New technology using microarrays for gene expression profiling and progesterone receptor polymorphism may shed more light in the near future. SUMMARY: Giant strides have been made in studying the causative factors of implantation failure, but these have not been matched by therapeutic solutions. Many proposed interventions are of unproven value, yet can have harmful side-effects.

Modification of the coaxial technique for selective salpingography with measurement of tubal perfusion pressures.

This article describes the use of the fallopotorque catheter system for transcervical selective salpingography and tubal catheterization under fluoroscopic guidance for the diagnosis and treatment of obstruction of the proximal Fallopian tube. The technique of tubal perfusion pressure assessment during the procedure, using the same catheter system, is also described. The relative advantages of this method of selective salpingography and tubal catheterization are then discussed in the background of previously described techniques.

Accuracy of sperm-cervical mucus penetration tests in evaluating sperm motility in semen: a systematic quantitative review.

BACKGROUND: Our objective was to determine the accuracy of in-vitro sperm penetration into cervical mucus or substitutes in evaluating sperm motility in semen. METHODS: This was a systematic quantitative review of test accuracy studies. The Cochrane library (2000:4), Medline (1966-2001), Embase (1988-2001) and SciSearch (1981-2001) were searched, in addition to manual searches of conference papers and bibliographies of known primary and review articles. Primary studies measuring in-vitro sperm penetration into cervical mucus, or substitutes (i.e. sperm-mucus penetration test, SMPT) and comparing results with sperm motility in semen were included. RESULTS: There were 18 primary diagnostic studies published in 17 papers, involving a total of 2580 samples. Fourteen primary diagnostic tests used vanguard distance as diagnostic criteria (SMPT(vd)) and the pooled likelihood ratio (LR) for positive (LR+) and negative (LR-) tests were 2.29 (1.82-2.87) and 0.52 (0.44-0.63) respectively. Four studies used diagnostic criteria based directly or indirectly on swim-up sperm count per high power field (SMPT(sc)) instead. Their pooled LR+ and LR- were 5.24 (3.36-8.18) and 0.15 (0.06-0.39) respectively. CONCLUSIONS: SMPT(vd) has a low accuracy in the evaluation of sperm motility in semen. However, SMPT(sc) was found to be more accurate. This method of using sperm concentration, instead of vanguard distance, as diagnostic criteria of in-vitro SMPT has potential as a useful laboratory-based sperm function test.

Diagnostic and therapeutic value of selective salpingography and tubal catheterization in an unselected infertile population.

OBJECTIVE: To present diagnostic findings and fertility outcome after selective salpingography and tubal catheterization in an unselected infertile population. DESIGN: Cohort study. SETTING: Tertiary reproductive medicine unit. PATIENT(S): One hundred ten consecutive infertile women. No exclusion criteria were applied. Follow-up ranged from 16 to 54 months. INTERVENTION(S): Selective salpingography and tubal catheterization under fluoroscopic guidance as the primary test for the assessment of the fallopian tubes. MAIN OUTCOME MEASURE(S): Incidence of tubal disease at selective salpingography, therapeutic effectiveness of tubal catheterization, and fertility outcome after the procedure. RESULT(S): Tubal disease was present in 31.4% of the tubes examined. Of tubes proximally blocked at selective salpingography, 52.1% were found to be normal after tubal catheterization. Proximal tubal blockage (bilateral or unilateral) was detected in 34.8% of women. This was reduced to 5.5% after tubal catheterization. Spontaneous conceptions occurred in 21.9% of the women. In total, 36.2% conceived without IVF or ICSI. CONCLUSION(S): Selective salpingography and tubal catheterization can be useful as a primary tubal assessment tool in the investigation of infertility. In cases of proximal tubal blockage, an effective see-and-treat approach can be adopted. More research into the possible therapeutic benefits of the procedure is justified.

The effect on pregnancy rates of tubal perfusion pressure reductions achieved by guide-wire tubal catheterization.

BACKGROUND: Selective salpingography enables us to measure the Fallopian tube perfusion pressure which, when high, can be effectively reduced with the use of transcervical guide-wire tubal catheterization. Whether fertility prognosis improves as a result is currently unknown. Our objective was to clarify the issue. METHODS: Infertile women undergoing selective salpingography were classified into poor, mediocre and good tubal perfusion pressure groups, based on the distribution of tubal perfusion pressures in an unselected infertile population. Of 325 women, 150 (46.1%) were classified in the poor group and underwent guide-wire tubal catheterization. RESULTS: Complete pregnancy and tubal perfusion pressure data were available for 104 (69.4%) subjects. Following tubal catheterization, 29 women (group A) could be classified in the good, 25 (group B) in the mediocre, while 50 women (group C) remained in the poor tubal perfusion pressure group. Survival analysis showed that the pregnancy rate in group A was significantly higher than the rates in groups B and C (P = 0.036 and 0.005 respectively). CONCLUSIONS: Reductions of tubal perfusion pressures achieved with transcervical guide-wire tubal catheterization resulted in an improved fertility prognosis for women. Selective salpingography and tubal catheterization might have a wider role in the management of the infertile couple than currently believed.

The learning curve of selective salpingography and tubal catheterization.

OBJECTIVE: To determine the effect of increasing experience in fluoroscopically guided selective salpingography and tubal catheterization on radiation doses and screening times, thus establishing a learning curve for the procedure. DESIGN: Retrospective case note analysis. SETTING: IVF center of an academic teaching hospital. PATIENTS: Three hundred sixty-six patients with infertility seen over 3.5 years. INTERVENTION(S): Fluoroscopically guided selective salpingography and tubal catheterization. MAIN OUTCOME MEASURE(S): Reductions in radiation doses and screening times for different categories of selective salpingography and tubal catheterization, expressed as percentage reductions during the study period and reductions per 10 procedures. RESULT(S): During the study period, The median dose of radiation decreased by 62.6%-71.9%, and the median screening time declined by 61.5%-78.5%. Reductions per 10 procedures were 2.5%-4.2% and 2.7%-5%, respectively. CONCLUSION(S): Significant reductions in radiation doses and screening times start early in a clinical team's practice of selective salpingography and tubal catheterization and continue even as trainees are added to the pool of operators.

Critical evaluation of methylcellulose as an alternative medium in sperm migration tests.

BACKGROUND: The aim of this study was to evaluate the ability of human spermatozoa to penetrate methylcellulose (MC) and to compare this with penetration in hyaluronic acid. METHODS: Spermatozoa from normal (>or=20 x 10(6) sperm/ml, >or=50% progressive motility, >or=5% normal forms) and oligozoospermic (<20 x 10(6) sperm/ml) semen samples were allowed to swim into glass capillary tubes containing methylcellulose with a viscosity of 15 centipoise (cp) (MC15) and 4000 cp (MC4000), hyaluronic acid (rooster comb) or Sperm Select. Penetration of the spermatozoa at 1, 2, 3 and 4 cm were correlated with basic semen parameters (concentration, motility and morphology). The effects of temperature on penetration into MC4000 were explored at 17-37 degrees C. RESULTS: Higher numbers of spermatozoa penetrated MC4000 (10 mg/ml) compared with MC15 and the hyaluronic acid preparations. There was a highly significant correlation between the number of spermatozoa at all migration distances in MC4000 (10 mg/ml) and semen parameters. Increases in temperature from 17-37 degrees C were accompanied by significantly higher numbers of spermatozoa at each penetration distance. MC4000 at 10 mg/ml was at least as favourable to sperm penetration as human cervical mucus. Effective discrimination between normal and abnormal samples was achieved using MC4000 (10 mg/ml). CONCLUSION: Our results suggest the potential use of methylcellulose (MC4000, 10 mg/ml) as a reproducible and effective alternative to hyaluronic acid in sperm migration tests.