Abstract Mechanical endometrial injury (biopsy/scratch or hysteroscopy) in the cycle preceding ovarian stimulation for IVF has been proposed to improve implantation in women with unexplained ...recurrent implantation failure (RIF). This is a systematic review and meta-analysis of studies comparing the efficacy of endometrial injury versus no intervention in women with RIF undergoing IVF. All controlled studies of endometrial biopsy/scratch or hysteroscopy performed in the cycle preceding ovarian stimulation were included and the primary outcome measure was clinical pregnancy rate. Pooling of seven controlled studies (four randomized and three non-randomized), with 2062 participants, showed that local endometrial injury induced in the cycle preceding ovarian stimulation is 70% more likely to result in a clinical pregnancy as opposed to no intervention. There was no statistically significant heterogeneity in the methods used, clinical pregnancy rates being twice as high with biopsy/scratch (RR 2.32, 95% CI 1.72–3.13) as opposed to hysteroscopy (RR 1.51, 95% CI 1.30–1.75). The evidence is strongly in favour of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained RIF. However, large randomized studies are required before iatrogenic induction of local endometrial injury can be warranted in routine clinical practice. Some women undergoing IVF treatment fail to conceive despite several attempts with good-quality embryos and no identifiable reason. We call this ‘recurrent implantation failure’ (RIF) where the embryo fails to embed or implant within the lining of the womb. Studies have shown that inducing injury to the lining of the womb in the cycle before starting ovarian stimulation for IVF can help improve the chances of achieving pregnancy. Injury can be induced by either scratching the lining of the womb using a biopsy tube or by telescopic investigation of the womb using a camera. We performed a collective review of the available good-quality studies that used the above two methods in the cycle prior to starting ovarian stimulation for IVF. We pooled results from seven studies, which included 2062 women with RIF and assessed the difference in clinical pregnancy rates for those undergoing injury to the womb lining compared with no injury prior to IVF. The results suggest that inducing injury is 70% more likely to result in a clinical pregnancy as opposed to no treatment. Furthermore, scratching of the lining was 2-times more likely to result in a clinical pregnancy compared with telescopic evaluation of the lining of the womb. This study suggests that in women with RIF, inducing local injury to the womb lining in the cycle prior to starting ovarian stimulation for IVF can improve pregnancy outcomes. However, large studies are required before this can be warranted in routine clinical practice.
STUDY QUESTION
What is the variability of anti-Müllerian hormone (AMH) concentration in repeat samples from the same individual when using the Gen II assay and how do values compare to Gen I ...Diagnostic Systems Ltd (DSL) assay results?
SUMMARY ANSWER
The Gen II AMH assay displayed appreciable variability, which can be explained by sample instability.
WHAT IS KNOWN ALREADY
AMH is the primary predictor of ovarian performance and is used to tailor gonadatrophin dosage in cycles of IVF/ICSI and in other routine clinical settings. Thus, a robust, reproducible and sensitive method for AMH analysis is of paramount importance. The Beckman Coulter Gen II ELISA for AMH was introduced to replace earlier DSL and Immunotech assays. The performance of the Gen II assay has not previously been studied in a clinical setting.
STUDY DESIGN, SIZE AND DURATION
We studied an unselected group of 5007 women referred for fertility problems between 1 September 2008 and 25 October 2011; AMH was measured initially using the DSL AMH ELISA and subsequently using the Gen II assay. AMH values in the two assays were compared using a regression model in log(AMH) with a quadratic adjustment for age. Additionally, women (n = 330) in whom AMH had been determined in different samples using both the DSL and Gen II assays (paired samples) identified and the difference in AMH levels between the DSL and Gen II assays was estimated using the age-adjusted regression analysis. A subset of 313 women had repeated AMH determinations (n = 646 samples) using the DSL assay and 87 women had repeated AMH determinations using the Gen II assay (n = 177 samples) were identified. A mixed effects model in log(AMH) was utilized to estimate the sample-to-sample (within-subject) coefficients of variation of AMH, adjusting for age. Laboratory experiments including sample stability at room temperature, linearity of dilution and storage conditions used anonymized samples.
MAIN RESULTS AND THE ROLE OF CHANCE
In clinical practice, Gen II AMH values were ∼20% lower than those generated using the DSL assay instead of the 40% increase predicted by the kit manufacturer. Both assays displayed high within-subject variability (Gen II assay CV = 59%, DSL assay CV = 32%). In the laboratory, AMH levels in serum from 48 subjects incubated at RT for up to 7 days increased progressively in the majority of samples (58% increase overall). Pre-dilution of serum prior to assay, gave AMH levels up to twice that found in the corresponding neat sample. Pre-mixing of serum with assay buffer prior to addition to the microtitre plate gave higher readings (72% overall) compared with sequential addition. Storage at −20°C for 5 days increased AMH levels by 23% compared with fresh samples. The statistical significance of results was assessed where appropriate.
LIMITATIONS, REASONS FOR CAUTION
The analysis of AMH levels is a retrospective study and therefore we cannot entirely rule out the existence of differences in referral practices or changes in the two populations.
WIDER IMPLICATIONS OF THE FINDINGS
Our data suggests that AMH may not be stable under some storage or assay conditions and this may be more pronounced with the Gen II assay. The published conversion factors between the Gen II and DSL assays appear to be inappropriate for routine clinical practice. Further studies are urgently required to confirm our observations and to determine the cause of the apparent instability. In the meantime, caution should be exercised in the interpretation of AMH levels in the clinical setting.
CONFLICT OF INTEREST/STUDY FUNDING
S. Roberts is supported by the NIHR Manchester Biomedical Research Centre.
Objective To investigate the effect of surgical treatment of endometrioma on pregnancy rate and ovarian response to gonadotrophin stimulation in women undergoing IVF. Design A systematic review and ...meta-analysis. Setting Tertiary referral center for reproductive medicine. Patient(s) Subfertile women with endometrioma undergoing IVF. Intervention(s) Surgical removal of endometrioma or expectant management. Main Outcome Measure(s) Clinical pregnancy rate and ovarian response to gonadotrophins (number of gonadotrophin ampoules, peak E2 levels, number of oocytes retrieved, and number of embryos available for transfer). Result(s) A search of three electronic databases for articles published between January 1985 and November 2007 yielded 20 eligible studies. Meta-analysis was conducted for five studies that compared surgery vs. no treatment of endometrioma. There was no significant difference in clinical pregnancy rate between the treated and the untreated groups. Similarly, no significant difference was found between the two groups with regard to the outcome measures used to assess the response to controlled ovarian hyperstimulation with gonadotrophins. Conclusion(s) Collectively the available data in the literature show that surgical management of endometriomas has no significant effect on IVF pregnancy rates and ovarian response to stimulation compared with no treatment. Randomized controlled trials are needed before producing best-practice recommendations on this topic.
Background
Chronic intestinal pseudo‐obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be ...non‐specific, and result in this condition being diagnosed incorrectly or too late with consequences for morbidity and even mortality.
Purpose
The present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis and therapeutic options for CIPO. Although pediatric and adult CIPO share many clinical aspects distinctive features can be identified. There is no single diagnostic test or pathognomonic finding of CIPO, thus a stepwise approach including radiology, endoscopy, laboratory, manometry, and histopathology should be considered in the diagnostic work‐up. Treatment of patients with CIPO is challenging and requires a multidisciplinary effort with participation of appropriately experienced gastroenterologists, pathologists, dieticians, surgeons, psychologists, and other subspecialists based on the presence of comorbidities. Current treatment options invariably involve surgery and specialized nutritional support, especially in children. Medical therapies are mainly aimed to avoid complications such as sepsis or intestinal bacterial overgrowth and, where possible, restore intestinal propulsion. More efficacious therapeutic options are eagerly awaited for such difficult patients.
Chronic intestinal pseudo‐obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be non‐specific, and result in an incorrect or too late diagnosis with consequences in terms of morbidity and even mortality. Thus, the present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis, and therapeutic options for CIPO.
Objective To determine whether a policy of elective single-embryo transfer (e-SET) lowers the multiple birth rate without compromising the live birth rate. Design Systematic review and meta-analysis. ...Setting Tertiary referral center for reproductive medicine and IVF unit. Patient(s) None. Intervention(s) Searches of the Cochrane Controlled Trials Register, Meta-register for Randomized Controlled Trials (RCTs), EMBASE, MEDLINE, and SCISEARCH with no limitation on language and publication year, 1974 to 2008. Selection criteria: randomized, controlled trials comparing e-SET with double-embryo transfer (DET) for live birth and multiple birth rates after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). Nonrandomized trials and studies that included only patients who had blastocyst transfer were excluded. Main Outcome Measure(s) The likelihood of live birth per patient and multiple birth per total number of live births. Other outcomes included implantation rate, pregnancy rate, miscarriage and ectopic pregnancy rates, clinical pregnancy rate, ongoing pregnancy rate per patient, and preterm delivery rate per live birth. Result(s) Six trials (n = 1354 patients) were included in the meta-analysis. Compared with DET, the e-SET policy was associated with a statistically significant reduction in the probability of live birth (RR 0.62; 95% CI, 0.53–0.72) and multiple birth (RR 0.06; 95% CI, 0.02–0.18). Conclusion(s) Elective-SET of embryos at the cleavage stage reduces the likelihood of live birth by 38% and multiple birth by 94%. Evidence from randomized, controlled trials suggests that increasing the number of e-SET attempts (fresh and/or frozen) results in a cumulative live birth rate similar to that of DET. Offering subfertile women three cycles of IVF will have a major impact on the uptake of an e-SET policy.
Purpose
Local and systemic inflammatory markers and pro-inflammatory cytokines are increased in children with obstructive sleep apnea syndrome (OSAS). Therefore, systemic or topical anti-inflammatory ...agents are used to treat this syndrome. We evaluated the treatment with systemic corticosteroids in children with severe OSAS and adenotonsillar hypertrophy before surgery.
Methods
This was an unblinded open label study. Children with severe OSAS (diagnosed through polysomnography, obstructive apnea–hypopnea index AHI > 10 eV/h) were recruited. Exclusion criteria included age < 3 years, history of acute or chronic cardiorespiratory or neuromuscular or metabolic disease; major craniofacial abnormalities; and chromosomal syndromes and epilepsy. Computer-generated random numbers were used for simple randomization of subjects. All children were treated with intranasal beclomethasone spray, and 15 children additionally received oral betamethasone and 0.1 mg/kg per day for 7 days. Sleep clinical record (SCR) and pulsoximetry were performed before and after 7 days in all children.
Results
Among 28 children with severe OSAS mean age was 4.5 ± 1.8 years, AHI 20.4 ± 1.8 eV/h). In children treated with intranasal and oral corticosteroids, mean (95.3 ± 1.1 vs 97.0 ± 0.8%,
p
= 0.0001) and minimum oxygen saturation (78.8 ± 6.3 vs 89.2 ± 4.2,
p
= 0.001) improved, and the SCR score (12.6 ± 1.2 vs 8.3 ± 1.1,
p
= 0.0001) was reduced. Children treated only with intranasal beclomethasone spray showed no differences in outcome measures before and after treatments. When we considered the oximetry measures, after corticosteroid treatment, we obtained statistical differences between the 2 groups (
p
< 0.01).
Conclusions
These results seem to suggest that a short course of oral betamethasone could be useful to treat children with severe OSAS and adenotonsillar hypertrophy waiting for surgery.
Objective To evaluate the clinical value of basal anti-Müllerian hormone (AMH) measurements compared with other available determinants, apart from chronologic age, in the prediction of ovarian ...response to gonadotrophin stimulation. Design Prospective cohort study. Setting Tertiary referral center for reproductive medicine and an IVF unit. Patient(s) Women undergoing their first cycle of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). Materials and methods Basal levels of FSH and AMH as well as antral follicle count (AFC) were measured in 165 subjects. All patients were followed prospectively and their cycle outcomes recorded. Main Outcome Measure(s) Predictive value of FSH, AMH, and AFC for extremes of ovarian response to stimulation. Result(s) Out of the 165 women, 134 were defined as normal responders, 15 as poor responders, and 16 as high responders. Subjects in the poor response group were significantly older then those in the other two groups. Anti-Müllerian hormone levels and AFC were markedly raised in the high responders and decreased in the poor responders. Compared with FSH and AFC, AMH performed better in the prediction of excessive response to ovarian stimulation–AMH area under receiver operating characteristic curve (ROCAUC ) 0.81, FSH ROCAUC 0.66, AFC ROCAUC 0.69. For poor response, AMH (ROCAUC 0.88) was a significantly better predictor than FSH (ROCAUC 0.63) but not AFC (ROCAUC 0.81). AMH prediction of ovarian response was independent of age and PCOS. Anti-Müllerian hormone cutoffs of >3.75 ng/mL and <1.0 ng/mL would have modest sensitivity and specificity in predicting the extremes of response. Conclusion(s) Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC, and has the potential to be incorporated in to work-up protocols to predict patient's ovarian response to treatment and to individualize strategies aiming at reducing the cancellation rate and the iatrogenic complications of COH.
BACKGROUND
Anti-Müllerian hormone (AMH) is increasingly used to quantify ovarian reserve, but it has not yet realized its full clinical potential in assisted reproduction technology. We investigated ...the possible benefits of using novel, stratified ovarian hyperstimulation protocols, tailored to individual AMH levels, compared with conventional stimulation.
METHODS
Retrospective data were collected from 769 women (first cycle of IVF, using fresh embryos), in a UK tertiary care unit: 346 women using conventional stimulation protocols; 423 women treated under new AMH-tailored protocols.
RESULTS
Embryo transfer rates increased significantly (79–87%: P= 0.002) after the introduction of AMH-tailored stimulation protocols. Pregnancy rate per cycle started and live birth rate also increased significantly compared with conventionally treated women (17.9–27.7%, P= 0.002 and 15.9–23.9%, P = 0.007, respectively). Moreover, in the AMH group, the incidence of the ovarian hyperstimulation syndrome (OHSS) fell significantly (6.9–2.3%, P = 0.002) and failed fertilization fell from 7.8 to 4.5%. The cost of fertility drug treatment fell by 29% per patient and the overall cost of clinical management of OHSS fell by 43% in the AMH group. GnRH antagonist protocols, introduced as part of AMH-tailored treatment, may have contributed to the observed improvements: however, within the AMH-tailored group, the live birth rate was not significantly different between agonist and antagonist-treated groups.
CONCLUSIONS
Although large, prospective, multicentre studies are indicated, we have clearly demonstrated that individualized, AMH-guided, controlled ovarian hyperstimulation protocols significantly improved positive clinical outcomes, reduced the incidence of complications and reduced the financial burden associated with assisted reproduction.
BACKGROUND Hyperandrogenaemia and insulin resistance are prominent features of polycystic ovary syndrome (PCOS) and influence the process of folliculogenesis in women with the endocrinopathy. ...Anti-Müllerian hormone (AMH) levels are elevated in women with PCOS and studies including IVF subjects have shown that this is a reliable marker of ovarian performance. The aims of this prospective study were to assess the relationship between insulin resistance, androgens and AMH, and whether AMH contributes to altered folliculogenesis in non-obese women with PCOS. METHODS A total of 232 IVF candidates, 49 of whom had PCOS according to the Rotterdam 2003 consensus criteria, were recruited. AMH levels and ovarian morphology were assessed. The relationships between AMH and insulin resistance and androgenaemia in patients with and without PCOS were studied. RESULTS PCOS patients were slightly older than controls (median ages 34 and 30 years, respectively). AMH generally increased with antral follicle count (AFC), insulin, homeostatic model assessment of tissue insulin sensitivity (HOMA-IR), testosterone, free androgen index and luteinising hormone, and decreased with chronological age, homeostatic model assessment of steady state beta cell function (HOMA-B) and serum sex hormone binding globulin (SHBG). For these relationships there were no significant differences in the slopes between PCOS and non-PCOS patients. The ratio of AMH per antral follicle (AMH/AF) was higher in PCOS patients. Both PCOS and non-PCOS groups showed a very similar increase in AMH with increases in AFC, but the PCOS patients had consistently higher AMH across all AFC levels. CONCLUSIONS These observations indicate that AMH is similarly related to insulin resistance and androgens in women with and without PCOS. This effect appears to be independent of age although an indirect causal effect due to ageing or some other mechanism cannot be ruled out. Excessive granulosa cell activity may be implicated in the abnormal follicular dynamic of the syndrome.
Chronic intestinal pseudo‐obstruction (CIPO) is a severe form of gastrointestinal dysmotility (often due to derangement of the innervation/smooth muscle/interstitial cells of Cajal) with recurrent ...episodes of intestinal subocclusion mimicking a mechanical obstruction. Because of its complexity and heterogeneity, CIPO is often misdiagnosed or remains unrecognized until advanced stages. Management is a critical aspect in CIPO patient care. So far, most prokinetic drugs have not proven efficacy in restoring intestinal propulsion, thus nutritional support, fluid/electrolyte replacement, and antibiotics are the mainstay of treatment. In this issue of the journal, Ohkubo et al showed promising data indicating that percutaneous endoscopic gastro‐jejunostomy (PEG‐J) can be proposed as a measure for intestinal decompression, thereby improving CIPO‐associated abdominal symptoms, including pain. In addition to a concise update of clinical and diagnostic features, the present minireview tackles management options, with a major emphasis on PEG‐J, for CIPO patients.
Abbreviated : Chronic intestinal pseudo‐obstruction (CIPO) is one of the most severe forms of gastrointestinal dysmotility with many debilitating and potentially life‐threatening symptoms / manifestations. Since most drugs failed to restore gastrointestinal coordinated motility, nutritional support, fluid / electrolyte replacement and antibiotics are still mandatory as life‐saving measures. Promising data indicate that percutaneous endoscopic gastro‐jejunostomy (PEG‐J) can be proposed as a measure for intestinal decompression in CIPO, thereby improving symptoms and preventing malnutrition.
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