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Synopsis: ART‐mediated births declined between December 2020 and February 2021, followed by a rapid recovery to 2019 levels. In 2022, ART‐mediated births exceeded pre‐pandemic rates. [ABSTRACT FROM AUTHOR]

Advanced endometriosis is associated with a reduction of IVF success. Surgical damage to the ovarian reserve following the excision of endometriomas has been claimed as a critical factor in the explanation of this detrimental effect. However, it is generally inferred that other mechanisms might also hamper IVF success in affected women. They include diminished responsiveness to ovarian stimulation, altered steroidogenesis, a decline in oocyte quality, reduced fertilization and embryo development, and impaired implantation. To navigate these limitations, we scrutinized available literature for studies specifically designed to address distinct phases of the IVF process. Utmost consideration was given to intra-patient ovarian response comparisons in women with unilateral endometriomas and to studies applying a meticulous matching to control confounders. The following observations have been drawn: 1) endometriosis has a negligible impact on ovarian response. A slight reduction in stimulation response can only be observed for endometriomas larger than 4 cm. Follicular steroidogenesis is unaffected; 2) oocyte quality is not hampered. Fertilization rates are similar, and intracytoplasmic sperm injection (ICSI) is not justified. Embryonic development is uncompromised, with no increase in aneuploidy rate; 3) endometrial receptivity is either unaffected or only slightly impacted. In conclusion, our study suggests that, aside from the well-known negative effect on ovarian reserve from excisional endometrioma surgeries, endometriosis does not significantly affect IVF outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Random start protocols are commonly used for oocyte cryopreservation in women with cancer. However, albeit generally reassuring, available evidence is still insufficient to rule out a sub-optimal cycle outcome. This study aimed to compare follicular steroidogenesis between women initiating the random start protocol in the luteal phase and those initiating in the follicular phase. Methods: Consecutive women with cancer scheduled for oocyte cryostorage were prospectively recruited. We excluded those requiring a concomitant letrozole assumption. All women received a standardized protocol with recombinant FSH and GnRH antagonists. At the time of oocyte retrieval, follicular fluids were pooled, and a sample was collected and frozen at −80 °C. All samples were assayed concomitantly after thawing by liquid chromatography-tandem mass spectrometry. The concentration of 15 different steroid hormones was determined. Results: Seventy-one women were recruited. Thirty-three initiated the ovarian stimulation in the luteal phase, while the remaining 38 initiated in the follicular phase. Baseline characteristics were generally similar. Cycle outcome did also not differ; the median (interquartile range) number of frozen mature oocytes was 9 (5–14) and 10 (5–21), respectively (p = 0.42). None of the 15 tested steroid hormones differed. Conclusions: The endocrine microenvironment surrounding oocytes is not markedly influenced by the phase of the menstrual cycle at the initiation of ovarian stimulation. This result further supports the validity of random start protocols. [ABSTRACT FROM AUTHOR]

A broader definition of infertility is the incapacity to have the intended number of children. However, most literature on ART exclusively focuses on live birth as an outcome, rather than on the capacity to fully realize the reproductive wishes of the couples. This issue has probably received scant attention because the total fertility rate is below replacement levels in affluent countries, and one may simplistically assume that only a minority of couples may be interested in more than one child. This assumption, however, is unproven and presumably erroneous. Unfortunately, evidence on the rate of return in couples who conceived their first child with ART is scant and information on the intended number of children in infertile couples is lacking. In general, we plea for more research on this subject. The documentation of an intended number of children above two and a high return rate in infertile couples may lead to changes in clinical practice, such as the storage of oocytes or embryos prior to initiating embryo transfers. This could improve the chance of conceiving the second child when the couple comes back some years later. In addition, the identification of the determinants for non-return as well as those explaining the gap between the intended and the realized number of children may reveal specific barriers and possibly how to tackle them. However, at present, available evidence is insufficient to advocate any intervention. Thorough research is warranted. [ABSTRACT FROM AUTHOR]

AGD is the distance measured from the anus to the genital tubercle. Recent evidence suggests that a shorter AGD, a sensitive biomarker of the prenatal hormonal environment, could be associated with higher endometriosis risk. However, studies investigating AGD in affected women are scanty. We have set up a case–control study recruiting nulliparous women (aged 18–40 years) with endometriosis between 2017 and 2018. Cases were 90 women with a surgical or with a current nonsurgical diagnosis of endometriosis (n = 45 deep infiltrating endometriosis (DIE), and n = 45 ovarian endometrioma (OMA)). Controls were 45 asymptomatic women referring for periodical gynaecological care and without a previous diagnosis of endometriosis. They were matched to cases for age and BMI. For each woman, two measures were obtained using a digital calliper: AGDAC, from the clitoral surface to the upper verge of the anus, and AGDAF, from the posterior fourchette to the upper verge of the anus. Each distance was derived from the mean of six measurements acquired from two different gynaecologists. The mean ± SD AGDAC in women with DIE, OMA and without a diagnosis of endometriosis was 76.0 ± 12.1, 76.1 ± 11.1 and 77.8 ± 11.4 mm, respectively (p = 0.55). The mean ± SD AGDAF in women with DIE, OMA and without a diagnosis of endometriosis was 22.8 ± 5.0, 21.7 ± 9.0 and 23.7 ± 7.8 mm, respectively (p = 0.38). Our study failed to find an association between AGD and the presence of endometriosis. AGD does not seem to represent a reliable indicator of the presence of endometriosis to be used in clinical practice. [ABSTRACT FROM AUTHOR]

Background: In pregnancies obtained by in-vitro fertilization (IVF) the exact day of conception is known. For that reason, IVF pregnancies are currently dated according to the day of oocytes retrieval and consequent embryo transfer. The aim of the present study is to determine whether the knowledge of the exact day of conception in IVF pregnancies is a sufficient argument against dating these pregnancies by first trimester ultrasound measurement of the crown-rump length (CRL), as it is recommended in natural conceptions. Methods: A retrospective study was performed, including all women with singleton pregnancies conceived by IVF who underwent the first-trimester ultrasound scan for the screening of aneuploidies between January 2014 and June 2019. For each pregnancy GA was determined using two alternative methods: one based on the date of embryo transfer (GAIVF), and one based on ultrasound measurement of CRL (GAUS). GA were compared to search for any discrepancy. The impact of pregnancy dating on obstetric outcome was evaluated. Results: Overall, 249 women were included. Comparing GAUS and GAIVF, a median difference of 1 [0 – 2] days emerged (p<0.001), with GAUS being in advance compared to GAIVF. This discrepancy persisted when subgroups were analyzed comparing different IVF procedures (conventional IVF versus ICSI, cleavage versus blastocyst transfer, frozen versus fresh transfer). No impact of the dating method on obstetric outcomes was observed, being no differences in the rate of preterm birth or abnormal fetal growth. Conclusions: In IVF pregnancies GAUS and GAIVF are not overlapping, since GAUS is mildly greater than GAIVF. This could be due to an anticipated ovulation and fertilization in IVF pregnancy, rather than an accelerated embryo development. For that reason, it would be appropriate to date IVF pregnancies according to GAUS, despite a known date of conception, to re-align IVF pregnancies to natural ones. [ABSTRACT FROM AUTHOR]

Background: The epidemiology of adenomyosis has been traditionally based on patients undergoing hysterectomy for gynecological indications, while its prevalence among hysterectomies performed for obstetric complications is unknown. The aim of this study was to assess the prevalence and clinical impact of adenomyosis diagnosed through histology among women undergoing pregnancy-related hysterectomy (PH). Methods: This was a retrospective cohort study. Women who delivered at a tertiary care regional obstetric hub in Milan between 2009 and 2020 were reviewed to identify cases of PH. Histopathological reports of surgical specimens were examined. Cases with adenomyosis were compared to those without adenomyosis for baseline characteristics, obstetric history and outcomes. Results: During the study period there were 71,061 births and a total of 130 PH, giving a PH incidence of 1.83 per 1000 deliveries. Adenomyosis cases were 18, giving a prevalence of 13.8%. Adenomyosis was associated with placenta previa (77.8 vs. 45.5%, p = 0.01), chorionamnionitis (27.8 vs. 5.4%, p = 0.008), lower gestational age at birth (32 ± 4.6 vs. 35.5 ± 3.6 weeks' gestation, p = 0.0004), and intrauterine fetal demise among twin pregnancies (50 vs. 4.5%, p = 0.048). Conclusion: Adenomyosis entails a relevant impact on obstetric and perinatal outcomes related to PH. More evidence is needed on the clinical relevance of an ultrasonographic diagnosis of adenomyosis before conception. [ABSTRACT FROM AUTHOR]

How endometriosis causes infertility, with the exception of tubal dysfunction caused by adhesions, is unclear. The inflammatory milieu in the pelvis and impaired receptivity of the eutopic endometrium are considered to be possible factors. Anatomical staging systems fail to predict the fertility status of endometriosis patients. Data from assisted reproductive technology cycles consistently suggest that oocytes from patients with endometriosis have a normal potential to develop into euploid blastocysts. Moreover, oocyte or embryo recipients with endometriosis seem to have similar or slightly lower pregnancy and live birth rates compared with recipients without endometriosis, suggesting that eutopic endometrium is not or is only minimally affected, which may be caused by undiagnosed adenomyosis. In-vivo observations from women with endometriomas provide evidence against a detrimental effect of endometriomas on oocytes. Combined with the absence of an obvious improvement in fertility following the surgical destruction or excision of peritoneal endometriosis or from temporary medical suppression of the disease and the associated inflammation, the available evidence makes endometriosis-associated infertility questionable in the absence of tubal dysfunction caused by adhesions. It is likely that no anatomical staging will correlate with fertility beyond assessing tubal function. In patients with endometriosis assisted reproductive technology is as effective as for other indications. [ABSTRACT FROM AUTHOR]

Background: Gonadotropins represent an important component of IVF costs. In order to reduce costs, much attention was given to the type of gonadotropins (recombinant versus urinary) and the daily dose. In this study, we decided to focus on gonadotropin wastage, a neglected aspect that may harbor a relevant source of useless economic expenditure.Materials and Methods: Women who performed oocytes collection following ovarian hyperstimulation with gonadotropins in two Italian IVF Centers were prospectively recruited. They were interviewed using a standardized questionnaire aimed at capturing drug wastage. Physicians of the participating units were blinded to the study. Recruited women were requested to hide their participation to their physicians.Results: Three-hundred nine women were recruited. Two hundred eighty-eight (93 %; 95 %CI: 90-96 %) reported to have wasted some drug. For the whole cohort, the median [Interquartile range] IUs of drug used and drug wasted was 2,100 [1,575 - 2,850] and 825 [400 - 1,200], respectively. This corresponds to a median increase in the costs of ovarian hyperstimulation of 39 %. When data on wastage was analyzed separately for the different available drugs, a statistically significant difference emerged (p = 0.026). Reasons behind this difference could not be clearly disentangled.Conclusions: IVF is associated with a considerable wastage of gonadotropins. Improving this aspect can allow to reduce the costs of the procedure. [ABSTRACT FROM AUTHOR]

Background: Anti-Müllerian hormone (AMH) serum concentration and antral follicle count (AFC), as measured by transvaginal ultrasonography, accurately reflect the antral follicle pool. However, AMH and AFC association with fertility surrogates (i.e. age at menopause, probability of conceiving naturally and ART success rate) is questioned. Miscarriage is often considered an alternative measure of reproductive capacity. Nonetheless, the impact of diminished ovarian reserve (DOR) on miscarriage incidence remains an understudied and unresolved issue.Objective and Rationale: The aim of this systematic review and meta-analysis was to elucidate associations between DOR and miscarriage risk, both in women who conceived naturally and in those who achieved pregnancy through ART.Search Methods: Relevant studies were identified by a systematic search in PubMed, MEDLINE, Embase and Scopus, from database inception to 1 March 2021. Studies were included only if all the following conditions were met: DOR was defined using serum AMH concentration or AFC; miscarriage rate was reported separately for different groups of women categorized according to the AMH and/or AFC level; authors reported either the rate of intrauterine pregnancy loss before 22 weeks of gestation or enough data were available to calculate it.Outcomes: From a total of 347 publications initially identified, 16 studies were included. Pooled results from 13 retrospective studies focusing on ART pregnancies showed a significantly higher rate of miscarriage in women with a low AMH, as compared to women with a medium or high serum AMH concentration (12 042 women, random effects model, odds ratio (OR) 1.35; 95% CI, 1.10-1.66; P = 0.004; I2=50%). The only prospective study on ART pregnancies failed to show any association (61 women, risk ratio (RR) 2.95; 95% CI, 0.66-3.18; P = 0.16). Data from two prospective studies, which included naturally conceived pregnancies, showed a significantly increased miscarriage risk for women with low serum AMH. However, these data could not undergo meta-analysis owing to differing study designs. Using three retrospective studies, we observed an association between low AFC and miscarriage incidence (three retrospective studies on ART pregnancies, random effects model, OR 1.81; 95% CI, 1.02-3.21; P = 0.04; I2=64%).Wider Implications: Our meta-analysis findings suggest that within the DOR patient subgroup, serum AMH and AFC biomarker levels may correlate with both the quantitative and qualitative aspects of ovarian reserve. However, owing to study limitations, the aetiology of this effect remains unclear and we are unable to define a causal relationship between DOR and increased miscarriage or to provide clinical recommendations based on this information. However, if confirmed by future well-designed studies, these findings would be profoundly informative for guiding women in family planning decisions. [ABSTRACT FROM AUTHOR]

Most proposed definitions of recurrent implantation failure (RIF) are based on clinical judgement, probably affected by patients' demands. They are not based on robust statistical considerations. As a result, a diagnosis of RIF is commonly made too early, exposing couples to the risk of overdiagnosis and overtreatment. However, the situation is changing, and three statistical approaches have recently been proposed. The first is a probability model based on the chances of success per cycle and suggests for the definition three failed oocyte retrieval cycles with all embryos being transferred in women younger than 40 years of age. The second approach suggests an individualized diagnosis that takes into consideration multiple factors, while the third is also based on individualization but mainly relies on anticipated euploidy rates across the female age range. All these approaches have their pros and cons. Regardless of the specific peculiarities, they represent steps in the right direction, with the intent of providing a statistically sound definition. However, these attempts will not be useful unless endorsed by the scientific community in general. There is a pressing need for a rigorous and shared definition of RIF that will be widely accepted by researchers, scientific societies and other stakeholders, including patients. [ABSTRACT FROM AUTHOR]

Purpose: The risk of monozygotic (MZT) twinning is increased in pregnancies after assisted reproductive technologies (ART). However, determinants remain poorly understood. To shed more light on this issue, we analyzed the estimated frequency of MZT twins from ART in Lombardy, Northern Italy, during the period 2007–2017. Methods: This is a population-based study using regional healthcare databases of Lombardy Region. After having detected the total number of deliveries of sex-concordant and sex-discordant twins from ART, we calculated MZT rate using Weinberg's method. Standardized ratios (SRs) and corresponding 95% confidence intervals (CI) of MZT deliveries, adjusted for maternal age, were computed according to calendar period, parity, and type of ART. Results: On the whole, 19,130 deliveries from ART were identified, of which 3,446 were twins. The estimated rate of MZT births among ART pregnancies was higher but decreased over time (p-value = 0.03); the SRs being 1.33 (95% CI: 1.18–1.51), 0.96 (95% CI: 0.83–1.11), and 0.92 (95% CI: 0.79–1.07) for the periods 2007–2010, 2011–2014, and 2015–2017, respectively. The SRs of MZT among women undergoing first-level techniques, conventional in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) were 0.47 (95% CI: 0.38–0.57), 1.02 (95% CI: 0.88–1.17), and 1.43 (95% CI: 1.27–1.61) (p-value < 0.0001). The ratio of MZT births was significantly higher in women younger than 35 years (p-value < 0.0001) and slightly higher among nulliparae (p-value < 0.0001). Conclusion: Despite a reduction of MZT rate from ART over the time, the risk remains higher among ART pregnancies rather than natural ones. Younger women and women undergoing ICSI showed the highest risk of all. [ABSTRACT FROM AUTHOR]

Available evidence from IVF studies supports a detrimental effect of submucosal and intramural fibroids on embryo implantation. It is misleading, however, to infer evidence obtained in IVF settings to natural fertility. Therefore, a systematic review and meta-analysis was conducted on the effect of fibroids on natural fertility. Studies comparing fertile and infertile women, and those investigating whether the presence of fibroids was a risk factor, were reviewed, as well as studies comparing women with and without fibroids. The aim was also to establish whether the frequency of infertility differed between the two groups. Seven out of 11 selected studies did not aim to establish whether fibroids caused infertility but, rather, whether a history of infertility could be a risk factor for fibroids. A meta-analysis of the four remaining studies that concomitantly evaluated the presence of fibroids and infertility studies highlighted a common odds ratio of fibroids in subfertile women of 3.54 (95% CI 1.55 to 8.11). When focusing on the two most informative studies, i.e. the studies comparing time to pregnancy in women with and without fibroids, the common OR was 1.93 (95% CI 0.89 to 4.18). In conclusion, the association between fibroids and infertility has been insufficiently investigated. Epidemiological studies suggest, but do not demonstrate, that fibroids may interfere with natural fertility. Given the high prevalence of these lesions in women seeking pregnancy, further evidence is urgently needed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether sperm banking is under-used in adolescents with cancer.Study Design: We reviewed our 33 years long experience of semen cryopreservation and identified male subjects with cancer aged 14-21 years who banked their sperm. We hypothesized as a referring model a constant rate of referral in every age category (uniform distribution). In addition, we evaluated whether the distribution of the referrals per age varied according to historical periods and compared semen quality in the different age groups.Results: Overall, 317 subjects were selected. A sharp increase with age emerged (p < 0.001): the number of cases augmented from 4 at age 14 years to 79 at age 21 years. This significant increase persisted even when focussing only on subjects older than 16-18 years. An improvement of the distribution of cases per age group emerged when limiting the analysis to the last decade of activity; however, the increase remained significant (p < 0.001). Finally, we investigated whether semen quality differed according to age groups and failed to show marked differences, suggesting that sperm banking even at the youngest ages could be of potential benefit.Conclusions: This study confirmed that sperm banking is under-used in adolescents with cancers. Future studies should better clarify the determinants of this low referral and identify interventions that can improve the situation. [ABSTRACT FROM AUTHOR]

In recent years, increasing efforts have been made to develop advanced techniques that could predict the potential of implantation of each single embryo and prioritize the transfer of those at higher chance. The most promising include non-invasive preimplantation genetic testing for aneuploidy and artificial intelligence-based algorithms using time lapse images. The psychological effect of these add-ons is neglected. One could speculate that embarking on another transfer after one or more failures with the prospect of receiving an embryo of lower potential may be distressing for the couple. In addition, the symbolic and mental representation of an embryo with 'lower capacity to implant' is currently unknown but could affect couples' choices and wellbeing. These emotional responses may also undermine adherence to the programme and, ultimately, its real effectiveness. Future trials aimed at evaluating the validity of prioritization procedures must also consider the emotional burden on the couples. [ABSTRACT FROM AUTHOR]

The aim of the present systematic review and meta-analysis was to assess the effect of the different therapeutic options for repeated embryo implantation failure (RIF) on a subsequent IVF cycle outcome. Twenty-two RCTs and nineteen observational studies were included. Pooling of results showed a beneficial effect of intrauterine PBMC infusion on both CPR (RR 2.18; 95% CI 1.58–3.00; p < 0.00001; OR 2.03; 95% CI 1.22–3.36; p = 0.006) and LBR (RR 2.41; 95% CI 1.40–4.16; p = 0.002; OR 3.73; 95% CI 1.13–12.29; p = 0.03), of subcutaneous G-CSF administration on CPR (RR 2.29; 95% CI 1.58–3.31; p < 0.0001) and of intrauterine PRP infusion on CPR (RR 2.45; 95% CI 1.55–3.86; p = 0.0001). Observational studies also demonstrated a positive effect of IVIG and intrauterine hCG infusion on both CPR and LBR and of atosiban on CPR. Studies investigating intrauterine G-CSF infusion, LMWH, intravenous intralipid, hysteroscopy, blastocyst-stage ET, ZIFT, PGT-A and AH failed to observe an impact on IVF outcome. The quality of the evidence that emerged from RCTs focused on intrauterine PBMC infusion and subcutaneous G-CSF administration was moderate. For all other therapies/interventions it varied from low to very low. In conclusion, intrauterine PBMC infusion and subcutaneous G-CSF administration are the most promising therapeutic options for RIF. However, further well conducted RCTs are necessary before their introduction into clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Modern strategies for the screening and diagnosis of Gestational Diabetes Mellitus (GDM) rely on universal Oral Glucose Tolerance Test (OGTT). However, they are unsustainable in low-income countries. In this study, we aimed at assessing the feasibility of a simplified diagnostic policy. Methods: The study took place in an urban referral hospital in Freetown, Sierra Leone. During an 11-month period, pregnant women were offered capillary blood test for glucose assessment. They could be screened at any time during pregnancy. GDM was diagnosed if fasting glucose was ≥ 92 mg/dl or if the OGTT was positive. The latter was prescribed only to women presenting after 24 weeks' gestation with at least one risk factor for GDM and fasting capillary glucose between 85 and 91 mg/dl. A definitive diagnosis required confirmation to this aim, women with values above the thresholds were invited to refer the next working day for repeating the test after fasting overnight. Results: Overall, 7827 women were referred for screening, of whom 6872 (87%) underwent at least one capillary glucose assessment. However, 895 of those who had a positive test did not return for confirmation. Overall, a definite assessment could be done in 5799 subjects corresponding to 76% (95% CI 75–77%) of those eligible. GDM was diagnosed in 128 women (1.9%, 95% CI 1.6–2.2%). Based on an expected confirmation rate of 22% (calculated from those who referred for confirmation) in the 895 women who did not come back, one could infer that GDM would have been diagnosed in additional 197 women, raising the prevalence to 4.7% (95% CI 4.2–5.3%). Conclusion: Three quarters of subjects could be assessed with our approach. Data also suggest that GDM is not rare even if identification of affected cases remains challenging. [ABSTRACT FROM AUTHOR]

Available evidence shows that the presence of ovarian endometriomas does not interfere with the ovarian response to ovarian stimulation. However, the mean size of the endometriomas in these studies is generally small, and two recent investigations suggested that follicular development could be impaired when focusing on larger endometriomas. However, these studies could not identify a clear threshold above which endometriomas could become detrimental. To identify this threshold, the study retrospectively selected women without a history of surgery for ovarian cysts who underwent IVF in the presence of unilateral endometriomas with a mean diameter between 20 and 49 mm. Selected women were divided into three categories of endometrioma size: 20–29 mm (group 1, n = 23), 30–39 mm (group 2, n = 2323), and 40–49 mm (group 3, n = 2321). Recruitment for each category was censored at about 21 women to ensure equal statistical power for each group. The response to ovarian stimulation was equal or superior in the affected gonads in eight women (35%, 95% confidence interval [CI] 16–57%), seven women (30%, 95% CI 13–53%) and two women (10%, 95% CI 2–30%) in groups 1, 2 and 3, respectively. The median (interquartile range) number of developed follicles in the affected and intact ovaries was 6 (3–7) and 5 (4–9) in group 1 (P = 0.21), 4 (1–6) and 4 (3–7) in group 2 (P = 0.08), 5 (3–7), and 7 (4–8) in group 3 (P = 0.01), respectively. The threshold to be used to distinguish between endometriomas that might and might not interfere with ovarian response is 4 cm in diameter. [ABSTRACT FROM AUTHOR]

The advent of random start protocols to shorten the time needed to store oocytes in women with malignancies has represented an important improvement in the field of fertility preservation. However, Randomized Controlled Trials are difficult to implement in this area and available evidence that supports this approach remains modest. To shed more light on this issue, we compared the follicular development between the ovary carrying the dominant follicle or the corpus luteum and the contralateral resting ovary in 90 women who underwent random start controlled ovarian stimulation (COS). In fact, ovarian response did not differ between the two ovaries. Subgroup analyses according to the phase of the cycle at the initiation of COS, the type of malignancy, the use of letrozole and the magnitude of the ovarian response did not allow to identify any condition showing a difference in the follicular response between the active and the resting ovaries. In conclusion, follicular growth does not seem to be perturbed by the presence of a dominant follicle or a corpus luteum. [ABSTRACT FROM AUTHOR]

Natural fecundity and the success of IVF and intracytoplasmic sperm injection (ICSI) rate both decrease with age. For this reason, in women older than 35 years, it is generally recommended to start the infertility work-up after only 6 months. This assumption, however, may expose couples to over-diagnosis and over-treatment. A theoretical model aimed at assessing the effects of starting the infertility work-up after 6 rather than 12 months of trying to conceive naturally was developed. The assumptions of the model were as follows: infertile women are treated with IVF/ICSI for up to three cycles; IVF/ICSI success rate at first cycle linearly declines with age (3% per year between the ages of 35 and 45 years); the drop-out rate after the first and second cycle is 18% and 25%, respectively; the relative reduction of the success rate at second and third cycle is 16% and 26%, respectively. Early initiation of treatment moderately improved the cumulative chances of live birth resulting from a full IVF/ICSI programme. This improvement is dependent on age. Specifically, it increased from 2.0% at age 35 years to 3.0% at age 43 years. Conversely, the incremental success rate per single IVF cycle was mainly stable, varying only from 1.4% at age 35 years to 1.3% at age 43 years. In women older than 35 years, early initiation of the infertility work-up is associated with only a modest increase in the rate of success of IVF/ICSI. In most scenarios, this advantage may compare unfavourably with the chances of natural conception during the 6-month period. [ABSTRACT FROM AUTHOR]

A consistent body of in vitro evidence supports a detrimental effect of endometriosis on ovarian steroidogenesis, in particular the synthesis of estrogens. However, clinical evidence is scanty and methodologically weak. This study aimed at clarifying whether peripheral 17-β-estradiol during IVF are influenced by the presence of endometriosis. Women undergoing IVF were retrospectively reviewed. Cases were women with a diagnosis of endometriosis. Controls were matched to cases in a 1:1 ratio by study period, age, total number of developed follicles on the day of hCG administration, protocol of hyperstimulation, gonadotropin used, and starting dose. The primary outcome was the ratio between serum levels of 17-β-estradiol and the total number of developed follicles. Fifty-three women with endometriosis and 53 controls were selected. The median ratio (interquartile range) between serum 17-β-estradiol and the total number of developed follicles in the two groups was 207 (164–282) and 201 (144–268) pg/ml, respectively (p = 0.46). Sensitivity analyses on the magnitude of the follicular response, the history of surgery for endometriomas, and the presence of endometriomas did not show any subgroup at increased risk of peripheral estrogens impairment. Endometriosis does not influence peripheral levels of 17-β-estradiol during IVF. Our findings argue against a biologically relevant effect of the disease on ovarian estrogen-synthesis. [ABSTRACT FROM AUTHOR]

Several pathogenetic mechanisms have been postulated to explain the association between endometriosis and subfertility. However, to date, definitive conclusions cannot be drawn. In this study, we hypothesized that the reduced exploitation of the natural chances of conception could be an additional detrimental factor. Due to dyspareunia or the need for hormonal treatment to temper pelvic pain, one may expect affected women to exploit less the chances of natural pregnancy. In this cross-sectional study of 292 women undergoing IVF, we investigated the severity of pelvic pain symptoms, the sexual function (using the Female Sexual Function Index [FSFI]), and the reproductive strategies of women with (n = 62) and without (n = 230) endometriosis. Basal clinical and demographic characteristics did not differ between the two groups. Conversely, all pelvic pain symptom scores were increased in women with endometriosis. Endometriosis patients also showed greater pain at the FSFI, but no other significant differences were detected as regards sexual function. The use of hormonal contraceptive agents did not differ between the study groups. Moreover, questions aimed at disentangle whether affected women exploited less the natural chances of pregnancy did not reveal any significant difference. In conclusion, this study does not support the hypothesis that women with endometriosis exploit less the chances of natural pregnancy, despite the presence of pelvic pain. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does endometriosis prevalence differ in patients with obstructive Müllerian anomalies (OMA) versus those with nonobstructive Müllerian anomalies (NOMA), and in patients with NOMA versus those without Müllerian anomalies? SUMMARY ANSWER The quantitative synthesis of published data demonstrates a substantially increased prevalence of endometriosis in patients with OMA compared with those with NOMA, and a similar prevalence in patients with NOMA and those without Müllerian anomalies. WHAT IS KNOWN ALREADY The pathogenesis of endometriosis has not been definitively clarified yet. A higher prevalence of endometriosis in patients with OMA than in those with NOMA would support the retrograde menstruation (RM)/implantation theory, whereas a higher prevalence of endometriosis in the NOMA group than in the group without Müllerian anomalies would support the embryonic remnants/celomic metaplasia hypothesis. STUDY DESIGN, SIZE, DURATION This systematic review with meta-analysis was restricted to full-length, English-language articles published in peer-reviewed journals between 1980 and 2023. The PubMed and EMBASE databases were searched using the keyword 'endometriosis' in combination with 'Müllerian anomalies', 'obstructive Müllerian anomalies', 'female genital malformations', 'retrograde menstruation', 'infertility', 'pelvic pain', and 'classification'. References from relevant publications were screened, and PubMed's 'similar articles' and 'cited by' functions were used. PARTICIPANTS/MATERIALS, SETTING, METHODS Studies were selected if they reported the prevalence of surgically confirmed endometriosis in either individuals with OMA compared to those with NOMA, or patients with NOMA compared to those without Müllerian anomalies. Cohort and case-control studies and case series were deemed eligible for inclusion. Noncomparative studies, studies not reporting both the number of individuals with endometriosis and the total number of those with Müllerian anomalies or with other gynecological conditions, those including exclusively data on patients with absent or uncertain menstrual function (e.g. complete Müllerian agenesis category), or with imperforate hymen were excluded. Two reviewers independently abstracted data. The risk of bias was assessed with the Risk of Bias In Non-randomized Studies of Exposures tool. The overall certainty of the evidence was graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. MAIN RESULTS AND THE ROLE OF CHANCE Seven retrospective studies were included. The overall mean estimate of endometriosis prevalence was 47% (95% CI, 36–58%) in patients with OMA, and 19% (95% CI, 15–24%) in patients with NOMA, with a common odds ratio (OR) of 4.72 (95% CI, 2.54–8.77). The overall mean estimate of endometriosis prevalence in patients with NOMA was 23% (95% CI, 20–27%), and that in patients without Müllerian anomalies was 21% (95% CI, 20–22%), with a common OR of 0.95 (95% CI, 0.57–1.58). The overall certainty of the evidence according to GRADE guidelines was judged as low for both comparisons. LIMITATIONS, REASON FOR CAUTION Some NOMA subtypes may create a partial obstacle to menstrual efflux and/or generate dysfunctional myometrial contractions that favor transtubal reflux, thus increasing the risk of endometriosis and limiting the difference between OMA and NOMA. As infertility and pelvic pain are strongly associated with endometriosis, women with these symptoms are inappropriate controls. Confounding by indication could explain the lack of difference in endometriosis prevalence between patients with NOMA and those without Müllerian anomalies. WIDER IMPLICATIONS OF THE FINDINGS The results of this meta-analysis support the validity of the RM theory but do not definitively rule out alternative hypotheses. Thus, RM may be considered the initiator for the development of endometriotic lesions, while not excluding the contribution of both inheritable and tissue-specific genetic and epigenetic modifications as disease-promoting factors. STUDY FUNDING/COMPETING INTEREST(S) No funding was received for this review. P.Ve. is a member of the Editorial Board of Human Reproduction Open , the Journal of Obstetrics and Gynaecology Canada , and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica ; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate; and maintains both a public and private gynecological practice. E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest. REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

What effects did the early phase of the COVID-19 pandemic have on natural and assisted reproductive technology (ART)-mediated birth rates? Regional registries were consulted with permission from the Health Authorities of Lombardy Region, Northern Italy, an area particularly affected by the early phase of the epidemic. Deliveries occurring in the area between 1 January 2019 and 31 December 2020 from women beneficiaries of the National Health System and resident in Lombardy were identified. Comparisons mainly focused on December 2020, when women who conceived after 8 March (the start of the stringent lockdown imposed by the authorities) were expected to deliver. When comparing the periods January to November in 2019 and 2020, a 5.1% reduction of monthly general birth rate (from 5732 in 2019 to 5438 in 2020) was observed. The contribution of ART births was similar in 2019 and 2020, being 4.4% and 4.5%, respectively. In December 2020, a notable drop in natural (–17.8%), ART-mediated (–86.6%) and overall (–21.0%) births was observed compared with December 2019. After adjusting for the expected 5.1% reduction, the inferred effect of the COVID-19 crisis corresponded to a 16.7% reduction in birth rate, of which 76% was related to natural (707 births) and 24% to ART (218 births) conceptions. This is the first study providing population-based evidence on the effects of COVID-19 and its related stringent restrictions on birth rates. The birth rate was dramatically reduced following the critical period, and the closure of ART centres played only a marginal role (24%) in the overall detrimental effect. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the economical benefit of preimplantation genetic testing of aneuploidies (PGT-A) when applied in an extended culture and stringent elective single ET framework.Design: Theoretical cost-effectiveness study.Setting: Not applicable.Patients/animal(s): None.Intervention(s): Comparison of the cost-effectiveness between two IVF treatment strategies: serial transfer of all available blastocysts without genetic testing (first fresh transfer and subsequent frozen-thawed transfer); and systematic use of genetic testing (trophectoderm biopsy, freeze-all, and frozen-thawed transfers of euploid blastocysts). The costs considered for this analysis are based on regional public health system provider.Main Outcome Measure(s): Costs per live birth.Result(s): Cost-effectiveness profile of PGT-A improves with female age and number of available blastocysts. Sensitivity analyses varying the costs of ET, the costs of genetic analyses, the magnitude of the detrimental impact of PGT-A on live birth rate, and the crude live birth rates change to some extent the thresholds for effectiveness but generally confirm the notion that PGT-A can be economically advantageous in some specific subgroups.Conclusion(s): PGT-A can be cost-effective in specific clinical settings and population groups. Economic considerations deserve attention in the debate regarding the clinical utility of PGT-A. [ABSTRACT FROM AUTHOR]

Study Question: Is infertility-related distress a risk factor for impaired female sexual function in women undergoing assisted reproduction?Summary Answer: Infertility-related distress, and especially social, sexual, and relationship concerns, is associated with female sexual dysfunction.What Is Known Already: Women with infertility are more likely to present sexual dysfunction relative to those without infertility. Moreover, assisted reproduction is associated with increased risk for female sexual problems. To date, this higher proportion of sexual impairment in infertile women has been simplistically linked to the stress associated with the condition and investigated risk factors included mainly demographic and clinical variables. Quantitative studies aimed at identifying risk factors for sexual dysfunction that also included the evaluation of infertility-related distress are conversely lacking.Study Design, Size, Duration: This observational study was conducted at the Infertility Unit of the Fondazione Ca' Granda, Ospedale Maggiore Policlinico of Milan between 2017 and 2018.Participants/materials, Setting, Methods: We included 269 consecutive patients with infertility aged 24-45 (37.8 ± 4.0 years). Sexual function outcomes were sexual dysfunction (assessed with the Female Sexual Function Index), sexual distress (evaluated with the Female Sexual Distress Scale-Revised), dyspareunia, and number of intercourses in the month preceding ovarian stimulation. Infertility-related distress was measured with the Fertility Problem Inventory (FPI). The effects of potential confounders such as demographic variables (women's and partners' age and level of education) and infertility-related factors (type and cause of infertility, number of previous IVF cycles, and duration of infertility) were also examined.Main Results and the Role Of Chance: Women with higher infertility-related distress were more likely to report sexual dysfunction (odds ratio = 1.02 per point of score; 95% CI, 1.01-1.03; P = 0.001). Three FPI domains (i.e. social, relational, and sexual concerns) were correlated with almost all sexual function outcomes (Ps < 0.05).Limitations, Reasons For Caution: Women who were not sexually active were not included, thus reasons for sexual inactivity should be further explored in future studies. Data regarding men (e.g. sexual function and infertility-related distress) were lacking, thus cross-partner effects were not examined. Recall bias (also due to the fact that questionnaires were administered on the day of oocytes retrieval) and social desirability bias may have also affected women's responses to the questionnaires.Wider Implications Of the Findings: Social, relational, and sexual concerns should be assessed and addressed in psychological counselling with the infertile couple.Study Funding/competing Interest(s): None.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Chemotherapy during childhood damages ovarian reserve and can affect future fertility. However, recent large epidemiological studies showed that the detrimental impact on fertility is less severe if women seek for pregnancy at a younger age. To explain this observation, we hypothesize that the detrimental effects of previous chemotherapy on the ovarian reserve may be attenuated in young adults for two main reasons. Firstly, recent evidence showed that the amount of ovarian reserve is not a critical factor for effective natural conceptions. Provided that the residual ovarian reserve allows regular ovulatory cycles, the chances of pregnancy are similar in women with intact or reduced ovarian reserve. Secondly, ovarian reserve depletion appears to be a phenomenon that is inversely related to the residual ovarian reserve rather than to age. From a mathematical perspective, this kind of regulation intrinsically attenuates the effects of an early loss of a significant amount of primordial follicles. In conclusion, the detrimental effects of chemotherapy on natural fertility may be less severe if women with a history of chemotherapy during childhood seek for pregnancy early. This information should be part of the counseling. [ABSTRACT FROM AUTHOR]

The immunomodulatory, anti-inflammatory, and antiproliferative properties of vitamin D have laid the basis for a possible function of this prohormone in the pathogenesis of endometriosis. The aim of this case-control study was to investigate vitamin D status, by measuring 25-hydroxyvitamin D [25(OH)D] serum levels, in women with and without endometriosis. Only Italian women of Caucasian origin aged between 18 and 45 years were deemed eligible. Enrollment was limited to the period October to May. Cases and controls were matched for month of recruitment and secondarily for age and parity. Overall, 434 women were enrolled (endometriosis n = 217; controls n = 217). The group of cases included 127 women with ovarian endometrioma and 90 patients with deep endometriosis. Mean (standard deviation) levels of 25(OH)D in women with and without endometriosis were 17.9 (7.0) ng/mL and 18.4 (7.6) ng/mL, respectively (P = .46). Analyzing the two endometriosis subgroups separately, no statistically significant differences emerged (18.7 [7.4] ng/mL in deep endometriosis group vs 17.3 [6.6] ng/mL in women with ovarian endometrioma; P = .14). Comparing the subgroup of women with deep endometriosis with paired controls, no differences occurred (18.7 [7.4] ng/mL vs 18.5 [7.7] ng/mL, P = .80). Similar data emerged when performing the same analysis for ovarian endometriomas (17.4 [6.6] ng/mL vs 18.3 [7.6] ng/mL, P = .23). The results of the present case-control study do not support an association between serum vitamin D levels and different phenotypes of endometriosis. [ABSTRACT FROM AUTHOR]

Abstract Available evidence on the impact of ovarian stimulation on the progression of endometriosis or its recurrence was systematically reviewed. Data from ovarian stimulation alone, or associated with intrauterine insemination (IUI) or IVF, were included. Sixteen studies were selected. Initial case reports (n = 11) documented some severe clinical complications. However, subsequent observational studies were more reassuring. Overall, five conclusions can be drawn: (i) IVF does not worsen endometriosis-related pain symptoms (moderate quality evidence); (ii) IVF does not increase the risk of endometriosis recurrence (moderate quality evidence); (iii) the impact of IVF on ovarian endometriomas, if present at all, is mild (low quality evidence); (iv) IUI may increase the risk of endometriosis recurrence (low quality evidence); (v) deep invasive endometriosis might progress with ovarian stimulation (very low quality evidence). In conclusion, available evidence is generally reassuring (at least for IVF) and does not justify aggressive clinical approaches such as prophylactic surgery before assisted reproductive technology treatment to prevent endometriosis progression or recurrence. However, further evidence is required before being able to reach definitive conclusions. In particular, the potential effects on deep invasive endometriosis and the possible synergistic effect of stimulation and pregnancy are two areas that need to be explored further. [ABSTRACT FROM AUTHOR]

Objective: To explore the potential benefits of pregnancy on endometriosis symptoms. This is a retrospective study that has been conducted at Academic department and referral center for endometriosis.Study Design: We included all conservative women who had a live birth after at least one surgery for endometriosis and who reported pre-pregnancy moderate to severe pelvic pain symptoms (at least one among dysmenorrhea, deep dyspareunia, non menstrual pelvic pain and dyschezia). Data were collected before pregnancy and two years after delivery. The main aim of the study was comparing endometriosis-related pain symptoms before and after pregnancy. Mental health and quality of life were also assessed to investigate the possible psychological benefits of pregnancy.Results: One-hundred thirty- one women were identified. Forty- nine women (37%, 95% CI: 29-47%) had a clinically relevant recurrence of symptoms requiring medical or surgical treatment. Two years after delivery, 84% of women (95% CI 77-90%) reported at least one moderate-severe pain symptom. A statistically significant improvement was observed for HADS and SF-12 scores but not for FSFI.Conclusion: Women with endometriosis experiencesymptoms relief during and immediately after pregnancy. However, as for hormonal medical therapy, symptoms rapidly recur in the vast majority of cases. [ABSTRACT FROM AUTHOR]

The most common definition of repeated implantation failure (RIF) is the failure to obtain a clinical pregnancy after three completed IVF cycles. This definition, however, may lead to misuse of the diagnosis. To disentangle this, we set up a mathematical model based on the following main assumptions: rate of success of IVF constant and set at 30%; and RIF postulated to be a dichotomous condition (yes or no) with a prevalence of 10%. On this basis, the expected cumulative chance of pregnancy after three and six cycles was 59% and 79%, respectively. Consequently, the false–positive rate of a diagnosis of RIF is 75% and 51%, respectively. Increasing the rate of success of IVF or the prevalence of RIF lowers but does not make unremarkable the rate of false–positive diagnoses. Overall, this model shows that the commonly used definition of RIF based on three failed attempts in a standard population with good prognosis leads to over-diagnosis and, potentially, to over-treatments. [ABSTRACT FROM AUTHOR]

Gender inequalities in Sub-Saharan Africa are deemed relevant but data to support this view are scanty. Retrospective analysis of a large dataset of 105,025 patients admitted to an Ethiopian rural private, non-for-profit hospital over a 11 years period (2005-2015). Since 2001, the hospital and the local community are involved in a long-term, comprehensive and externally-supported health care intervention. The total number of admissions was higher for females (61.9% of the total) mainly because of the high frequency of admissions for obstetrics conditions. The total male-to-female ratio (M:F) was 0.6. Except for malaria, men had more admissions for the other leading causes, with the highest M:F being found for injuries (2.7) and musculoskeletal diseases (1.7). Overall, excluding admissions for pregnancy-related issues, the M:F was 1.4. The frequency of admissions changed with age and gender. Female admissions prevailed in the reproductive age period (from 15 to 44 years of age) while males admissions prevailed in the younger and older age groups. The case fatality rate was higher for men (M:F = 2.0). The total M:F and the M:F excluding pregnancy-related admissions did not change during the study period. Gender inequalities do exist in rural remote setting but tend to affect women differently during their lifespan. Even if gender inequalities generally favor males, the substantial proportion of admissions for pregnancy-related situations is encouraging. [ABSTRACT FROM AUTHOR]

Background: To estimate the cost-effectiveness of an ambulance-based referral system an dedicated to emergency obstetrics and neonatal care (EmONC) in remote sub-Saharan settings.Methods: In this prospective study performed in Oromiya Region (Ethiopia), all obstetrical cases referred to the hospital with the ambulance were consecutively evaluated during a three-months period. The health professionals who managed the referred cases were requested to identify those that could be considered as undoubtedly effective. Pre and post-referral costs included those required to run the ambulance service and the additional costs necessary for the assistance in the hospital. Local life expectancy tables were used to calculate the number of year saved.Results: A total of 111 ambulance referrals were recorded. The ambulance was undoubtedly effective for 9 women and 4 newborns, corresponding to 336 years saved. The total cost of the intervention was 8299 US dollars. The cost per year life saved was 24.7 US dollars which is below the benchmarks of 150 and 30 US dollars that define attractive and very attractive interventions. Sensitivity analyses on the rate of effective referrals, on the costs of the ambulance and on the discount rate confirmed the robustness of the result.Conclusions: An ambulance-based referral system for EmONC in remote sub-Saharan areas appears highly cost-effective. [ABSTRACT FROM AUTHOR]

In the last decade, testosterone replacement therapy (TRT) has been increasingly prescribed to treat a controversial condition known as 'late-onset hypogonadism (LOH)'. This syndrome is diagnosed in men who, for no discernible reason other than older age, obesity or ill health have serum testosterone concentrations below the normal range for healthy young men and report one or more of the following symptoms: muscle weakness or wasting, mood, behaviour and cognition-related symptoms and sexual function or libido impairment. However, recent evidence has demonstrated that testosterone drugs do not substantially ameliorate these symptoms and, more worryingly, that their long-term use may be associated with severe adverse effects (i.e. increased risk of prostate cancer, stroke and myocardial infarction, worsening of benign prostatic hyperplasia symptoms and testicular atrophy). Nonetheless, testosterone drugs have exhibited extraordinary commercial success and their pharmaceutical sales are steadily rising. Behind this apparently unjustifiable trend there are deliberate, well designed direct and indirect pharmaceutical marketing initiatives that exploit the conviction rooted in contemporary society that testosterone can reverse the effects of ageing and ensure social accomplishment. Commercial mechanisms have laid the foundation for disease mongering of LOH and also have resulted a considerable expansion of the indications for treatment. This promotion model deserves particular attention since it is applicable to any drug with a purportedly favourable risk-benefit ratio not supported by evidence. [ABSTRACT FROM AUTHOR]

Deep endometriosis, occurring approximately in 1% of women of reproductive age, represents the most severe form of endometriosis. It causes severe pain in the vast majority of affected women and it can affect the bowel and the urinary tract. Hormonal treatment of deep endometriosis with progestins, such as norethindrone acetate or dienogest, or estroprogestins is effective in relieving pain in more than 90% of women at one year follow up. Progestins and estroprogestins can be safely administered in the long-term, may be not expensive and are usually well tolerated. Therefore, they should represent the first-line treatment of deep endometriosis associated pain in women not seeking natural conception. However, hormonal treatment is ineffective or not tolerated in about 30% of women, the most common side effects being erratic bleeding, weight gain, decreased libido and headache. Surgical excision of deep endometriosis is mandatory in presence of symptomatic bowel stenosis, ureteral stenosis with secondary hydronephrosis, and when hormonal treatments fail. Surgical treatment is similarly effective as compared to hormonal treatment in relieving dismenorhea, dyspareunia and dyschezia at one year follow up in more than 90% of women with deep endometriosis. Surgical removal of the nodules may require resection of the bowel, ureter or bladder, with possible severe complications such as rectovaginal or ureterovaginal fistula and anastomotic leakage. A thorough counsel with the patient is necessary in order to pursue a therapeutic plan centered not on the endometriotic lesions, but on the patient's symptoms, priorities and expectations. [ABSTRACT FROM AUTHOR]

The clinical management of women with deep peritoneal endometriosis remains controversial. The debate focuses mainly on the precise role of hormonal medical treatment and surgery and on the most suitable surgical technique to be used. In particular, considering the risks of second-line surgery, prevention of recurrences after first-line surgery is a priority in this context. Post-surgical medical therapy has been advocated to improve the effectiveness of surgery and prevent recurrences. However, adjuvant therapy, i.e. a short course of 3-6 months of hormonal therapy after surgery, has been proven to be of limited or no benefit for endometriosis in general and for deep peritoneal endometriosis in particular. On the other hand, two cohort studies suggest a beneficial effect of prolonged hormonal therapy after surgery for deep endometriosis. Even if this evidence is too weak to confidently advocate systematic administration of prolonged medical therapy after surgery, we argue in favour of this approach because of the strong association of deep endometriosis with other disease forms. In fact, women operated on for deep endometriosis may also face recurrences of endometriomas, superficial peritoneal lesions and pelvic pain in general. The demonstrated high effectiveness of prolonged postoperative therapy for the prevention of endometriomas' formation and dysmenorrhea recurrence should thus receive utmost consideration in the decision-making process. [ABSTRACT FROM AUTHOR]

The management of endometriosis-related infertility remains debated. However, in recent years, the role of in vitro fertilization (IVF) has progressively grown. Reasons to explain this change include (1) the improvement of the effectiveness and safety of IVF, (2) the raised awareness of the modest effectiveness of surgery, (3) the inherent risks of surgery including in particular the damage to the ovarian reserve when ovarian endometriomas have to be removed, (4) the ineffectiveness of intrauterine insemination and the possible risks of endometriosis progression associated with the use of this technique. However, IVF is not able to overcome all the potential detrimental effects of endometriosis and can actually fail. Future efforts should aim at improving the effectiveness and safety of both surgery and IVF. Fertility preservation techniques may play a role in the future, but data are currently too scanty to support its recommendation. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate whether natural fertility is related to serum 25-hydroxyvitamin D (25-OH-vitamin D) levels.Methods: A nested case-control study was designed from a prospective cohort of pregnant women undergoing first trimester screening for aneuploidies. Cases included women seeking pregnancy for 12-24 months. Controls were the subsequent age-matched women conceiving in less than 1 year. We excluded women aged ≥40 or <18 years, those assuming supplementary products that included vitamin D before or during pregnancy, those with irregular menstrual cycles or known causes of subfertility, those conceiving through assisted reproductive techniques or requiring ovarian stimulation and those who were overweight or obese. A quantitative detection of serum 25-OH-vitamin D and patients' interview were performed.Results: Seventy-three cases and 73 matched controls were selected. The mean ± SD serum 25-OH-vitamin D was 21.2 ± 6.8 and 19.7 ± 7.3 ng/ml, respectively (p = 0.16). The number (%) of women with serum levels <20 ng/ml (vitamin D insufficiency) was 34 (47%) and 37 (51%), respectively (p = 0.73). The adjusted OR of longer time to pregnancy in women with vitamin D insufficiency was 0.84 (95% CI 0.42-1.66).Conclusions: Our study does not support a crucial role of 25-OH-vitamin D in natural fertility. [ABSTRACT FROM AUTHOR]

A diagnosis of unexplained infertility is commonly made when clinical investigations fail to identify any obvious barriers to conception. As a consequence, unexplained infertility includes several heterogeneous conditions, one being women with age-related infertility. However, the latter represent a peculiar and different situation. Women with age-related infertility may have a different prognosis and may benefit from different treatments. Unfortunately, since fecundity declines with age, discerning between unexplained infertility and age-related infertility becomes more and more difficult as the woman's age increases. In this opinion, with the use of a mathematical model we show that the rate of false positive diagnoses of unexplained infertility increases rapidly after 35 years of age. Using a threshold of 2 years of unfruitful, regular unprotected intercourse, this rate exceeds 50% in women starting pregnancy seeking after 37 years. The scenario is much worse using a threshold of 1 year. From a clinical perspective, extrapolating results obtained in a population of young women with unexplained infertility to those with age-related infertility is not justified. It is noteworthy that, if Assisted Reproductive Technologies are unable to overcome age-related infertility, the older women erroneously labeled with unexplained infertility may receive inappropriate therapies. These may expose women to unjustified risks and waste financial resources. Unfortunately, the available literature about older women is scanty and does not provide valid evidence. Randomized controlled trials aimed at identifying the most suitable clinical management of older women with a normal infertility work-up are pressingly needed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the functionality of an ambulance service dedicated to emergency obstetric care (EmOC) that referred pregnant women to health centers for delivery assistance or to a hospital for the management of obstetric complications.Methods: A retrospective study investigated an ambulance referral system for EmOC in a rural area of Ethiopia between July 1 and December 31, 2013. The service was available 24h a day and was free of charge. Women requesting referral were transported to nearby health centers. Assistance was provided locally for uncomplicated deliveries. Women with obstetric complications were referred from health centers to a hospital.Results: A total of 528 ambulance referrals were recorded. The majority of patients (314 [59.5%]) were transported from villages to health centers. The remaining individuals were brought to a hospital, having been referred from health centers (179 [33.9%]) or were referred directly from villages owing to hospital proximity (35 [6.6%]). Of the 179 patients referred to the hospital from health centers, 84 (46.9%) were diagnosed with major direct obstetric complications. No maternal deaths were recorded among patients using the ambulance service. The cost of the ambulance service was US$ 18.47 per referred patient.Conclusions: An ambulance service dedicated to EmOC that interconnected health centers and a hospital facilitated referrals and better utilized local resources. [ABSTRACT FROM AUTHOR]

Endometriosis is an estrogen-dependent chronic inflammatory condition that affects women in their reproductive period. Alterations in ovarian follicle morphology and function have been documented in affected women. The local intrafollicular environment has been as well examined by various groups. In the present review, we aimed to summarize the molecular evidence supporting the idea that endometriosis can negatively influence growth, steroidogenesis and the function of the granulosa cells (GCs). Reduced P450 aromatase expression, increased intracellular ROS generation and altered WNT signaling characterize the GCs of women with endometriosis. Clear evidence for an increased level of GC apoptosis has been provided in association with the downregulation of pro-survival factors. Other potentially negative effects include decreased progesterone production, locally decreased AMH production and lower inflammatory cytokine expression, although these have been only partially clarified. The possibility that endometriosis per se may influence IVF clinical results as a consequence of the detrimental impact on the local intrafollicular environment is also discussed. [ABSTRACT FROM AUTHOR]

Introduction: The correlation between ovarian reserve and infertility remains unclear. Albeit poorly predictive of pregnancy success in in vitro fertilization cycles, serum anti-Müllerian hormone (AMH) has been acknowledged as a surrogate measure of ovarian reserve and is commonly evaluated in women seeking pregnancy. Disentangling whether low serum AMH affects natural fecundity is clinically important, as this information helps physicians in providing appropriate counseling to women and may impact on management strategies.Material and Methods: This was a nested case-control study from a prospective cohort of pregnant women undergoing first trimester screening for aneuploidies. Cases were subfertile women having tried to become pregnant for 12-24 months. Controls were subsequent age-matched fertile women. Inclusion criteria for both cases and controls were: (i) age > 18 years, (ii) natural conception, (iii) regular menstrual cycles (24-35 days). We used quantitative detection of serum AMH and interviews with the women. The main outcome measure was the proportion of women with serum AMH < 1.1 ng/mL.Results: Seventy-six subfertile women and 76 matched fertile controls were selected. In the two study groups, there were 11 (15%) and 15 (20%) women with serum AMH < 1.1 ng/mL, respectively (p = 0.52). The crude odds ratio for subfertility in women with low serum AMH was 0.69 [95% confidence interval (CI) 0.29-1.62]. The adjusted odds ratio was 0.85 (95% CI 0.35-2.10). The median (interquartile range) serum concentration of AMH in subfertile and control women was 2.6 (range 1.6-4.0) and 2.8 (range 1.4-4.3) ng/mL, respectively (p = 0.91).Conclusions: Low serum AMH is not associated with female subfertility. [ABSTRACT FROM AUTHOR]

Background: Patients, now generally well informed through dedicated websites and support organizations, are beginning to look askance at clinical experimentation. We conducted a survey investigation to verify whether women with endometriosis would still accept to participate in a randomized controlled trial (RCT) on treatment for pelvic pain.Methods: A total of 500 patients consecutively self-referring to an academic outpatient endometriosis clinic, were asked to compile two questionnaires focused on hypothetical comparisons between a new drug and a standard drug, and between medical and surgical treatment, for endometriosis-associated pelvic pain. The main outcome measure was the percentage of patients willing to participate in a theoretical RCT.Results: A total of 239 (48 %) women would decline participation in a comparative study on a new drug and a standard drug, as 204 (41 %) would prefer the former medication, and 35 (7 %) the latter. Fifty women (10 %) would participate in a RCT, but only 24 (5 %) would accept blinding. The most frequently chosen option was the patient preference trial (211; 42 %). No significant differences were observed in demographic and clinical characteristics between the 50 women who would accept and the 450 who would decline to be enrolled in a RCT. A total of 229 women (46 %) would decline participation in a comparative study on medical versus surgical treatment, as 186 (37 %) would prefer pharmacological therapy and 43 (9 %) a surgical procedure. Only 11 (2 %) women would participate in such a RCT. More than half of the women (260; 52 %) selected the patient preference trial. No significant variations in distributions of answers were observed between women who did or did not undergo a previous surgical procedure.Conclusion: Only a small minority of the women included in our study sample would accept randomization, and even less so blinding. Patient preference appears to play a central role when planning interventional trials on endometriosis-associated pelvic pain. Adequately designed observational analytic studies could be considered when recruitment in a RCT appears cumbersome. [ABSTRACT FROM AUTHOR]

Deep endometriosis is a demanding condition that is associated with infertility. However, evidence supporting a direct link between deep endometriosis and infertility is weak. In fact, infertility in affected patients is more likely to be explained by the strong association between deep endometriosis and adhesions, superficial endometriotic implants, ovarian endometriomas, and adenomyosis. The purported beneficial effects of surgery on infertility are mainly based on the 40%-42% pregnancy rate (PR) after surgery observed in published case series. However, this level of evidence is questionable and overestimates the benefits of the intervention. Even if comparative studies are lacking, IVF may be a valid alternative. The procedure may be less effective in affected women compared with other indications and it is not without additional deep endometriosis-related risks. Some case reports suggest that lesions might progress during IVF causing ureteral or intestinal complications or can decidualize during pregnancy causing intestinal perforation, pneumothorax, and pelvic vessels rupture. Finally, in the decision-making process, physicians should also consider that women with a history of deep endometriosis may face an increased risk of pregnancy complications. In conclusion, clear recommendation for the management of infertile women with deep endometriosis cannot be extrapolated from the literature. The therapeutic decision should be based on a comprehensive evaluation that includes clinical history, instrumental findings, pain symptoms, risks of pregnancy complications, and the woman's wishes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Classical surgical management of endometriotic ovarian cysts using the laparoscopic stripping technique has been recently questioned because of the surgical-related injury to the ovarian reserve. Accordingly, available guidelines suggest that endometriomas with amean diameter below4 cm should not be systematically removed before IVF procedures. However, conservative management may have some potential drawbacks and risks. The presence of the endometrioma may theoretically interfere with ovarian responsiveness to hyperstimulation and oocyte competence, the retrieval of the oocytes may be more difficult and risky, the disease may progress during the procedure, pregnancy outcome may be affected and there is the risk of missing occult malignancies with cancer development later in life. In the present review, we aimed at assessing whether these risks do exist and, if so, at estimating their clinical relevance. METHODS: We searched PubMed for articles published in the English language between January 1990 and August 2014 that reported on endometriomas and assisted reproductive techniques. Special care was given to studies reporting data purporting to distinguish the effects of ovarian endometriomas per se' from those consequent to surgery for endometriosis or from endometriosis in general. RESULTS: Based on the evidence reviewedin the present study, it can be concluded that conservativemanagement mayactually exposewomen to four of the following theoretical risks, i.e. infection of the endometriomas, follicular fluid contamination with the endometrioma content, higher risk of pregnancy complications and cancer development later in life. The first three conditions do not justify surgery because these events are uncommon and the number of women needed to be treated would be exceedingly high and would not justify the costs and risks of the intervention. Albeit also very rare, the possibility of developing ovarian cancer later in life is more troublesome because it is a life-threatening condition. However, this alarmism is supported by only one cohort study and this risk can be effectively prevented by postponing surgery until after the IVF programme is concluded or when women have definitely satisfied their reproductive wishes. CONCLUSIONS: The available evidence on the risks of conservative management does not support systematic surgery before IVF in women with small ovarian endometriomas. [ABSTRACT FROM AUTHOR]

The increasing confidence with the techniques of oocyte and ovarian cortex freezing has prompted their potential use for patient categories other than those at risk of early menopause due to cancer treatments. Women affected by every iatrogenic or pathologic condition known to compromise ovarian function severely have been considered as potential candidates for fertility preservation. Among them, women with endometriosis may represent a particularly suitable group since they are at increased risk of premature ovarian exhaustion and about half of them will experience infertility. Based on the currently available notions on the intricate relationships between endometriosis, infertility and damage to the ovarian reserve, we speculate that fertility preservation may be of interest for women with endometriosis, in particular for those with bilateral unoperated endometriomas and for those who previously had excision of unilateral endometriomas and require surgery for a contralateral recurrence. Young age at diagnosis may be an independent but pivotal additional factor to be taken into consideration in the balance of the pros and cons of fertility preservation. On the other hand, we argue against the introduction of fertility preservation for endometriosis in routine clinical practice. To date, only few cases have been reported and there are insufficient data for robust cost-utility analyses. It is noteworthy that endometriosis is a relatively common disease and systematically including affected women in a fertility preservation program would have profound clinical, logistic and financial effects. More clinical data and in-depth economic analysis are imperative prior to recommending its routine use. [ABSTRACT FROM AUTHOR]

Objective To assess provision of emergency obstetric care (EmOC) in Greater Yirol, South Sudan, after implementation of a hospital-centered intervention with an ambulance referral system. Methods In a descriptive study, data were prospectively recorded for all women referred to Yirol County Hospital for delivery in 2012. An ambulance referral system had been implemented in October 2011. Access to the hospital and ambulance use were free of charge. Results The number of deliveries at Yirol County Hospital increased in 2012 to 1089, corresponding to 13.3% of the 8213 deliveries expected to have occurred in the catchment area. Cesareans were performed for 53 (4.9%) deliveries, corresponding to 0.6% of the expected number of deliveries in the catchment area. Among 950 women who delivered a newborn weighing at least 2500 g at the hospital, 6 (0.6%) intrapartum or very early neonatal deaths occurred. Of 1232 women expected to have major obstetric complications in 2012 in the catchment area, 472 (38.3%) received EmOC at the hospital. Of 115 expected absolute obstetric indications, 114 (99.1%) were treated in the hospital. Conclusion A hospital-centered approach with an ambulance referral system effectively improves the availability of EmOC in underprivileged remote settings. [ABSTRACT FROM AUTHOR]

Background: While there is a large body of evidence showing a significant impact of controlled ovarian hyperstimulation (COH) on thyroid function in euthyroid patients undergoing in vitro fertilization (IVF), information on the effect of this treatment on thyroid axis equilibrium in hypothyroid-treated patients is insufficient. The goal of this prospective study was to investigate serum thyroid-stimulating hormone (TSH) modifications in hypothyroid-treated patients during IVF. Methods : Hypothyroid-treated women selected for IVF between November 2010 and December 2011 were considered for study entry. They were eligible if serum TSH tested the month preceding the IVF cycle was 0.4-2.5 mIU/L. Additional inclusion criteria were as follows: (1) a certified diagnosis of clinical or subclinical hypothyroidism; (2) consumption of at least 25 μg of levothyroxine daily; (3) serum free triiodothyronine and free thyroxine tested the month preceding the IVF cycle within the reference range; (4) no previous IVF cycles; (5) regular menstrual cycles; and (6) day 3 serum follicle-stimulating hormone <12 IU/mL and anti-Müllerian hormone >0.5 ng/mL. Serum TSH was tested at three time points: between day 1 and day 8 of the cycle during the month preceding the start of controlled ovarian hyperstimulation (COH), at the time of human chorionic gonadotropin (hCG) administration and at 16 days after hCG administration. Results: Seventy-two women met our selection criteria. The serum levels of TSH at basal assessment, at the time of hCG administration, and at 16 days after hCG administration were 1.7±0.7, 2.9±1.3, and 3.2±1.7 mIU/L, respectively. All pairwise comparisons were statistically significant. Serum TSH exceeded the threshold of 2.5 mIU/L in 46 subjects at the time of hCG administration (64%, [CI: 53-75%]) and in 49 subjects 16 days after hCG administration (68%, [CI: 57-79%]). Conclusions: Serum TSH increased considerably during COH in adequately treated hypothyroid women undergoing IVF. We suggest strictly monitoring these women during IVF cycles and, if necessary, promptly adjusting the levothyroxine dose. This is the most pragmatic approach but, to date, it is not supported by clinical evidence. Further studies aimed at clarifying the most suitable therapeutic strategy are thus warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND Compared with the general population, cancer patients have a higher risk of venous thromboembolism as well as arterial thrombotic events such as stroke, myocardial infarction and peripheral arterial embolism. Therefore a possible concern for women with malignancies undergoing ovarian stimulation for fertility preservation is the increased risk of venous or arterial thrombosis. METHODS In this article, we revised current available literature on the risk of thrombosis in patients with cancer and in women undergoing ovarian stimulation, with the ultimate aim of drawing some indications for preventive measures. RESULTS Unfortunately, there are no specific data on the risk of thrombosis in women with cancer undergoing ovarian stimulation for fertility preservation. However, the literature suggests that the cancer type and stage, surgery, and chemotherapy all influence the risk of venous and, possibly, arterial thrombosis. Reports of cases of ovarian stimulation in women without malignancies have shown that venous thrombosis rarely occurs unless a pregnancy is achieved, while arterial thrombosis can occur in the absence of pregnancy but is usually only associated with ovarian hyperstimulation syndrome (OHSS). OHSS increases the risk of thrombotic events, but only the early form of the syndrome is relevant for women undergoing fertility preservation. CONCLUSIONS The available evidence on the risks of thrombosis for women undergoing ovarian stimulation for fertility preservation due to a malignancy is reassuring. However the avoidance of the early form of OHSS in women preserving oocytes/embryos due to malignancy is crucial. For these cycles, we advocate the use of a regimen of ovarian stimulation with gonadotrophin releasing hormone (GnRH) antagonists using GnRH agonists to trigger ovulation, an approach that has been shown to markedly reduce the risk of OHSS. Antithrombotic prophylaxis should be administered only to selected subgroups of women such as those with other risk factors or those who do develop early OHSS. [ABSTRACT FROM AUTHOR]