Low ovarian reserve and risk of miscarriage in pregnancies derived from assisted reproductive technology.

STUDY QUESTION: Do low levels of anti-Müllerian hormone (AMH) or antral follicle count (AFC) properly predict miscarriage in young women conceiving with ART? SUMMARY ANSWER: Low ovarian reserve, as indicated by AMH or AFC, is not associated with miscarriage in young women conceiving with ART. WHAT IS KNOWN ALREADY: Presently, the impact of low ovarian reserve on the risk of miscarriage remains controversial. Some studies have reported an association between serum AMH levels and AFC and miscarriage, but others have failed to confirm these findings. The main limitation that undermines the reliability and consistency of the results is the confounding effect of female age. Indeed, after 35 years of age, on the one hand, the risk of miscarriage starts increasing because of impaired oocyte quality while, on the other, the physiological decline in AMH and AFC levels continues, thus hampering the possibility to properly explore the real effects of reduced ovarian reserve. Indeed, the two processes, i.e. the gradual loss of resting primordial follicles and the loss of oocyte quality, progress in parallel. In other words, the older the woman becomes, the higher is the risk of miscarriage, but one cannot distinguish between the effects of biological aging on oocyte quality and those mediated by a lower ovarian reserve. STUDY DESIGN SIZE DURATION: The present retrospective monocentric cohort study was carried out at Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico, Milan. All women referred to the ART Unit between 2014 and 2021 and who underwent either conventional IVF (c-IVF), ICSI, or IUI were reviewed. Only women younger than 35 were eligible because, up to this age, the risk of miscarriage is steady and not strictly related to age. PARTICIPANTS/MATERIALS SETTING METHODS: Women younger than 35 who achieved a singleton clinical pregnancy with c-IVF, ICSI, or IUI were selected. Women with patent causes of recurrent miscarriage were excluded, as well as those undergoing pregnancy termination for fetal or medical causes. Women who did and did not have a pregnancy loss before 20 weeks' gestation were compared. Detailed information was obtained from charts of the consulting patients. ART procedures were performed according to the standardized policy of our Unit. All women underwent serum AMH measurement and a transvaginal assessment of AFC prior to initiation of treatment. AMH levels were measured by a commercially available ELISA assay. To assess AFC, all identifiable antral follicles 2-10 mm in diameter at ultrasound were recorded. The primary outcome was the risk of miscarriage for women with serum AMH levels below 5 pmol/l. MAIN RESULTS AND THE ROLE OF CHANCE: There were 538 women were included, of whom 92 (17%) had a miscarriage. The areas under the ROC curves for prediction of miscarriage based on AMH levels and AFC were 0.51 (95% CI: 0.45-0.58) and 0.52 (95% CI: 0.45-0.59), respectively. The odds ratio (OR) of miscarriage for women with serum AMH levels below 5.0 pmol/l was 1.10 (95% CI: 0.51-2.36); the adjusted OR was 1.12 (95% CI: 0.51-2.45). Analyses were repeated considering other thresholds for AMH (2.9, 3.6 and 7.9 pmol/l) and for AFC (thresholds of 7 and 10). No associations emerged. LIMITATIONS REASONS FOR CAUTION: The retrospective design of the study hampered the collection of more precise but potentially relevant clinical information of the couples. We did not exclude women suffering from PCOS, a condition possibly associated with miscarriage. Moreover, the baseline characteristics of women who did and did not have a miscarriage differed in some characteristics. Thus, we adjusted the OR using a multivariate analysis, but we cannot fully exclude residual confounding effects. Finally, our results cannot be inferred to women older than 35. The mechanisms causing premature exhaustion of ovarian reserve may be different in younger and older women and this may lead to a different impact on the risk of miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Women embarking on ART with low ovarian reserve should be informed of their likely poor response to ovarian stimulation but can be reassured that, if conception occurs, their risk of miscarriage is not increased. STUDY FUNDING/COMPETING INTERESTS: This study was partially funded by Italian Ministry of Health-Current research IRCCS. E.S. reports grants from Ferring and honoraria for lectures from Merck-Serono and Gedeon-Richter. All the other authors do not have any competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Expectant, Medical, and Surgical Management of Ovarian Endometriomas.

Management options for ovarian endometriomas include expectant management, medical treatment, surgical treatment, in vitro fertilization (IVF), or a combination of the above. The choice of management depends on many clinical parameters that should be taken into consideration, the first of which is the main presenting symptom. Most patients are today referred to medical therapy as a first option in the case of associated pain, and to IVF in the case of associated infertility. When both symptoms are present, usually surgery is the preferred approach. Recently, however, surgical excision of an ovarian endometrioma has been associated with a postoperative reduction in the ovarian reserve, and recent guidelines suggest that the clinician should caution the patient as to the possible damage to the ovarian reserve in the case of surgery. However, evidence has been published as to a possible detrimental effect of the ovarian endometrioma on the ovarian reserve even if expectant management is followed. In this review, the current evidence on the conservative management of ovarian endometriomas, with particular focus on the issue of the ovarian reserve, is evaluated, and the different surgical techniques for the treatment of ovarian endometriomas are discussed.

Is There a Correlation between the Second-to-Four Digit Ratio (2D:4D) and Endometriosis? Results of a Case-Control Study.

The second-to-four digit ratio (2D:4D) has been proposed as a marker of prenatal hormonal exposure. It is suggested that prenatal exposure to androgens results in a shorter 2D:4D ratio, whereas a prenatal oestrogenic environment results in a longer one. In addition, previous research has shown an association between exposure to endocrine-disrupting chemicals and 2D:4D in animals and humans. On the endometriosis side, hypothetically, a longer 2D:4D ratio, reflecting a lower androgenic intrauterine milieu, could represent an indicator of the presence of the disease. In this light, we have designed a case-control study to compare 2D:4D measurements between women with and without endometriosis. Exclusion criteria included the presence of PCOS and previous trauma on the hand that could impact the measurement of the digit ratio. The 2D:4D ratio of the right hand was measured using a digital calliper. A total of 424 participants (endometriosis n = 212; controls n = 212) were recruited. The group of cases included 114 women with endometriomas and 98 patients with deep infiltrating endometriosis. The 2D:4D ratio was significantly higher in women with endometriosis compared to controls (p = 0.002). There is an association between a higher 2D:4D ratio and the presence of endometriosis. Our results support the hypothesis claiming potential influences of intrauterine hormonal and endocrine disruptors exposure on the onset of the disease.

The role of ultrasonographic adipose tissue thickness measurement in the first trimester in predicting gestational diabetes: a prospective study.

BACKGROUND: This prospective observational study aimed to assess the association between maternal abdominal subcutaneous and visceral fat thickness measured with ultrasound scan during the first trimester and the risk of developing gestational diabetes mellitus (GDM). METHODS: We recruited 43 non-diabetic women with singleton pregnancy between 11 and 14 week of gestation and evaluated ultrasonographic measurements of subcutaneous fat thickness (SFT) and preperitoneal fat (PF) above the umbilicus. During the 2nd trimester, GDM screening was performed by 75 g two-hour oral glucose tolerance test (OGTT) and diagnosis was made when one or more plasma glucose values meets or exceeds the values indicated by International Association of the Diabetes and Pregnancy Study Groups (IADPSG). RESULTS: Among the 43 woman, 8 developed GDM (18.6%). Of these 37,5% (N.=3) had been diagnosed with GDM during a previous pregnancy, with a statistically significant correlation (P=0.035). Mean SFT for all patients was significantly higher in the GDM group compared to non-GDM group (27.30±8.78 mm vs. 18.56±9.99 mm; P=0.049). Mean PF for all women showed a statistically significant correlation with GDM (13.27±9.07 mm for non GDM group vs. 23.52±10.24 mm for GDM group; P=0.038). CONCLUSIONS: Abdominal adiposity, both subcutaneous and visceral, seem to be a suitable predictor of GDM in early pregnancy and it can be easily assessed during a first trimester routine ultrasound, although further studies are needed to evaluate their role in the screening protocols.

Placenta Accreta Spectrum (PAS) Disorder: Ultrasound versus Magnetic Resonance Imaging.

OBJECTIVE: PAS is one of the most dangerous conditions associated with pregnancy and remains undiagnosed before delivery in from half to two-thirds of cases. Correct prenatal diagnosis is essential to reduce the burden of maternal and fetal morbidity. The purpose of our study is to evaluate the accuracy of US and MRI in the diagnosis of PAS. STUDY DESIGN: In this retrospective study, 104 patients with suspected placenta accreta were enrolled and had been investigated with US and MRI. They were divided into four groups: no PAS, accreta, increta, and percreta. RESULTS: Compared to MRI, US results were higher in the diagnosis and in the identification of PAS severity (85% US vs. 80% MRI). For both methods, in the case of posterior placenta, there is greater difficulty in identifying the presence/absence of the disease (67% in both methods) and the severity level (61% US vs. 55% MRI). CONCLUSION: US, properly implemented with the application of defined and standardized scores, can be superior to MRI and absolutely sufficient for the diagnosis of PAS, limiting the use of MRI to a few doubtful cases and to cases in which surgical planning is necessary.

Fertility after Cancer: Risks and Successes.

The incidence of cancer in reproductive-aged women is 7%, but, despite the increased number of cancer cases, advances in early diagnosis and treatment have raised the survival rate. Furthermore, in the last four decades, there has been a rising trend of delaying childbearing. There has been an increasing number of couples referred to Reproductive Medicine Centers for infertility problems after one partner has been treated for cancer. In these cases, the main cause of reduced fertility derives from treatments. In this review, we describe the effects and the risks of chemotherapy, radiotherapy, and surgery in women with cancer, and we will focus on available fertility preservation techniques and their efficacy in terms of success in pregnancy and live birth rates.

Endometriosis-associated infertility: surgery or IVF?

Endometriosis is a chronic disease frequently associated with female infertility. The choice of treatment in case of endometriosis is one of the most discussed topics in Reproductive Medicine. The approach to the patient with endometriosis and infertility should be tailored based on different parameters. The localization of the disease, the severity of symptoms and the age of the patient are just some of them. Management options include surgery, in-vitro fertilization (IVF), or a combination of both. Data, mostly uncontrolled, would favor surgery at any stage of endometriosis, increasing the chances of natural conception compared to expectant management. Laparoscopic excision of the ovarian endometrioma should be the treatment of choice when there is associated pain. Surgery should be performed following appropriate techniques to reduce the possible damage to the ovarian reserve. Pregnancy rates around 50% have been consistently reported after surgery, which compare favorably with those obtained with IVF. IVF, on the other hand, may be preferred in case of associated male or tubal factor, in case of a reduced ovarian reserve, or if previous surgery has failed, particularly if there is no associated pain, and when the ultrasonographic features of the ovarian cyst are reassuring. Sometimes IVF may be preceded by surgery, when a difficult access to follicles at pick-up, due to the size and location of the ovarian cyst, or to severe adhesions, is anticipated. Due to the lack of solid evidence in the scenario of endometriosis-associated infertility, robust data from randomized clinical trials (RCTs) are strongly needed.

BRCA1/2 genes mutations, ovarian reserve and female reproductive outcomes: a systematic review of the literature.

INTRODUCTION: BRCA1 and BRCA2 genes mutations seems to impact female fertility, in addition to increasing the risk of ovarian and breast cancer. Several studies had investigated this issue but data available are still controversial. In order to clarify the role of BRCA1 and BRCA2 mutations in female fertility and ovarian function we carried out a systematic review of the literature with the aim to establish a possible management's strategy of these patients. EVIDENCE ACQUISITION: A review of current literature regarding BRCA mutation (BRCAm) and fertility was conducted using the PubMed tool to select remarkable articles with the keywords "BRCA1/2 gene," "BRCA1/2 mutation," "anti-Müllerian hormone," "female fertility," "ovarian reserve" and "premature ovarian failure." EVIDENCE SYNTHESIS: In current literature there are controversial findings about the relation between BRCA genes mutations and lifespan of female reproductive age. Several studies showed an higher risk of premature ovarian insufficiency of BRCAs mutations carriers, according to lower serum AMH level, primordial follicle count, or fewer oocyte yield after ovarian stimulation; on the other hand more recent studies reported not significant differences in serum AMH level or in reproductive outcomes between mutated and non-mutated BRCA patients. For this reason, currently there is not a strict recommendation for routine evaluation of fertility in female carriers of BRCA mutations. Nevertheless, the strong advice to complete childbearing by age 40 and then to undergo a risk-reducing salpingo-oophorectomy and the increased risk of infertility as a result of anticancer treatment in breast cancer BRCAm patients, make the issue of fertility and pregnancy planning in these women worthy of consideration. CONCLUSIONS: A dedicated counseling to discuss these issues, eventually associated with a personalized assessment of serum AMH or antral follicle count in order to have a panoramic view of ovarian reserve, may be useful in the management of these patients.