Epigenetic clocks and female fertility timeline: A new approach to an old issue?

Worldwide increase in life expectancy has boosted research on aging. Overcoming the concept of chronological age, higher attention has been addressed to biological age, which reflects a person’s real health state, and which may be the resulting combination of both intrinsic and environmental factors. As epigenetics may exert a pivotal role in the biological aging, epigenetic clocks were developed. They are based on mathematical models aimed at identifying DNA methylation patterns that can define the biological age and that can be adopted for different clinical scopes (i.e., estimation of the risks of developing age-related disorders or predicting lifespan). Recently, epigenetic clocks have gained a peculiar attention in the fertility research field, in particular in the female counterpart. The insight into the possible relations between epigenetic aging and women’s infertility might glean additional information about certain conditions that are still not completely understood. Moreover, they could disclose significant implications for health promotion programs in infertile women. Of relevance here is that the impact of biological age and epigenetics may not be limited to fertility status but could translate into pregnancy issues. Indeed, epigenetic alterations of the mother may transfer into the offspring, and pregnancy itself as well as related complications could contribute to epigenetic modifications in both the mother and newborn. However, even if the growing interest has culminated in the conspicuous production of studies on these topics, a global overview and the availability of validated instruments for diagnosis is still missing. The present narrative review aims to explore the possible bonds between epigenetic aging and fertility timeline. In the “infertility” section, we will discuss the advances on epigenetic clocks focusing on the different tissues examined (endometrium, peripheral blood, ovaries). In the “pregnancy” section, we will discuss the results obtained from placenta, umbilical cord and peripheral blood. The possible role of epigenetic aging on infertility mechanisms and pregnancy outcomes represents a question that may configure epigenetic clock as a bond between two apparently opposite worlds: infertility and pregnancy

A new definition of recurrent implantation failure on the basis of anticipated blastocyst aneuploidy rates across female age.

Objective: To present a definition of recurrent implantation failure that accounts for the effects of female age and anticipated blastocyst euploidy rates on cumulative implantation rates. Design: Mathematical modeling. Setting: Not applicable. Patient(s): Not applicable. Intervention(s): Mathematical modeling of cumulative implantation probability on the basis of published blastocyst euploidy rates across categories of female age. Main Outcome Measure(s): The number of blastocysts required to achieve 95% cumulative implantation probability under the assumption of the absence of any other factor affecting implantation. Result(s): When the euploidy status of the transferred embryo is unknown (i.e., not subjected to preimplantation genetic testing for aneuploidies), our simulation shows that no age category reaches 95% cumulative probability of implantation of at least one embryo until after transfer of seven blastocysts. The number of blastocysts required to reach the same threshold is higher for older patients. For example, women older than 38 years require transfer of more than 10 untested blastocysts for the upper range of predictive probability to meet the threshold of 95%. On the other hand, if the implantation rate for a euploid blastocyst is assumed to be 55%, then 4 blastocysts are enough to reach a cumulative probability rate greater than 95%, regardless of age. Conclusion(s): The term "recurrent implantation failure"should be a functional term guiding further management. We suggest that recurrent implantation failure should not be called until implantation failure becomes reasonably likely to be caused by factors other than embryo aneuploidy, the leading cause of implantation failure. We propose a new definition that factors in anticipated blastocyst euploidy rates across categories of female age, euploid blastocyst implantation rate, and a specified threshold of cumulative probability of implantation

Trends in the incidence of major birth defects after assisted reproductive technologies in Lombardy region, northern Italy

Purpose: The incidence of birth defects is increased in children born after assisted reproductive technologies (ART). However, changes in ART over time could influence this incidence. To investigate this issue, we present the frequency and trends of birth defects in ART and natural pregnancies in Lombardy, Northern Italy, during the period 2014-2020. Methods: This is a population-based study using automated system of healthcare utilization (HCU) databases. ART pregnancies included only those obtained with conventional IVF or ICSI. After identifying the total number of deliveries, the rate of newborns with birth defects was compared between natural and ART pregnancies. A logistic regression model was used to calculate the adjusted odd ratio (OR). Analyses were repeated for every calendar year. Results: Overall, 508,421 deliveries were identified, of which 14,067 (2.8%) were achieved after IVF-ICSI. A decreasing trend in birth defects over time was highlighted. The adjusted OR dropped from 1.40 (95%CI: 1.03-1.91) in 2014 to 0.92 (95%CI: 0.69-1.22) in 2020. During the study period, a significant reduction in multiple pregnancy and in the ratio of ICSI to conventional IVF was also observed, explaining at least in part the positive trend observed for birth defects. Conclusion: The increased risk of birth defects in children born after IVF-ICSI is not steady over time. A decline of this risk emerged in our region. Policy changes in ART may explain this beneficial effect

Maternal age and risk of low birth weight and premature birth in children conceived through medically assisted reproduction : Evidence from Finnish population registers

STUDY QUESTION Does the risk of low birth weight and premature birth increase with age among mothers who conceive through medically assisted reproduction (MAR)? SUMMARY ANSWER Among MAR mothers, the risk of poorer birth outcomes does not increase with maternal age at birth except at very advanced maternal ages (40+). WHAT IS KNOWN ALREADY The use of MAR treatments has been increasing over the last few decades and is especially diffused among women who conceive at older ages. Although advanced maternal age is a well-known risk factor for adverse birth outcomes in natural pregnancies, only a few studies have directly analysed the maternal age gradient in birth outcomes for MAR mothers. STUDY DESIGN, SIZE, DURATION The base dataset was a 20% random sample of households with at least one child aged 0-14 at the end of 2000, drawn from the Finnish population register and other administrative registers. This study included children who were born in 1995-2000, because the information on whether a child was conceived through MAR or naturally was available only from 1995 onwards. PARTICIPANTS/MATERIALS, SETTING, METHODS The outcome measures were whether the child had low birth weight (LBW, MAIN RESULTS AND THE ROLE OF CHANCE A total of 56026 children, 2624 of whom were conceived through MAR treatments, were included in the study. Among the mothers who used MAR to conceive, maternal age was not associated with an increased risk of LBW (the overall prevalence was 12.6%) at ages 25-39. For example, compared to the risk of LBW at ages 30-34, the risk was 0.22 percentage points lower (95% CI: -3.2, 2.8) at ages 25-29 and was 1.34 percentage points lower (95% CI: -4.5, 1.0) at ages 35-39. The risk of LBW was increased only at maternal ages >= 40 (six percentage points, 95% CI: 0.2, 12). Adjustment for maternal characteristics only marginally attenuated these associations. In contrast, among the mothers who conceived naturally, the results showed a clear age gradient. For example, compared to the risk of LBW (the overall prevalence was 3.3%) at maternal ages 30-34, the risk was 1.1 percentage points higher (95% CI: 0.6, 1.6) at ages 35-39 and was 1.5 percentage points higher (95% CI: 0.5, 2.6) at ages >= 40. The results were similar for preterm births. LIMITATIONS, REASON FOR CAUTION A limited number of confounders were included in the study because of the administrative nature of the data used. Our ability to reliably distinguish mothers based on MAR treatment type was also limited. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to analyse the maternal age gradient in the risk of adverse birth outcomes among children conceived through MAR using data from a nationally representative sample and controlling for important maternal health and socio-economic characteristics. This topic is of considerable importance in light of the widespread and increasing use of MAR treatments.Peer reviewe

Opportunities and Limits of Conventional IVF versus ICSI: It Is Time to Come off the Fence

Conventional IVF (c-IVF) is one of the most practiced assisted reproductive technology (ART) approaches used worldwide. However, in the last years, the number of c-IVF procedures has dropped dramatically in favor of intracytoplasmic sperm injection (ICSI) in cases of non-male-related infertility. In this review, we have outlined advantages and disadvantages associated with c-IVF, highlighting the essential steps governing its success, its limitations, the methodology differences among laboratories and the technical progress. In addition, we have debated recent insights into fundamental questions, including indications regarding maternal age, decreased ovarian reserve, endometriosis, autoimmunity, single oocyte retrieval-cases as well as preimplantation genetic testing cycles. The “overuse” of ICSI procedures in several clinical situations of ART has been critically discussed. These insights will provide a framework for a better understanding of opportunities associated with human c-IVF and for best practice guidelines applicability in the reproductive medicine field

Contraception after pregnancy

Whatever the outcome, pregnancy provides the opportunity to offer effective contraception to couples motivated to avoid another pregnancy. This narrative review summarizes the evidence for health providers, drawing attention to current guidelines on which contraceptive methods can be used, and when they should be started after pregnancy, whatever its outcome. Fertility returns within 1 month of the end of pregnancy unless breastfeeding occurs. Breastfeeding, which itself suppresses fertility after childbirth, influences both when contraception should start and what methods can be used. Without breastfeeding, effective contraception should be started as soon as possible if another pregnancy is to be avoided. Interpregnancy intervals of at least 6 months after miscarriage and 1‐2 years after childbirth have long been recommended by the World Health Organization in order to reduce the chance of adverse pregnancy outcome. Recent research suggests that this may not be necessary, at least for healthy women <35 years old. Most contraceptive methods can be used after pregnancy regardless of the outcome. Because of an increased risk of venous thromboembolism associated with estrogen‐containing contraceptives, initiation of these methods should be delayed until 6 weeks after childbirth. More research is required to settle the questions over the use of combined hormonal contraception during breastfeeding, the use of injectable progestin‐only contraceptives before 6 weeks after childbirth, and the use of both hormonal and intrauterine contraception after gestational trophoblastic disease. The potential impact on the risk of ectopic pregnancy of certain contraceptive methods often confuses healthcare providers. The challenges involved in providing effective, seamless service provision of contraception after pregnancy are numerous, even in industrialized countries. Nevertheless, the clear benefits demonstrate that it is worth the effort

Clinical comparison between conventional and microdissection testicular sperm extraction for non-obstructive azoospermia: Understanding which treatment works for which patient

Objectives: The superiority of microdissection testicular sperm extraction (mTESE) over conventional TESE (cTESE) for men with non-obstructive azoospermia (NOA) is debated. We aimed to compare the sperm retrieval rate (SRR) of mTESE to cTESE and to identify candidates who would most benefit from mTESE in a cohort of Caucasian-European men with primary couple’s infertility. Material and methods: Data from 49 mTESE and 96 cTESE patients were analysed. We collected demographic and clinical data, serum levels of LH, FSH and total testosterone. Patients with abnormal karyotyping were excluded from analysis. Age was categorized according to the median value of 35 years. FSH values were dichotomized according to multiples of the normal range (N) (N and 1.5 N: 1-18 mIU/mL, and > 18 mIU/mL). Testicular histology was recorded for each patient. Descriptive statistics and logistic regression analyses tested the impact of potential predictors on positive SRR in both groups. Results: No differences were found between groups in terms of clinical and hormonal parameters with the exception of FSH values that were higher in mTESE patients (p = 0.004). SRR were comparable between mTESE and cTESE (49.0% vs. 41.7%, p = 0.40). SRRs were significantly higher after mTESE in patients with Sertoli cell-only syndrome (SCOS) (p = 0.038), in those older than 35 years (p = 0.03) and with FSH >1.5N (p 1.5N (p = 0.018). Moreover, increased FSH levels (p = 0.03) and both SCOS (p = 0.01) and MA histology (p = 0.04) were independent predictors of SRR failure. Conclusions: Microdissection and cTESE showed comparable success rates in our cohort of patients with NOA. mTESE seems beneficial for patients older than 35 years, with high FSH values, or when SCOS can be predicted. Given the high costs associated with the mTESE approach, the identification of candidates most likely to benefit from this procedure is a major clinical need