Explore the vast range of titles available.

Aims/hypothesis In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential mediators. Methods We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study. Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, <40 years; early, 40–44 years; normal, 45–55 years; and late menopause, >55 years [reference]). Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits. HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C-reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens. Results During a median follow-up of 9.2 years, we identified 348 individuals with incident type 2 diabetes. After adjustment for confounders, HRs for type 2 diabetes were 3.7 (95% CI 1.8, 7.5), 2.4 (95% CI 1.3, 4.3) and 1.60 (95% CI 1.0, 2.8) for women with premature, early and normal menopause, respectively, relative to those with late menopause ( p trend  <0.001). The HR for type 2 diabetes per 1 year older at menopause was 0.96 (95% CI 0.94, 0.98). Further adjustment for BMI, glycaemic traits, metabolic risk factors, C-reactive protein, endogenous sex hormone levels or shared genetic factors did not affect this association. Conclusions/interpretation Early onset of natural menopause is an independent marker for type 2 diabetes in postmenopausal women.

ObjectiveWomen with obesity have an increased risk of pregnancy complications. Although complications generally present in the second and third trimester of pregnancy, most of them develop in the periconception period. Moreover, fetal sex also impacts pregnancy course and outcome. Therefore, our aim is to study (sex-specific) associations between periconceptional maternal body mass index (BMI) and embryonic growth and morphological development.MethodsA total of 884 women with singleton pregnancies were selected from the Rotterdam Periconception Cohort, comprising 15 women with underweight, 483 with normal weight, 231 with overweight and 155 with obesity. Longitudinal three-dimensional ultrasound examinations were performed at 7, 9, and 11 weeks of gestation for offline measurements of crown-rump length (CRL), embryonic volume (EV), and Carnegie stages. Analyses were adjusted for maternal age, parity, ethnicity, education, and periconceptional lifestyle.ResultsA negative trend was observed for embryos of women with obesity (βEV −0.03, p = 0.086), whereas embryonic growth and developmental trajectories in women with overweight were comparable to those with normal weight. Maternal underweight was associated with faster morphological development (βCarnegie 0.78, p = 0.004). After stratification for fetal sex, it was demonstrated that female embryos of underweight women grow and morphologically develop faster than those of normal weight women (βEV 0.13, p = 0.008; βCarnegie 1.39, p < 0.001), whereas female embryos of women with obesity grow slower (βEV −0.05, p = 0.027).ConclusionWe found that periconceptional maternal underweight is associated with faster embryonic growth, especially in females. In contrast, female embryos of women with obesity grow slower than female embryos of women with normal weight. This may be the result of altered female adaptation to the postnatal environment. Future research should focus on strategies for optimizing preconceptional maternal weight, to reduce BMI-related pregnancy complications and improve the health of future generations.

Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 μm (500-615) versus 684 μm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. ClinicalTrials.gov Identifier: NCT02616510.

Recent studies have investigated if and how the vaginal and endometrial microbiome might affect endometrial receptivity and reproductive health. Although there is no consensus on the existence of a core uterine microbiome yet, evidence shows that the dominance of Lactobacillus spp. in the female reproductive tract is generally associated with eubiosis and improved chances of successful implantation and an ongoing pregnancy. Conversely, vaginal and endometrial dysbiosis can cause local inflammation and an increase of pro-inflammatory cytokines, compromising the integrity and receptivity of the endometrial mucosa and potentially hampering successful embryonic implantation. This review provides a critical appraisal of the influence of the vaginal and endometrial microbiome as parts of the female reproductive tract on fertility outcomes, focusing on repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It seems that RIF as well as RPL are both associated with an increase in microbiome diversity and a loss of Lactobacillus dominance in the lower female reproductive system.

Background The posttranslational histone modification H3K9me3 is crucial for constitutive heterochromatin (cHC) and supports genome stability and gene regulation during development. This epigenetic mark persists in human sperm post histone-to-protamine transition and is transmitted to the embryo. Although H3K9me3 variability is linked to abnormal sperm parameters, its role in fertilization and embryo development remains unclear. Given its retention in sperm, aberrant H3K9me3 levels may underlie cases of unexplained male infertility. Objective Investigate the variability of H3K9me3 levels in sperm from normozoospermic men and assess its association with early embryo development and IVF outcomes. Material and methods H3K9me3 and histone H3 levels were quantified by Western blot in surplus sperm from 99 normozoospermic men undergoing IVF-treatment. Patients were stratified into quartiles based on the H3K9me3/H3 ratio. Pre-implantation embryo development was assessed by time-lapse imaging, focusing on nuclear precursor body (NPB) dynamics and morphokinetics. IVF outcomes were reported as cumulative biochemical and ongoing pregnancy rates per ovum pick-up and compared across H3K9me3/H3 quartiles. Results H3K9me3/H3 ratios exhibited substantial inter-individual variability among normozoospermic patients. Embryos from the third H3K9me3/H3 ratio quartile (Q3) demonstrated the highest proportion of zygotes with NPB clustering and faster, more consistent development through the first two cleavage divisions compared to other quartiles. A significant non-linear association was found between H3K9me3/H3 ratio and cumulative biochemical pregnancy rates: couples in the lowest quartile (Q1) had significantly reduced odds of biochemical pregnancy compared to Q3 (adjusted OR [95% CI]: 0.30 [0.09–0.97], p  = 0.045). No significant association was found for ongoing pregnancy rates. Discussion and conclusions This study reveals that sperm H3K9me3 levels vary among normozoospermic men and correlate with early embryo development and biochemical pregnancy rates following IVF. However, no significant association was found with ongoing pregnancy, suggesting that additional mechanisms may determine long-term pregnancy viability. The non-linear relationship between H3K9me3/H3 ratio and embryo development suggests an optimal range for this epigenetic mark. These findings highlight the potential influence of paternal epigenetic variation, undetectable by standard semen analysis, on embryo quality and IVF outcomes. Further studies in larger cohorts are warranted to confirm these findings and clarify underlying mechanisms.

Advances in cancer management have resulted in improved survival rates, particularly in children and young adults. However, treatment may adversely affect reproductive outcomes among female cancer survivors. The objective of this study was to investigate their risk of adverse perinatal outcomes compared to the general population. We performed a population-based analysis, including all female cancer survivors diagnosed before the age of 40 years between 1981 and 2012. Pregnancy and perinatal complications were identified through linkage of the Scottish Cancer Registry with hospital discharge records based on the Community Health Index (CHI) database. We compared 1,629 female cancer survivors with a first ever singleton pregnancy after diagnosis, with controls matched on age, deprivation quintile, and year of cancer diagnosis selected from the general population (n = 8,899). Relative risks and 95%-confidence intervals of perinatal risks were calculated using log-binomial regression. Survivors were more likely to give birth before 37 weeks of gestation (relative risk (RR]) 1.32, 95%-CI 1.10-1.59), but did not show an increased risk of low birth weight (<2.5kg: RR 1.15, 95%-CI 0.94-1.39), and were less likely to give birth to offspring small for gestational age (RR 0.81, 95%-CI 0.68-0.98). Operative delivery and postpartum haemorrhage were more common but approached rates in controls with more recent diagnosis. The risk of congenital abnormalities was not increased (RR 1.01, 95%-CI 0.85-1.20). Cancer survivors have an increased risk of premature delivery and postpartum haemorrhage, but their offspring are not at increased risk for low birth weight or congenital abnormalities. In recent decades there has been a normalisation of delivery method in cancer survivors, nevertheless careful management remains appropriate particularly for those diagnosed in childhood.

Background Despite all research efforts during this era of novel time-lapse morphokinetic parameters, a morphological grading system is still routinely being used for embryo selection at the blastocyst stage. The blastocyst expansion grade, as evaluated during morphological assessment, is associated with clinical pregnancy. However, this assessment is performed without taking the dynamics of blastocoel expansion into account. Here, we studied the dynamics of blastocoel expansion by comparing longitudinal blastocoel surface measurements using time-lapse embryo culture. Our aim was to first assess if this is impacted by fertilization method and second, to study if an association exists between these measurement and ongoing pregnancy. Methods This was a retrospective cohort study including 225 couples undergoing 225 cycles of in vitro fertilization (IVF) treatment with time-lapse embryo culture. The fertilization method was either conventional IVF, intracytoplasmic sperm injection (ICSI) with ejaculated sperm or ICSI with sperm derived from testicular sperm extraction (TESE-ICSI). This resulted in 289 IVF embryos, 218 ICSI embryos and 259 TESE-ICSI embryos that reached at least the full blastocyst stage. Blastocoel surface measurements were performed on time-lapse images every hour, starting from full blastocyst formation (tB). Linear mixed model analysis was performed to study the association between blastocoel expansion, the calculated expansion rate (µm 2 /hour) and both fertilization method and ongoing pregnancy. Results The blastocoel of both ICSI embryos and TESE-ICSI embryos was significantly smaller than the blastocoel of IVF embryos (beta -1121.6 µm 2 ; 95% CI: -1606.1 to -637.1, beta -646.8 µm 2 ; 95% CI: -1118.7 to 174.8, respectively). Still, the blastocoel of transferred embryos resulting in an ongoing pregnancy was significantly larger (beta 795.4 µm 2 ; 95% CI: 15.4 to 1575.4) and expanded significantly faster (beta 100.9 µm 2 /hour; 95% CI: 5.7 to 196.2) than the blastocoel of transferred embryos that did not, regardless of the fertilization method. Conclusion Longitudinal blastocyst surface measurements and expansion rates are promising non-invasive quantitative markers that can aid embryo selection for transfer and cryopreservation. Trial registration Our study is a retrospective observational study, therefore trial registration is not applicable.

Background Overweight and obesity affect millions of people globally, which has also serious implications for reproduction. For example, treatment outcomes after in vitro fertilisation (IVF) are worse in women with a high body mass index (BMI). However, the impact of maternal BMI on embryo quality is inconclusive. Our main aim is to study associations between preconceptional maternal BMI and morphokinetic parameters of preimplantation embryos and predicted implantation potential. In addition, associations with clinical IVF outcomes are investigated. Methods From a tertiary hospital, 268 women undergoing IVF or IVF with intracytoplasmic sperm injection (ICSI) were included; 143 normal weight, 79 overweight and 46 obese women. The embryos of these women were cultured in the EmbryoScope, a time-lapse incubator. The morphokinetic parameters of preimplantation embryos and predicted implantation potential, assessed by the KIDScore algorithm were longitudinally evaluated as primary and secondary outcomes, respectively. The tertiary outcomes included clinical outcomes, i.e., fertilization, implantation and live birth rate. Results After adjustment for patient- and treatment-related factors, we demonstrated in 938 embryos that maternal BMI is negatively associated with the moment of pronuclear appearance (β tPNa -0.070 h (95%CI -0.139, -0.001), p  = 0.048), pronuclear fading (β tPNf -0.091 h (95%CI -0.180, -0.003), p  = 0.043 and the first cell cleavage (β t2 -0.111 h (95%CI -0.205, -0.016), p  = 0.022). Maternal BMI was not significantly associated with the KIDScore and tertiary clinical treatment outcomes. In embryos from couples with female or combined factor subfertility, the impact of maternal BMI was even larger (β tPNf -0.170 h (95%CI -0.293, -0.047), p  = 0.007; β t2 -0.199 h (95%CI -0.330, -0.067), p  = 0.003). Additionally, a detrimental impact of BMI per point increase was observed on the KIDScore (β -0.073 (se 0.028), p  = 0.010). Conclusions Higher maternal BMI is associated with faster early preimplantation development. In couples with female or combined factor subfertility, a higher BMI is associated with a lower implantation potential as predicted by the KIDScore. Likely due to power issues, we did not observe an impact on clinical treatment outcomes. However, an effect of faster preimplantation development on post-implantation development is conceivable, especially since the impact of maternal BMI on pregnancy outcomes has been widely demonstrated.

Polycystic ovary syndrome (PCOS) affects 5–20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) — with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder. Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Here, Azziz et al . describe the current state of knowledge regarding the epidemiology, pathophysiology, diagnosis, management and future investigational directions of the disorder.

Background The predictive capability of time-lapse monitoring (TLM) selection algorithms is influenced by patient characteristics, type and quality of data included in the analysis and the used statistical methods. Previous studies excluded DET cycles of which only one embryo implanted, introducing bias into the data. Therefore, we wanted to develop a TLM prediction model that is able to predict pregnancy chances after both single- and double embryo transfer (SET and DET). Methods This is a retrospective study of couples ( n  = 1770) undergoing an in vitro fertilization cycle at the Erasmus MC, University Medical Centre Rotterdam (clinic A) or the Reinier de Graaf Hospital (clinic B). This resulted in 2058 transferred embryos with time-lapse and pregnancy outcome information. For each dataset a prediction model was established by using the Embryo-Uterus statistical model with the number of gestational sacs as the outcome variable. This process was followed by cross-validation. Results Prediction model A (based on data of clinic A) included female age, t3-t2 and t5-t4, and model B (clinic B) included female age, t2, t3-t2 and t5-t4. Internal validation showed overfitting of model A (calibration slope 0.765 and area under the curve (AUC) 0.60), and minor overfitting of model B (slope 0.915 and AUC 0.65). External validation showed that model A was capable of predicting pregnancy in the dataset of clinic B with an AUC of 0.65 (95% CI: 0.61–0.69; slope 1.223, 95% CI: 0.903–1.561). Model B was less accurate in predicting pregnancy in the dataset of clinic A (AUC 0.60, 95% CI: 0.56–0.65; slope 0.671, 95% CI: 0.422–0.939). Conclusion Our study demonstrates a novel approach to the development of a TLM prediction model by applying the EU statistical model. With further development and validation in clinical practice, our prediction model approach can aid in embryo selection and decision making for SET or DET.