Women Of Advanced Maternal Age Research Articles

Aneuploidy in Oocytes From Women of Advanced Maternal Age: Analysis of the Causal Meiotic Errors and Impact on Embryo Development

ABSTRACT Many chromosome abnormalities are commonly observed and can lead to early pregnancy loss, miscarriage, or the birth of children with chromosomal defects. Such abnormalities are considered a major factor in the low pregnancy rate after assisted reproductive technology and natural conception. Preimplantation genetic testing for aneuploidy (PGT-A) aims to minimize the transfer of aneuploid embryos. Embryonic aneuploidies arising from errors in meiosis have an incidence of approximately 25% in embryos from women younger than 35 years, to more than half in embryos from women aged older than 35 years. Although these embryos are able to develop to the blastocyst stage, they tend to be of lower morphological quality. A recent multicenter randomized clinical trial (ESTEEM) analyzed polar bodies (PBs) from women after intracytoplasmic sperm injection aged between 36 and 40 years using microarrays in 205 cycles and found that the transfer of embryos from euploid oocytes did not lead to a higher live birth rate but was associated with a reduction in the number of embryo transfers and miscarriages. This study aimed to evaluate all PB results from this RCT and characterize the types of chromosomal abnormalities and the chromosomes most frequently affected. The ESTEEM trial obtained biopsy of first (PB1) and second (PB2) PB in the cohort receiving PGT-A and analyzed them using array comparative genomic hybridization (aCGH). A total of 693 PB pairs had full results available, including 676 confirmed fertilized oocytes. Chromosome segregations, including likely underlying mechanisms, from these pairs are reported here. To estimate the reliability of the aCGH procedure, 72 PB pairs from a single center were reanalyzed using next-generation sequencing (NGS). Embryos were classified into 4 categories based on morphology: good, fair, poor, and degenerated. A comparative analysis was performed to assess the association between chromosome status and embryo quality as well as study group (PGT-A vs control) and embryo quality. A total of 213/676 oocytes were euploid and 413/676 were aneuploid, whereas in the remaining 50 oocytes, an abnormality observed in PB1 was compensated by an abnormality in PB2. A total of 693 PB pairs reported chromatic numbers with results for 15,939 chromosomes. An abnormal segregation, in PB1 and/or PB2, was observed in 1162 chromosomes (7.3%) in 461 PB pairs. Chromosomes 22 (16.7%), 16 (16.6%), 19 (14.4%), 21 (13.7%), and 15 (12.4%) had the highest frequencies for abnormal segregations. The abnormal segregations were compatible with precocious separation of sister chromatids in meiosis 1 (M1) (n = 568; 48.9%), nondisjunction of chromatics in meiosis 2 (M2) or reverse segregation (n = 417; 35.9%), and nondisjunction in M1 (n = 65; 5.6%). However, 112 chromosomes had segregation patterns that could not be categorized into 1 of the 9 known mechanisms causing aneuploidy in oocytes. Concordance between aCGH and NGS was obtained for both PBs for 1650 of 1656 analyzed chromosomes (99.6%). Embryos predicted to be aneuploid had significantly worse quality scores on day 3 (adjusted odds ratio [aOR], 0.62; 95% confidence interval [CI], 0.43–0.90), day 4 (aOR, 0.15; 95% CI, 0.06–0.39), and day 5 (aOR, 0.28; 95% CI, 0.14–0.58). This study represents one of the largest analyses of chromosomal copy number in both PBs to date and highlights the frequent unexplained chromosome copy numbers underscoring the gap of knowledge into the mechanisms causing aneuploidy in oocytes.

Mitochondrial Dysfunction in Advanced Maternal Aged Cumulus Cells: A Possible Link to ATP Synthase Impairment?

Age-related changes in the mitochondrial status of human cumulus cells (hCCs) impact oocyte quality; however, the relationship between hCC mitochondrial (dys)function and reproductive aging remains poorly understood. This study aimed to establish the interplay between hCC mitochondrial dysfunction and women's reproductive potential. In this investigation, 266 women were enrolled and categorized into two groups based on their age: a young group (<35 years old) and an advanced maternal age (AMA) group (≥35 years old). Comprehensive analysis of reproductive outcomes was conducted in our population. Various mitochondrial-related parameters were analyzed across distinct subsets. Specifically, mitochondrial membrane potential (∆Ψm) and mitochondrial mass were examined in 53 samples, mtDNA content in 25 samples, protein levels in 23 samples, bioenergetic profiles using an XF24 Extracellular Flux Analyzer in 6 samples, and levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) in 39 and 43 samples, respectively. In our study, the reproductive potential of AMA women sharply decreased, as expected. Additionally, an impairment in the mitochondrial function of hCCs in older women was observed; however, no differences were found in terms of mitochondrial content. Regarding oxidative phosphorylation, metabolic profiling of hCCs from AMA women indicated a decrease in respiratory capacity, which was correlated with an age-dependent decrease in the ATP synthase (ATP5A1) protein level. However, intracellular ROS and ATP levels did not differ between groups. In conclusion, our study indicates that age-related dysfunction in hCCs is associated with impaired mitochondrial function, and, although further studies are required, ATP synthase could be relevant in this impairment.

Optimal timing of GnRH antagonist initiation in IVF-ET: a retrospective cohort study on advanced maternal age women.

Several studies have compared the effects of fixed and flexible gonadotropin releasing hormone antagonist (GnRH-ant) protocols during in vitro fertilization and embryo transfer (IVF-ET). However, which GnRH-ant initiation strategy is better remains controversial. Moreover, no studies have assessed the optimal timing of GnRH-ant initiation in women of advanced maternal age (AMA). In this retrospective cohort study, a total of 472 infertile women aged ≥ 35 years old undergoing their first IVF cycle from August 2015 to September 2021 at a tertiary academic medical center were recruited, of whom 136 followed fixed GnRH-ant protocol and 336 followed flexible GnRH-ant protocol. The primary outcomes measured were the cumulative live birth rate (CLBR) per IVF cycle and the time to live birth (TTLB) from the date of oocyte retrieval. Cox proportional models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of CLBR regarding GnRH-ant timing. No significant difference in CLBR was found between the fixed and flexible GnRH-ant groups (27.9% vs 20.5%, p=0.105). The TTLB was also comparable between groups (10.56 vs 10.30 months, p=0.782). The Kaplan-Meier analysis for CLBR also showed comparable results between groups (P=0.351, HR=0.83; 95%CI: 0.56-1.23). After establishing a multiple Cox proportional hazard model, the fixed GnRH-ant group still had comparable CLBR with the flexible GnRH-ant group (HR=0.85; 95%CI: 0.53-1.38; P=0.518). Subgroup and sensitivity analyses also demonstrated similar results. GnRH-ant protocols can be tailored to the needs of AMA women, and timing of GnRH-ant initiation can be adjusted flexibly.

Perinatal characteristics and pregnancy outcomes of advanced maternal age women with gestational diabetes mellitus: A retrospective cohort study.

The prevalence of gestational diabetes mellitus (GDM) continues to increase, and the phenomenon of women giving birth at an older age is becoming more common worldwide. Less is known abouts the impact of GDM combined with advanced maternal age (AMA) on pregnancy outcomes. To explore the impact of AMA complicated with GDM on pregnancy outcomes. This study included 34,602 pregnancies between 2018 and 2020 in Hangzhou, China. The pregnant women were divided into four groups according to advanced age (≥35 years) and GDM as follows: AMA women without GDM (non-AGDM) group (n = 2614), young pregnant women with GDM (YGDM) group (n = 4016), AMA women with GDM (AGDM) group (n = 850), and young pregnant women without GDM (non-YGDM) group (n = 27,122). Univariate analysis was carried out by Mann-Whitney U test or Pearson's χ 2 test. Multivariate logistic regression analysis was used to investigate the effect of AMA and GDM on pregnancy outcomes. Multivariate logistic regression analysis showed that in the comparison against non-YGDM garoup, the ORs of fetal chromosome abnormality, parity, urgent cesarean section, gravidity, scheduled cesarean section, body mass index (BMI) ≥30 kg/m2, pre-eclampsia, thrombocytopenia, hyperlipidemia, BMI 25-29.9 kg/m2, blood urea nitrogen, fasting blood glucose, and creatinine in AGDM group were 16.044, 4.284, 3.530, 3.284, 3.257, 2.049, 1.935, 1.898, 1.690, 1.471, 1.304, 1.216, and 1.026 (all p < 0.05). The prevalence of pregnant women with AGDM was 2.46% in Hang Zhou, China. The increasing gravidity of AMA women was related to a greater risk of GDM. The AGDM group associated with a greater risks of chromosomal abnormality in offspring and cesarean section, especially urgent cesarean section.

The Impact of Serum Uric Acid Levels on Hypertensive Disorders of Pregnancy in Advanced Maternal Age Women: A Retrospective Study from a Single Center in China.

BACKGROUND In many countries, including China, women are delaying pregnancy until later in life; therefore, hypertensive disorders of pregnancy (HDP) are increasing. This retrospective study from a single center in China aimed to evaluate the association between serum uric acid (SUA) levels and HDP in 288 women of advanced maternal age >35 years. MATERIAL AND METHODS A total of 780 pregnant women of advanced maternal age were included in the study - 288 were had HDP (including gestational hypertension and preeclampsia) and 492 had normal blood pressure using 1: 2 (84: 168) propensity score matching. SUA (collected before 20 weeks' gestation) and HDP incidence in advanced maternal age women were assessed using multivariate logistic modeling and 3 propensity score-based methods. RESULTS Median patient age was 37 years. The risk of developing HDP increases with higher SUA (30.19% vs 13.65%, P<0.001). In the PS-matched cohort, the risk ratio (OR) for HDP with high uric acid after adjusting for confounders was 2.88 (95% CI: 1.44-5.75, P=0.0027). It has been demonstrated that high uric acid is strongly associated with HDP incidence in both the crude population (OR=3.43, 95% CI: 2.01-4.66, P<0.0001) and the weighted cohorts (OR=3.62, 95% CI: 2.81-4.66, P<0.0001). As a successive variable, after adjusting for the clinical confounders, a 1-SD increase in SUA was related to a 135% increased risk of HDP (OR=2.35; 95% CI: 1.57-3.50; P<0.0001) based on the fully adjusted model. There were similar conclusions in the sensitivity analysis. CONCLUSIONS There was a significant association between SUA and HDP in women of advanced maternal age, supporting the importance of early detection of SUA in pregnant women.

DETERMINANTS OF PREGNANCY LOSS AMONG WOMEN OF REPRODUCTIVE AGE IN INDONESIA

Background. Both miscarriage and stillbirth occur in almost 20% of clinical pregnancies, resulting in pregnancy loss. The incidence has been associated with several risk factors and events of maternal adverse health outcomes. Purpose. This study was conducted to analyze some associated factors of pregnancy loss in Indonesia. Methods. This cross-sectional study used the 2017 Indonesia DHS data involving 18,882 female participants aged 15–49 years who had ever had a gestation. Pregnancy loss was the dependent variable, whereas the independent variables included education, employment, wealth status, advanced maternal age, grand multiparity, and cigarette smokers. Finally, the author used binary logistic regression to calculate the determinants. Results. The adjusted risk of pregnancy loss was significantly higher in respondents with lower education levels (AOR=1.25; 95% CI: 1.11-1.41) and employed (AOR=1.19; 95% CI: 1.10-1.29). The lower the wealth status of women, the higher the chance of pregnancy loss. The adjusted risk of pregnancy loss was higher in women of advanced maternal age (AOR=2.03; 95% CI: 1.37-3.02), those with grand multiparity (AOR=1.91; 95% CI: 1.74-2.09), and those who cigarette smokers (AOR=1.53; 95% CI: 1.25-1.87). Conclusion. The study concluded that six variables i.e., education, employment, wealth status, advanced maternal age, grand multiparity, and cigarette smokers are strong predictors of pregnancy loss in Indonesian women. Therefore, the government should make a policy to address the determinants of the pregnancy issue.

Unplanned cesarean sections in advanced maternal age: Apredictive model.

As maternal age during pregnancy is rising all over the world, there is a growing need for prognostic factors that determine maternal and perinatal outcomes in older women. This study is a retrospective cohort study of women aged 40 years or older at the time of delivery in four Santeon hospitals across the Netherlands between January 2016 and December 2019. Outcomes were compared between women of 40-44 years (advanced maternal age) and 45 years and older (very advanced maternal age). Primary outcome was unplanned cesarean section, secondary outcomes included postpartum hemorrhage and neonatal outcomes. Multivariate regression analysis was performed to analyze predictive factors for unplanned cesarean sections in women who attempted vaginal delivery. Subsequently, a predictive model and risk scores were constructed to predict unplanned cesarean section. A cohort of 1660 women was analyzed; mean maternal age was 41.4 years, 4.8% of the women were 45 years and older. In both groups, more than half of the women had not delivered vaginally before. Unplanned cesarean sections were performed in 21.1% of the deliveries in advanced maternal age and in 29.1% in very advanced maternal age. Four predictive factors were significantly correlated with unplanned cesarean sections: higher body mass index (BMI), no previous vaginal delivery, spontaneous start of delivery and number of days needed for cervical priming. A predictive model was constructed from these factors with an area under the curve of 0.75 (95% confidence interval 0.72-0.78). A sensitivity analysis in nulliparous women proved that BMI, days of cervical priming, age, and gestational age were risk factors, whereas spontaneous start of delivery and induction were protective factors. There was one occurrence of neonatal death. Women of advanced maternal age and those of very advanced maternal age have a higher chance of having an unplanned cesarean section compared to the general obstetric population in the Netherlands. Unplanned cesarean sections can be predicted through use of our predictive model. Risk increases with higher BMI, no previous vaginal delivery, and increasing number of days needed for cervical priming, whereas spontaneous start of labor lowers the risk. In nulliparous women, age and gestational age also increase risk, but induction lowers the risk of having an unplanned cesarean section.

In Vitro Fertilization/Intracytoplasmic Sperm Injection with Autologous Oocytes in Healthy Women of Advanced Maternal Age: A Comparative Study Investigating Obstetric and Perinatal Outcomes Through Single Versus Double Embryo Transfer.

The aim of this study was to assess whether the choice between double embryo transfer (DET) and single embryo transfer (SET) in healthy women of advanced maternal age (AMA) was associated with an increased risk of adverse outcomes. Healthy women aged 39-40 years who achieved live birth after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment between 2009 and 2020 at Karolinska University Hospital, Stockholm in Sweden, were included in this prospective, single-center cohort study. A total of 310 women, who underwent IVF/ICSI treatments and achieved live births, were included in our analysis. Within this cohort, 78% of the women received SET, while 22% received DET. Nulliparity was common in both the SET (62.7%) and DET (85.3%) groups. Fresh embryo transfers were more prevalent in the DET group (91.2%) than in the SET group (31.1%). The rate of pregnancy-induced hypertension was higher in the SET group (8.3%) compared to the DET group (1.5%, p = 0.048). Furthermore, the DET group had a significantly higher rate of twin pregnancies (13.2%) compared to the SET group (0.4%). No statistically significant differences were observed in composite obstetric and perinatal complications between the SET and DET groups across all model estimates following different adjustments.Clinical Trial Registration number: ClinicalTrials.gov NTC04602962. While DET was more common in nulliparous women and associated with a higher rate of twin pregnancies, our analysis did not reveal significant differences in adverse outcomes between the SET and DET groups after comprehensive adjustments. Our study suggests that in the absence of co-morbidities, meticulous patient selection coupled with comprehensive maternal care can potentially mitigate potential DET-associated risks in women of AMA.

Clinical outcomes of preimplantation genetic testing for aneuploidy in high-risk patients: a retrospective cohort study.

The purpose of this study was to evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on clinical outcomes among high-risk patients. This retrospective study involved 1,368 patients and the same number of cycles, including 520 cycles with PGT-A and 848 cycles without PGT-A. The study participants comprised women of advanced maternal age (AMA) and those affected by recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), or severe male factor infertility (SMF). PGT-A was associated with significant improvements in the implantation rate (IR) and the ongoing pregnancy rate/live birth rate (OPR/LBR) per embryo transfer cycle in the AMA (39.3% vs. 16.2% [p<0.001] and 42.0% vs. 21.8% [p<0.001], respectively), RIF (41.7% vs. 22.0% [p<0.001] and 47.0% vs. 28.6% [p<0.001], respectively), and RPL (45.6% vs. 19.5% [p<0.001] and 49.1% vs. 24.2% [p<0.001], respectively) groups, as well as the IR in the SMF group (43.3% vs. 26.5%, p=0.011). Additionally, PGT-A was associated with lower overall incidence rates of early pregnancy loss in the AMA (16.7% vs. 34.3%, p=0.001) and RPL (16.7% vs. 50.0%, p<0.001) groups. However, the OPR/LBR per total cycle across all PGT-A groups did not significantly exceed that for the non-PGT-A groups. PGT-A demonstrated beneficial effects in high-risk patients. However, our findings indicate that these benefits are more pronounced in carefully selected candidates than in the entire high-risk patient population.

Optimising Rehabilitation Strategies for Postpartum Elderly Gravida with In Vitro Fertilisation Conception

Optimising Rehabilitation Strategies for Postpartum Elderly Gravida with In Vitro Fertilisation Conception

Risk factors and characteristics of the birth of patients with craniofacial microsomia, a case-control study.

Craniofacial microsomia (CM) is characterized by changes in the first and second branchial arches. It is a clinical condition whose etiology is still uncertain, but studies have shown that genetic, nutritional, and environmental factors can result in disorders of blastogenesis of the branchial arches. This study evaluates gestational aspects, focusing on possible risk factors associated with CM. This is a case-control study conducted with patients monitored at a medical genetics service and compared to a control group of patients without evidence of malformations, born in a mother and child hospital, both located in Porto Alegre, Southern Brazil. Mothers' data were obtained using questionnaires and by reviewing medical records. The sample consisted of 43 patients with CM (cases) and 129 patients without evidence of malformations (controls), paired by sex, totaling three controls for each case. Data analysis was performed using the two-tailed Fisher's exact test, Pearson's chi-square test, and the t-test. We identified several factors associated with the development of CM, including the use of abortion methods by the mothers of these babies (p = .001), maternal diabetes (p = .009), advanced maternal age (p = .035), and a history of vaginal bleeding (p < .001). Furthermore, these patients exhibited a tendency to be born prematurely (p = .027), with low birth weight (p = .007), and lower Apgar scores (p = .003) when compared to healthy infants. Using a multivariate model, the use of abortion methods (p = .003) and vaginal bleeding (p = .032) remained independently associated with craniofacial microsomia. We have identified several risk factors for the development of CM, including a propensity for premature birth, low birth weight, and respiratory difficulties. Additionally, women of advanced maternal age and/or those who used abortion methods and/or have diabetes have a higher risk of giving birth to a baby with CM. This information can be valuable in clinical practice, especially for the prevention of future cases.

Analysis of influencing factors and the construction of predictive models for postpartum depression in older pregnant women.

Changes in China's fertility policy have led to a significant increase in older pregnant women. At present, there is a lack of analysis of influencing factors and research on predictive models for postpartum depression (PPD) in older pregnant women. To analysis the influencing factors and the construction of predictive models for PPD in older pregnant women. By adopting a cross-sectional survey research design, 239 older pregnant women (≥ 35 years old) who underwent obstetric examinations and gave birth at Suzhou Ninth People's Hospital from February 2022 to July 2023 were selected as the research subjects. When postpartum women of advanced maternal age came to the hospital for follow-up 42 d after birth, the Edinburgh PPD Scale (EPDS) was used to assess the presence of PPD symptoms. The women were divided into a PPD group and a no-PPD group. Two sets of data were collected for analysis, and a prediction model was constructed. The performance of the predictive model was evaluated using receiver operating characteristic (ROC) analysis and the Hosmer-Lemeshow goodness-of-fit test. On the 42nd day after delivery, 51 of 239 older pregnant women were evaluated with the EPDS scale and found to have depressive symptoms. The incidence rate was 21.34% (51/239). There were statistically significant differences between the PPD group and the no-PPD group in terms of education level (P = 0.004), family relationships (P = 0.001), pregnancy complications (P = 0.019), and mother-infant separation after birth (P = 0.002). Multivariate logistic regression analysis showed that a high school education and below, poor family relationships, pregnancy complications, and the separation of the mother and baby after birth were influencing factors for PPD in older pregnant women (P < 0.05). Based on the influencing factors, the following model equation was developed: Logit (P) = 0.729 × education level + 0.942 × family relationship + 1.137 × pregnancy complications + 1.285 × separation of the mother and infant after birth -6.671. The area under the ROC curve of this prediction model was 0.873 (95%CI: 0.821-0.924), the sensitivity was 0.871, and the specificity was 0.815. The deviation between the value predicted by the model and the actual value through the Hosmer-Lemeshow goodness-of-fit test was not statistically significant (χ2 = 2.749, P = 0.638), indicating that the model did not show an overfitting phenomenon. The risk of PPD among older pregnant women is influenced by educational level, family relationships, pregnancy complications, and the separation of the mother and baby after birth. A prediction model based on these factors can effectively predict the risk of PPD in older pregnant women.

#38 : Maternal Age Affects Morula Compaction and Cell Polarity of Human Embryos

Background and Aims: With the exception of chromosome segregation errors, the molecular and biochemical mechanisms responsible for advanced maternal age (AMA)-related reduced embryo developmental competence remain unclear. In women of AMA, the blastocyst formation rate has been reported to decline due to an increase in embryo arrest at the morula stage. Therefore, we aimed to reveal the impact of AMA on cellular events during compaction, as assessed using morphokinetic analysis. We also assessed the possible influence of AMA on the expression of cell polarity markers, yes-associated protein (YAP) and protein kinase C-[Formula: see text] (PKC[Formula: see text]), during blastomere compaction. Method: We retrospectively analysed 2,058 fertilized oocytes, which were stratified by maternal age according to the Society for Assisted Reproductive Technology classification (&lt; 35, 35-37, 38–40, 41–42, and &gt; 42 years). The effects of AMA were assessed in relation to embryo morphokinetics and morphological alterations. Furthermore, 20 voluntarily donated human embryos were used for immunofluorescence staining of YAP and PKC-[Formula: see text]. Results: Delayed embryonic compaction and an increased number of extruded blastomeres post compaction were observed in the &gt; 42-year group. The time interval from the eight-cell stage to compaction initiation was prolonged with increasing age. The number of YAP-positive cells in the outer cells of the morulae was significantly higher in the young age group than in the AMA groups. The PKC[Formula: see text] fluorescence intensity in the cortical region of the morulae was significantly lower in the AMA groups than in the young age groups. Conclusion: Delayed compaction and blastomere extrusion occur more frequently in embryos from women of AMA due to insufficient regulation of cell polarity, which may lead to morula arrest. Further research is required to reveal the impacts of AMA on the mechanism underlying the expression of cell polarity factors and develop methods to avoid AMA-associated morula arrest.

Commentary on: Increased stiffness of omental arteries from late pregnant women at advanced maternal age.

Worldwide, pregnancy at age 35 or older, termed 'advanced maternal age (AMA)', is increasing exponentially. As the incidence of pregnancy at AMA has increased, a growing body of evidence has suggested that AMA is also associated with increased risk for adverse maternal and fetal outcomes outside of genetic anomalies. Importantly, despite the mounting evidence and the increased global risk of adverse perinatal outcomes observed, few studies have examined the potential mechanisms underlying this elevated risk in pregnant people ≥35 years of age. Wooldridge and colleagues begin to address this gap in the literature. In their recent report, they examine vessel stiffness in omental resistance vessels obtained from pregnant individuals ≥35 years of age compared with pregnant individuals <35 years of age. Omental arteries were isolated and assessed via pressure myography (mechanical properties) and histological analysis for collagen and elastin content. Overall, the findings from this investigation report that maternal resistance arteries collected from women of AMA were less compliant and had less elastin than arteries obtained from women <35 years of age, suggesting that maternal resistance vessel stiffening in AMA may contribute to increased risk of adverse pregnancy outcomes. The authors should be commended for completing these studies in human resistance vessels, which now open new avenues for investigation and provoke a cascade of questions related to maternal cardiovascular adaptations to pregnancy in women ≥35 years of age.

Effectiveness of recombinant human FSH: recombinant human LH combination treatment versus recombinant human FSH alone for assisted reproductive technology in women aged 35–40 years

Research questionAccording to real-world data, is recombinant human FSH (r-hFSH) combined with recombinant human LH (r-hLH) or r-hFSH alone more effective for women of advanced maternal age (AMA) in terms of live birth? DesignNon-interventional study comparing the effectiveness of r-hFSH and recombinant r-hLH (2:1 ratio) versus r-hFSH alone for ovarian stimulation during ART treatment in women aged 35–40 years, using real-world data from the Deutsches IVF-Register. ResultsOverall clinical pregnancy (29.8%, 95% CI 28.2 to 31.6 versus 27.8%, 95% CI 26.5 to 29.2) and live birth (20.3%, 95% CI 18.7 to 21.8 versus 18.0%, 95% CI 16.6 to 19.4) rates were not significantly different between the combined r-hFSH and r-hLH group and the r-hFSH alone group (P = 0.269 and P = 0.092, respectively). Treatment effect was significantly higher for combined r-hFSH and r-hLH compared with r-hFSH alone for clinical pregnancy (33.1%, 95% CI 31.0 to 35.0 versus 28.5%, 95% CI 26.6 to 30.4; P = 0.001, not adjusted for multiplicity) and live birth (22.5%, 95% CI 20.5 to 24.2 versus 19.4%, 95% CI 17.6 to 20.9; P = 0.014, not adjusted for multiplicity) in a post-hoc analysis of women with five to 14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of combined r-hFSH and r-hLH for ovarian stimulation in women aged 35–40 years with normal ovarian reserve. ConclusionsWomen of AMA with normal ovarian response benefit from treatment with combined r-hFSH and r-hLH in a 2:1 ratio versus r-hFSH alone in terms of live birth rate. The effectiveness of treatments is best assessed by RCTs; however, real-world data are valuable for examining the effectiveness of fertility treatment, especially among patient groups that are not well represented in clinical trials.

Colonisation of Group B Streptococcus and its effects on pregnancy outcomes in pregnant women in Guangzhou, China: a retrospective study

ObjectivesThis study was to investigate the colonisation rate of Group B Streptococcus (GBS) during pregnancy, and to evaluate the influence of GBS colonisation on pregnancy outcomes.DesignA retrospective cohort study.SettingData of...

An interpretation for Chinese expert consensus on how to manage pregnant women of advanced maternal age with scarred uterus

Deferral of marriage and child-bearing age as well as high occurrence of uterine surgery history such as cesarean section and myomectomy in women who are about to have babies are challenging obstetrical health care worldwide, since pregnancy at advanced maternal age and pregnancy with scarred uterus are both high-risk pregnancy. In China, one-child policy had been implemented for three decades and contributes to high cesarean section rates. With family planning policy turning to two and three-child, there are rising pregnancy at advanced maternal age with scarred uterus. A clinical management scheme can help obstetricians a lot to assess risks, prevent pregnancy complications and manage pregnancy in an organized manner. However, there are insufficient studies on relevant clinical issues for the specific population, and there is no consensus or practice guidelines until now. We have developed Chinese expert consensus based on our pioneering research findings on the prevention and treatment strategy for major pregnancy complications in women of advanced maternal age. We formulate the consensus comprising general management scheme to standardize clinical care, practical risk scoring systems to early warn major pregnancy complications, and nationwide expert recommendations to be in accordance with evidence-based appraisal method. Consecutive supervision along with stratified management are highly emphasized. We interpret the consensus containing up-to-date literature review, research findings interpretation and most concerned questions discussion. This consensus interpretation helps standardize how to manage pregnant women of advanced maternal age with scarred uterus and improve the maternal-fetal outcomes.

Benefits of Blastocyst Transfer With at Least Three Good-Quality Cleavage-stage Embryos in Women of Advanced Maternal Age: A Retrospective Analysis

ObjectivesLimited studies on the benefits of blastocyst transfer in advanced maternal age (AMA) (≥40 years) have been reported. Our objective was to find whether blastocyst-stage embryo transfer improves pregnancy and live birth rates in women ≥40 years who have 3 or more good-quality cleavage-stage embryos. MethodsAll fresh in vitro fertilization-intracytoplasmic sperm injection cycles performed from January 2020 to December 2021 in AMA women that progressed to transfer were considered for analysis. We compared fresh and cumulative ongoing pregnancy rates in AMA women of those who had a cleavage-stage transfer, while meeting the criteria for extended culture (≥3 high-quality embryos, group 1), and those who underwent blastocyst transfer (group 2). Demographic parameters, stimulation, embryology, fresh and cumulative ongoing pregnancy rates, and clinical miscarriage rates were compared. ResultsDuring the study period, 255 cycles were analyzed including group 1 (n = 99) and group 2 (n = 156). Group 1 participants were older and had a greater number of embryos for transfer. Fresh and cumulative ongoing pregnancy rates per transfer were higher in group 2 compared to group 1 (23.4% vs. 13.1%, P = 0.04; 25.5% vs. 14.1%, P = 0.03), while overall miscarriage rates were higher in group 1 than group 2 (51.7% vs. 25%, P = 0.01). ConclusionsBlastocyst culture provides a benefit to AMA women who have at least 3 good-quality embryos on day 3 resulting in significantly higher fresh and cumulative ongoing pregnancy rates and lower miscarriage compared to cleavage-stage transfers.

Aneuploidy in oocytes from women of advanced maternal age: analysis of the causal meiotic errors and impact on embryo development.

In oocytes of advanced maternal age (AMA) women, what are the mechanisms leading to aneuploidy and what is the association of aneuploidy with embryo development? Known chromosome segregation errors such as precocious separation of sister chromatids explained 90.4% of abnormal chromosome copy numbers in polar bodies (PBs), underlying impaired embryo development. Meiotic chromosomal aneuploidies in oocytes correlate with AMA (>35 years) and can affect over half of oocytes in this age group. This underlies the rationale for PB biopsy as a form of early preimplantation genetic testing for aneuploidy (PGT-A), as performed in the 'ESHRE STudy into the Evaluation of oocyte Euploidy by Microarray analysis' (ESTEEM) randomized controlled trial (RCT). So far, chromosome analysis of oocytes and PBs has shown that precocious separation of sister chromatids (PSSC), Meiosis II (MII) non-disjunction (ND), and reverse segregation (RS) are the main mechanisms leading to aneuploidy in oocytes. Data were sourced from the ESTEEM study, a multicentre RCT from seven European centres to assess the clinical utility of PGT-A on PBs using array comparative genomic hybridization (aCGH) in patients of AMA (36-40 years). This included data on the chromosome complement in PB pairs (PGT-A group), and on embryo morphology in a subset of embryos, up to Day 6 post-insemination, from both the intervention (PB biopsy and PGT-A) and control groups. ESTEEM recruited 396 AMA patients: 205 in the intervention group and 191 in the control group. Complete genetic data from 693 PB pairs were analysed. Additionally, the morphology from 1034 embryos generated from fertilized oocytes (two pronuclei) in the PB biopsy group and 1082 in the control group were used for statistical analysis. Overall, 461/693 PB pairs showed abnormal segregation in 1162/10 810 chromosomes. The main observed abnormal segregations were compatible with PSSC in Meiosis I (MI) (n = 568/1162; 48.9%), ND of chromatids in MII or RS (n = 417/1162; 35.9%), and less frequently ND in MI (n = 65/1162; 5.6%). For 112 chromosomes (112/1162; 9.6%), we observed a chromosome copy number in the first PB (PB1) and second PB (PB2) that is not explained by any of the known mechanisms causing aneuploidy in oocytes. We observed that embryos in the PGT-A arm of the RCT did not have a significantly different morphology between 2 and 6 days post-insemination compared to the control group, indicating that PB biopsy did not affect embryo quality. Following age-adjusted multilevel mixed-effect ordinal logistic regression models performed for each embryo evaluation day, aneuploidy was associated with a decrease in embryo quality on Day 3 (adjusted odds ratio (aOR) 0.62, 95% CI 0.43-0.90), Day 4 (aOR 0.15, 95% CI 0.06-0.39), and Day 5 (aOR 0.28, 95% CI 0.14-0.58). RS cannot be distinguished from normal segregation or MII ND using aCGH. The observed segregations were based on the detected copy number of PB1 and PB2 only and were not confirmed by the analysis of embryos. The embryo morphology assessment was static and single observer. Our finding of frequent unexplained chromosome copy numbers in PBs indicates that our knowledge of the mechanisms causing aneuploidy in oocytes is incomplete. It challenges the dogma that aneuploidy in oocytes is exclusively caused by mis-segregation of chromosomes during MI and MII. Data were mined from a study funded by ESHRE. Illumina provided microarrays and other consumables necessary for aCGH testing of PBs. None of the authors have competing interests. Data were mined from the ESTEEM study (ClinicalTrials.gov Identifier NCT01532284).

Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction.

Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes? We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resulted in the use of alternative energy sources. Signs of reactive oxygen species-induced damage and mitochondrial dysfunction have been observed in maturing follicles, and even in early stages of embryogenesis. However, although recent evidence indicates that also primordial follicles have metabolically active mitochondria, it is still often assumed that these follicles avoid oxidative phosphorylation to prevent oxidative damage in dictyate arrested oocytes. Data on the influence of ovarian aging on oocyte metabolism and mitochondrial function are still limited. A set of 39 formalin-fixed and paraffin-embedded ovarian tissue biopsies were divided into different age groups and used for immunofluorescence analysis of oxidative phosphorylation activity and oxidative damage to proteins, lipids, and DNA. Additionally, 150 immature oocytes (90 germinal vesicle oocytes and 60 metaphase I oocytes) and 15 cumulus cell samples were divided into different age groups and used for targeted metabolomics and lipidomics analysis. Ovarian tissues used for immunofluorescence microscopy were collected through PALGA, the nationwide network, and registry of histo- and cytopathology in The Netherlands. Comprehensive metabolomics and lipidomics were performed by liquid-liquid extraction and full-scan mass spectrometry, using oocytes and cumulus cells of women undergoing ICSI treatment based on male or tubal factor infertility, or fertility preservation for non-medical reasons. Immunofluorescence imaging on human ovarian tissue indicated oxidative damage by protein and lipid (per)oxidation already at the primordial follicle stage. Metabolomics and lipidomics analysis of oocytes and cumulus cells in advanced maternal-age groups demonstrated a shift in the glutathione-to-oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine, and pyrimidine depletion, while glycolysis substrates and glutamine accumulated, with age. Oocytes from women of advanced maternal age appeared to use alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly ATP which showed increased production in cumulus cells. The immature oocytes used in this study were all subjected to ovarian stimulation with high doses of follicle-stimulating hormones, which might have concealed some age-related differences. Further studies on how to improve mitochondrial function, or lower oxidative damage, in oocytes from women of advanced maternal age, for instance by supplementation of NAD+ precursors to promote mitochondrial biogenesis, are warranted. In addition, supplementing the embryo medium of advanced maternal-age embryos with such compounds could be a treatment option worth exploring. The study was funded by the Amsterdam UMC. The authors declare to have no competing interests. N/A.