Women Of Advanced Maternal Age Research Articles

Influence of Extracellular Vesicles from the Follicular Fluid of Young Women and Women of Advanced Maternal Age with Different miRNA Profiles on Sperm Functional Properties.

We studied the effect of co-culturing of extracellular vesicles in the follicular fluid of young women and women of advanced maternal age on sperm motility. Vesicles were obtained by differential centrifugation. The sperm fraction was isolated from the seminal fluid of 18 patients (age 28-36 years). The spermatozoa were incubated with vesicles (1:2 ratio) for 60 or 120 min at 37°C in a CO2 incubator. A fraction of spermatozoa incubated without vesicles served as the control. After the incubation, the sperm samples were sedimented by centrifugation, fixed in 2.5% glutaraldehyde, and analyzed by transmission electron microscopy. RNA was isolated from the follicular fluid vesicles by column method followed by cDNA synthesis in a reaction mixture according to miScript II RT Kit protocol (Qiagen). After 60-min incubation with extracellular vesicles from the follicular fluid of women of advanced maternal age, the sperm motility and hyperactivation slightly changed in comparison with the group where incubation was performed with follicular fluid vesicles from young women and control group. Follicular fluid miRNA profiles in women of different ages varied, which suggests different functional compositions and effects of follicular fluid vesicles of different age groups on sperm characteristics. Transmission electron microscopy revealed differences in the interaction of follicular fluid vesicles from women of different age groups with spermatozoa. Further study of the effect of extracellular vesicles from the follicular fluid and analysis of their transcriptomic, proteomic, and metabolomic composition on sperm mobility and fertilizing ability will improve the effectiveness of assisted reproductive technology programs in patients with male infertility.

Crude and adjusted comparisons of cesarean delivery rates using the Robson classification: A population-based cohort study in Canada and Sweden, 2004 to 2016

The Robson classification has become a global standard for comparing and monitoring cesarean delivery (CD) rates across populations and over time; however, this classification does not account for differences in important maternal, fetal, and obstetric practice factors known to impact CD rates. The objectives of our study were to identify subgroups of women contributing to differences in the CD rate in Sweden and British Columbia (BC), Canada using the Robson classification and to estimate the contribution of maternal, fetal/infant, and obstetric practice factors to differences in CD rates between countries and over time. We conducted a population-based cohort study of deliveries in Sweden (January 1, 2004 to December 31, 2016; n = 1,392,779) and BC (March 1, 2004 to April 31, 2017; n = 559,205). Deliveries were stratified into Robson categories and the CD rate, relative size of each group and its contribution to the overall CD rate were compared between the Swedish and the Canadian cohorts. Poisson and log-binomial regression were used to assess the contribution of maternal, fetal, and obstetric practice factors to spatiotemporal differences in Robson group-specific CD rates between Sweden and BC. Nulliparous women comprised 44.8% of the study population, while women of advanced maternal age (≥35 years) and women with overweight/obesity (≥25 kg/m2) constituted 23.5% and 32.4% of the study population, respectively. The CD rate in Sweden was stable at approximately 17.0% from 2004 to 2016 (p for trend = 0.10), while the CD rate increased in BC from 29.4% to 33.9% (p for trend < 0.001). Differences in CD rates between Sweden and BC varied by Robson group, for example, in Group 1 (nullipara with a term, single, cephalic fetus with spontaneous labor), the CD rate was 8.1% in Sweden and 20.4% in BC (rate ratio [RR] for BC versus Sweden = 2.52, 95% confidence interval [CI] 2.49 to 2.56, p < 0.001) and in Group 2 (nullipara, single, cephalic fetus, term gestation with induction of labor or prelabor CD), the rate of CD was 37.3% in Sweden and 45.9% in BC (RR = 1.23, 95% CI 1.22 to 1.25, p < 0.001). The effect of adjustment for maternal characteristics (e.g., age, body mass index), maternal comorbidity (e.g., preeclampsia), fetal characteristics (e.g., head position), and obstetric practice factors (e.g., epidural) ranged from no effect (e.g., among breech deliveries; Groups 6 and 7) to explaining up to 5.2% of the absolute difference in the CD rate (Group 2: adjusted CD rate in BC 40.7%, adjusted RR = 1.09, 95% CI 1.08 to 1.12, p < 0.001). Adjustment also explained a substantial fraction of the temporal change in CD rates among some Robson groups in BC. Limitations of the study include a lack of information on intrapartum details, such as labor duration as well as maternal and perinatal outcomes associated with the observed differences in CD rates. In this study, we found that several factors not included in the Robson classification explain a significant proportion of the spatiotemporal difference in CD rates in some Robson groups. These findings suggest that incorporating these factors into explanatory models using the Robson classification may be useful for ensuring that public health initiatives regarding CD rates are evidence informed.

Strategy for embryo transfer to improve pregnancy outcomes in advanced maternal age.

The purpose of this retrospective study was to optimize the transplantation strategy for women of advanced maternal age to achieve live births within the shortest time. Data were collected from patients older than 40 years who underwent assisted reproductive therapy at our centre from 1 January 2009 to 31 December 2019. In total, 1023 cases of fresh cleavage embryo transfer (CET) cycles, 280 cases of frozen-thawed blastocyst transfer (FBT) cycles, and 26 cases of frozen-thawed CET (FCET) cycles were included. The main outcome was the live birth rate (LBR). The secondary outcomes were the clinical pregnancy rate (CPR) and neonatal outcomes. Multivariable logistic regression was performed to adjust for confounding factors. The blastocyst formation rate of patients older than 40 years was 23.5%, the freezing cycle rate was 19.8%, and the fresh-embryo transfer rate was 83.0%. The implantation rate, CPR, and LBR were significantly different among the CET, FCET, and FBT groups. There were no significant differences in multiple pregnancies and abortion rates among the groups, and neonatal outcomes were similar. Multivariate logistic regression analysis showed that, compared with the CET group, LBR did not increase in the FCET group, whereas LBR increased in the FBT group. For patients older than 40 years when having approximately eight embryos after fertilization, blastocyst transfer can be considered after fully discussing the advantages and disadvantages of blastocyst culture. Alternatively, CET can be performed first, followed by FBT if the cleavage embryo transfer is unsuccessful.

Advanced Maternal Age as an Obstetric Risk Factor: Current Experience in a Hospital from Northwestern Spain

Studies updating the evidence in advanced maternal age as an independent factor of obstetric risk are needed. The aimof this study was to determine the prevalence of ≥ 35-years-old pregnant women who give birth in a Spanish hospital in NorthwesternSpain, and to describe the incidence of maternal and perinatal morbidity and mortality. Retrospective follow-up observational study including women ≥ 20 years-old who gave birth over one year (n= 1378). Data were collected from medical records, including socio-demographic characteristics, comorbidities, gestational conditions,variables related with the delivery and perinatal outcomes. Multivariable logistic regression analysis was performed to determine theassociation of advanced maternal age with obstetric and perinatal outcomes. Forty-two percent of pregnant women were ≥ 35 years old. In the multivariable analysis, advanced maternal age was associatedwith the likelihood of gestational diabetes (OR = 1.84; 95% CI = 1.10 - 3.07), hypothyroidism (OR = 2.11; 95% CI = 1.17 - 3.80),lower probability of an eutocic delivery (OR = 0.74; 95% CI = 0.56 - 0.98), and a hospital admission > four days (OR = 2.91; 95% CI =1.95 - 4.35). An association with the rate of C-sections was not found (OR = 1.24; 95% CI = 0.89 - 1.72). A high prevalence of pregnant women of advanced maternal age was confirmed. There was a higher rate of comorbiditiesand longer hospital admissions in older women but not a higher rate of higher C-sections and other complications.

P-216 Low meiotic progression rates in oocytes from older women are due to impaired mitochondrial metabolism

Abstract Study question Could a decreased mitochondrial metabolism explain the lower oocyte meiotic progression competence observed in advanced maternal age (AMA) oocytes? Summary answer Inhibition of mitochondrial activity in young oocytes mirrors the phenotype of AMA oocytes, pointing to a causative link between effective mitochondrial metabolism and meiotic competence What is known already Oocyte meiotic maturation is a fundamental and finely regulated process required to form haploid gametes, and errors during this process invariably cause loss of oocyte competence. Similarly, mitochondria metabolism is required for the acquisition of oocyte competence and support of embryo development. In oocytes from AMA women, both meiotic competence and mitochondrial activity are impaired; in mice, it has been suggested the two processes might be functionally linked. However, functional studies in human oocytes evaluating whether alterations in mitochondrial metabolism cause reduced meiotic competence are lacking Study design, size, duration A total of 216 oocytes from young (age ≤30) and AMA (age &amp;gt;37) women were included. Oocytes at the germinal vesicle (GV) stage were matured in vitro (in G2plus medium for 30 h; maturation was assessed by polar body (PB) extrusion. For loss of function studies on mitochondrial metabolism, 64 GVs from young women were treated with 1uM of the mitochondria inhibitor Trifluoromethoxy-carbonylcyanide-phenylhydrazone (FCCP) for 30 min and cultured for 30 h in G2plus Participants/materials, setting, methods The proteins Dihydrolipoamide S-Acetyltransferase (D-LAT) and Translocase of outer mitochondrial membrane (TOMM20) were analyzed by immunofluorescence in young and AMA oocytes to assess mitochondrial activity and localization, respectively. Fluorescent mean intensities were quantified with ImageJ and compared with t-test. For D-LAT, we assessed an area of 30 um approx. inward from the oocyte cortex, whereas for TOMM20, the whole oocyte diameter was used. Maturation rates were compared between groups by Chi-squared test Main results and the role of chance Mitochondrial staining of the two proteins showed a common pattern in the two age groups, with a uniform localization of mitochondria in the whole ooplasm observed by TOMM20, and a subcortical localization of active organelles detected by D-LAT. Quantification of the fluorescent signal showed no differences in term of total mitochondrial presence (intensity of 61674±24322 AU in young, 32186±33414 AU in AMA, p = 0.195), whereas a significant decrease in activity (D-LAT) was measured in the AMA group (intensity of 78614±58534 AU in young, 12517±10187 AU in AMA, p = 0.003). Young oocytes also matured at a higher rate (86.3%; 63/73) than AMA oocytes (62.3%; 38/61; p = 0.002). Young GV oocytes treated with FCCP presented a phenotype similar to AMA oocytes, with a significant decrease in of DLAT (intensity of 78614±58534 AU in non-treated, 11554±16131 AU in treated, p = 0.019), indicating a decrease in mitochondria activity, and a concomitant drop in maturation rate, with only 39.5% (17/43) of the treated oocytes able to extrude the PB Limitations, reasons for caution Maturation rates have been assessed by PB extrusion and some variability in spindle assembly may have been overlooked. We assessed one mitochondria activity inhibitor, FCCP, so indirect effects of this molecule on the observed phenotype cannot be ruled out Wider implications of the findings We show a functional link between decreased mitochondrial metabolism and impaired meiotic progression. The metabolic inhibition with FCCP in young oocytes might serve as tool to further investigate the molecular mechanisms driving the loss of quality observed in AMA oocytes Trial registration number NA

P-154 growth hormone supplementation decline quality of maternally aged oocytes via reducing aneuploidy

Abstract Study question Does growth hormone (GH) supplementation ameliorate the quality of oocytes in aged mice via reducing aneuploidy? Summary answer Daily injections of growth hormone for 2 months improve the age-related decline in ovarian reserve, and promote oocyte quality by reducing the aneuploidy rate. What is known already Women of advanced maternal age, particular over 35 years, could consequently bear poor quality oocytes, which are mainly caused by chromosomal aneuploidy. Age-related decline in GH levels may be related to the insufficient reproductive potential in women of advanced maternal age. To date, the role of GH in in vitro fertilization remains controversial. GH has been reported to affect oocyte quality, and studies in vivo have shown that intraperitoneal administration of GH reduces the occurrence rate of spindle/chromosome defects. Study design, size, duration The young (6-week-old) and aged (8-month-old) C57BL/6J mice were used in the study. In the in vivo experiment, aged mice were intraperitoneally injected daily with GH (1.6 mg/kg body weight, n = 85) or the equivalent volume of NS (n = 81) for consecutive for two months. In the in vitro experiment, GV oocytes from aged mice were treated with GH (Gene Science Pharmaceuticals, Changchun, China) (200ng/ml) in M16 medium for 14∼16 hours. Participants/materials, setting, methods We analyzed the number of oocytes and hormone levels to assess ovarian reserve, by immunohistochemistry and ELISA methods. The expression of GHR was measured by real-time quantitative RT-PCR and immunofluorescence. Time–lapse incubator was utilized to record the developmental potential of oocytes and embryos. Immunofluorescence was performed to assess parameters of oocyte quality (mitochondrial functions, ROS level, spindle/chromosome defects, and DNA damage). Chromosome spread and single-cell DNA sequencing were used to analyze chromosome aneuploidy rate. Main results and the role of chance The expression of GHR decreased in aged oocyte (21.68±1.08) and increased after GH treatment(30.64±0.70, P &amp;lt; 0.001). GH ameliorated decline in ovarian reserve of aged mice, with increased ovarian index (0.040%±0.0031 vs 0.023%±0.0019, P &amp;lt; 0.01), number of preantral follicles (7.33±0.89 vs 4.12±0.58, P &amp;lt; 0.05) and antral follicles (8.67±1.2 vs 3.33±0.88, P &amp;lt; 0.05) compared to the aged controls, but no other hormonal differences were detected. After GH supplementation, aged oocyte showed better quality and developmental potential, including restored mitochondrial functions (P &amp;lt; 0.05) and decreased ROS level (19.83±1.50 vs 23.6±1.72, P &amp;lt; 0.05). As expected, GH effectively promoted the fertilization rate (39.9%±1.10 vs 14.4%±0.62, P &amp;lt; 0.001) and early embryo development (P &amp;lt; 0.01). In addition, the spindle/chromosome defects (31.6%±2.12 vs 48.9%±1.83, P &amp;lt; 0.01), DNA damage (16.37±1.76 vs 49.35±2.52, P &amp;lt; 0.001) and aneuploidy rate (21.5%±1.61 vs 34.6%±1.84, P &amp;lt; 0.01) were lower in GH group than that in control group. Overall, GH treatment restored age-related decline in ovarian reserve, and decreased the occurrence rate of aneuploidy caused by spindle/chromosome defects, inducing a better oocyte quality in aged mice. Limitations, reasons for caution The molecular and mechanism of GH to regulate spindle/chromosome function remains to be determined. Besides, future work should be extended to human oocyte to determine whether this mechanism is conserved between mice and humans. Wider implications of the findings Our work expounds a theoretical basis for application of GH to improve the fertility of aged women. Besides, the results also feed new ideas for the prevention and treatment of oocyte quality decline in assisted reproductive technology. Trial registration number not applicable

P-159 The role of Embryo transfer medium containing high concentrations of hyaluronic acid on IVF outcome: A systematic review and meta-analysis

Abstract Study question Does embryo transfer medium containing high concentrations of hyaluronic acid (HA) increase In Vitro Fertilisation (IVF) success rate? Summary answer Embryo transfer medium containing high concentration of HA has increased the live birth (LBR) and clinical pregnancy rate (CPR) whilst decreasing the miscarriage rate. What is known already The recent Cochrane systematic review reported low to moderate evidence to support the use of high concentration hyaluronic acid (HA) in the treatment group. Previous studies have also shown no effect of high concentration HA on frozen embryo transfer (FET) rate and have identified the supplementation of the transfer media with HA to have no significance on adverse effect rate. Study design, size, duration A literature search was performed on three online databases: Ovid Medline, PsychInfo and Central Cochrane. 1162 citations were retrieved and after screening abstracts and titles 1099 citations were removed and a following 37 removed after screening full texts. This left 26 publications for the review. Bias was assessed for in RCTs using Cochrane collaboration tool of bias and STROBE for observational studies. Meta-analysis was performed using Review manager identifying the risk ratio (RR) and heterogeneity. Participants/materials, setting, methods In the review, 6304 participants in the treatment group and, 5965 in the control group were included. The primary outcomes was LBR and secondary outcomes were CPR; miscarriage rate; multiple pregnancy rate; ectopic pregnancy and congenital abnormalities. A subgroup analysis was performed looking into the outcome based on the stage of embryos transferred, the exposure time to the transfer medium and difference between frozen and fresh embryo transfer. Main results and the role of chance There was a significant increase in LBR (RR: 1.25; 95% CI 1.17 to 1.33) with use of high concentration HA and this positive effect was seen in both cleavage stage and blastocyst transfer cycles. CPR was also higher (RR: 1.16 (95% CI 1.10 to 1.22), while Miscarriage rate was significantly reduced (RR: 0.75; 95% CI 0.66 to 0.85) in the treatment group. Multiple pregnancy rate were higher in the study group (RR: 1.33; 95% CI: 1.16 to 1.53), although one study had a large influence on these results. The ectopic pregnancy rates (RR: 0.62; 95% CI 0.19 to 1.99) and congenital abnormalities (RR: 0.84; 95% CI 0.37 to 1.92) were similar. On subgroup analysis, the higher LBR was seen only for fresh cycles (RR: 1.2; 95% CI 1.1 to 1.3) but were similar for frozen embryo transfer (RR: 0.99; 95% CI 0.8 to 1.24). Further, LBR were higher in both short (10 minutes) and long exposure (&amp;gt;10 minutes) groups (RR: 1.32; 95% CI 1.19 to 1.45 and RR: 1.23; 95% CI 1.14 to 1.33 respectively. Limitations, reasons for caution The high heterogeneity across the studies may increase the risk of bias in the results. Inclusion of observational studies also has an inherent risk of selection bias. The review did not have a restrictive exclusion criterion resulting in inclusion of patients from a large demographic, limiting the specificity of results. Wider implications of the findings The data from this review support the use of embryo transfer medium containing high concentration of HA during fresh IVF cycles but not for frozen cycles. However, a large RCT is warranted particularly for selected groups like women of advanced maternal age and those with recurrent implantation failure. Trial registration number Not applicable

P-322 Does endometrium age? The endometrial transcriptome of advanced reproductive age patients reveals the signs of cellular ageing, altered immune response and compromised receptivity

Abstract Study question What changes occur in the endometrium during ageing and how they may affect fertility? Summary answer The endometrial transcriptome of women of advanced maternal age is significantly different from the young women, indicating specific pathways involved in endometrial ageing. What is known already A woman’s peak reproductive years are considered in her twenties. Trending postponed family planning, unfortunately, brings more women in their late forties to fertility specialists to seek for assisted conception. In vitro fertilization (IVF) using donated oocytes is a common approach to overcome the impact of maternal age on ovarian reserve. However, even with the implementation of embryo that underwent pre-implantation genetic testing, the IVF success rate drops significantly in the late forties. It still remains unclear which age-related molecular processes take place in the endometrium and whether it may impact the ability to support embryo implantation. Study design, size, duration Endometrial transcriptome profiling was done in 44 women undergoing endometrial receptivity evaluation at hormonal replacement therapy before IVF. Patients younger than 29 were considered as young maternal age group (YMA, age 23-27) and women older than 45 were considered as advanced maternal age group (AMA, age 47-50). Participants/materials, setting, methods Endometrial biopsies were obtained on day 5 of progesterone treatment and RNA was extracted. All endometrial samples were evaluated as receptive based on the expression of 57 common endometrial receptivity markers. Study group samples (12 YMA + 12 AMA) were subject to Illumina RNA sequencing. The sequences were annotated using the RefSeq database and differential expression analysis was performed using DeSeq2.We validated our results (10 YMA + 10 AMA) usingquantitative-PCR and histological validation. Main results and the role of chance A total of 37228 mRNA transcripts were expressed in the analyzed endometrial samples. After multiple testing corrections, 144 significantly differentially expressed(DE) transcripts (92 up-regulated, 52 down-regulated) were identified in the endometrium of the AMA versus YMAgroup. Overexpressed genes were associated with decidualization (ALDH3A1), endometrial receptivity (EML5, GALNT12), cell cycle (CDKN2A) and signal transduction, while down-regulated genes included sugar metabolism and inflammation (C2CD4B, NFKB), cellular motility (SPAG6)and progesterone signaling (RPL9). The pathways most affected by age were cellular remodeling, cell motility and migration, and immune response. Interestingly, some of the identified DE genes have been previously associated with ageing. Our results suggest the involvement of p16-associated cellular senescence and the suppression of metabolic and inflammatory processes essential for endometrial preparation for embryo transfer. Limitations, reasons for caution The study includes only patients undergoing hormonal replacement therapy and it is unclear whether the same processes are affected by age in the natural cycles. Wider implications of the findings These findings allow us to explain the age-related molecular changes that take place in the endometrial tissue. Understanding these alterations and using them in assisted reproductive technology may help to improve infertility management in women with advanced reproductive age. Trial registration number None

P-192 ATP5G3 and VEGFC expression in cumulus cells are non-invasive markers of fertilization rate

Abstract Study question Could expression of aging- and hypoxia-related genes in cumulus cells be used as non-invasive markers of fertilization rate in ART? Summary answer The expression levels of specific aging- (ATP5G3) and hypoxia-related genes (VEGFC) in human cumulus cells correlate with oocyte ability to be fertilized. What is known already Throughout a woman reproductive life, cumulus cells (CC) protect the dormant oocyte from damage, act as sensors of the follicular microenvironment and act as gatekeeper for the oocyte developmental potential. One such mechanism relays on the hypoxia-dependent response, which controls the cell metabolic and oxidative state. With age, hypoxia tolerance decreases in the whole organism, including the ovary. Recently, alterations in CC response to the follicular microenvironment have been described in advanced maternal age (AMA) women. We investigate whether expression levels of hypoxia-responsive genes in CC could be used as non-invasive marker of fertilization rate in human oocytes. Study design, size, duration Prospective study of 94 women (41 oocyte donors and 53 patients) recruited from 2018 to 2021. The overall age was 32±8.0 (range 18-46); 25±4.3 (range 18-34) for oocyte donors and 38±4.6 (range 26-46) for patients. The mean antral follicular count (AFC) was 18±10.9 (range 1-48) and the mean MII rate at ovum pick-up (OPU) was 75±17.8% (range 20-100%). Participants/materials, setting, methods Pooled CC were collected from each woman after OPU; total RNA was extracted, reverse transcribed to cDNA using random hexamers and expression of aging- (LYZ, FGF2, ATP5G3, AMH, ANXA5) and hypoxia-related genes (HIF-1A, NOS2, NOS3, HMOX1, TXNIP, CLU, FABP3, TGFBR3, VEGFC) was detected by qPCR and normalized against TBP. Expression levels were plotted against woman age, AFC, MII rate at OPU (MR), and fertilization rates (FR) and non-parametric Spearman’s correlation was applied. Main results and the role of chance Overall, MII and FR rates did not decrease with increasing woman’s age (rs= -0.2, p = 0.06 and rs= -0.1, p = 0.39, respectively). When analyzing expression levels of aging markers (LYZ, FGF2, ATP5G3, AMH, ANXA5), none of them correlate with age, AFC, or MR (rs&amp;lt;│0.1│, p &amp;gt; 0.05) in CCs. Moreover, although abundant, the expression of HIF1A, the main hypoxia-related gene, was not correlated with age, AFC, MR or FR. However, the expression of several genes regulated by HIF1A did show correlation with age, MR or FR. CLU (a secreted chaperone involved in cell death), TXNIP (a tumor suppressor gene involved in redox regulation) and NOS2 (an inducible and calcium-independent isoform of nitric oxide synthase) correlated positively with age (rs=0.25, p = 0.014; rs=0.31, p = 0.0027; and rs=0.24, p = 0.03, respectively). We further analyzed CC gene expression against FR and we found that ATP5G3 and VEGFC levels decreased with increasing FR, independently of age (rs=-0.26, p = 0.044 and rs=-0.31, p = 0.014; respectively). Limitations, reasons for caution The analysis of pooled CC allows for cohort interpretation of results, and they cannot be extrapolated at this time to single oocyte’s reproductive outcome prediction. Wider implications of the findings We found that the fertilization potential of a cohort of oocytes is related to the ability of CC to respond to oxidative stress and hypoxia, pointing at ATP5G3 and VEGFC expression as markers for fertilization success. Further research is needed to assess their association with embryo quality and pregnancy outcomes. Trial registration number NA

Comparing pregnancy outcomes between symptomatic and asymptomatic COVID-19 positive unvaccinated women: Multicenter study in Saudi Arabia

IntroductionCOVID-19 infection in pregnancy ranges from asymptomatic infection to severe disease. However, the maternal and pregnancy outcomes are primarily favorable. Acute Respiratory Illness (ARI) score is a Visual Triage Checklist for Acute Respiratory symptoms created by the ministry of health of Saudi Arabia 12 to screen the patient for acute respiratory infection with MERS-CoV. It has been used during the COVID-19 pandemic to identify suspected cases and place patients in isolation precautions if the score is≥ 4. MethodThis study is a cross-sectional study of all pregnant women who tested positive for COVID-19 in four medical centers located in four different cities in Saudi Arabia. The study period was from 1/3/2020 until 31/10/2020. Outcomes investigated were the prevalence of COVID infection in pregnant women at the time of delivery. Rate of asymptomatic disease, different maternal and pregnancy outcomes. Women were divided into symptomatic and asymptomatic groups according to the ARI score. The two groups were compared in maternal, perinatal, and neonatal outcomes. Furthermore, the cohort was divided according to maternal age into two groups: women of advanced maternal age ≥ 35 years and younger. The two groups were compared in maternal, perinatal, and neonatal outcomes ResultsDuring the study period, 9573 women gave birth at KAMCs, and 402 pregnant women were identified as COVID positive. Out of all COVID-positive women, only 394 women gave birth at KAMCs. The screening for COVID infection differed between the centers, but the testing was the same by the Nasopharyngeal polymerase chain reaction (PCR) swab. In Riyadh, screening was based on ARI scoring at the beginning of the pandemic. Then, it became universal. In Jeddah, the screening was based on ARI scoring. Any woman who scored four or more was labeled as suspected, and she was tested. Finally, in Madinah and Dammam, the screening was universal throughout the study.The prevalence of COVID-19 infection among women who gave birth at KAMCs was 4.2% (402/9573). (CI 3.8–4.6%). At the time of diagnosis, most women (62%) were asymptomatic. The most common symptoms were cough and shortness of breath. Twenty-two women (5.5%) had Pneumonia, and five women (1.3%) needed admission to Intensive care units (ICU). One woman died due to respiratory failure.When pregnancy outcomes were compared between symptomatic and asymptomatic women, pregnancy in symptomatic women was more likely to be complicated by Abortion (6 versus 2% p-value 0.00), fetal death (3 versus 1.3%), and cesarean delivery (30.8 versus 22.4%, p-value 0.001). COVID-positive pregnant women of advanced maternal age (AMA) were more likely to be symptomatic, have Abortion (5 versus 1%, p-value 0.01), and have Preterm delivery (17 versus 11% p-value 0.01) than younger women. In addition, neonatal death was more common in AMA COVID-positive women than younger (4 versus 0%), regardless of COVID-related symptoms. ConclusionMost of the COVID-infected pregnant women are asymptomatic. Therefore, the ARI scoring system does not help to triage patients. Symptomatic women, especially those older than 35, tend to have a higher maternal and pregnancy complication rate.

Women With Advanced Maternal Age Have Gastric Volume Similar to That of Nonpregnant Women: A Prospective Pilot Study Using Preoperative Gastric Ultrasound

(J Clin Anesth. 2021;72:110270) Contrary to conventional wisdom, previous studies have established the similarity of the gastric volume (GV) of women with full-term pregnancies to that of nonpregnant women. This finding is relevant to assessing the risk threshold for receiving anesthesia based on preoperative ultrasound determination of the quantity of gastric contents. Cut-off values for measurements of the antral cross-sectional area (CSA) indicate reliably if the stomach contents are too great for safe anesthesia administration. Incidence of advanced maternal age (AMA) pregnancy is also increasing, and with it the caseload of elective cesarean deliveries (CD) in the world-wide AMA population. Although it is not fully understood why, AMA pregnant women have lower GV than their younger counterparts. Further investigation is merited to assess the necessity of longer preoperative fasting times in AMA women undergoing CD. This study compares GV in nonpregnant women to women with AMA pregnancy to determine if there is elevated risk of aspiration as assessed by gastric ultrasound.

Risk for Cesarean Delivery by Severity of Hypertension in Women of Advanced Maternal Age [A151

INTRODUCTION: Advanced maternal age (AMA) is associated with increased risk for hypertensive disorders of pregnancies (HDP) as well as cesarean delivery (CD). We sought to determine if severity of HDP increases CD risk among AMA women. METHODS: Cohort study of women with HDP, delivering at a single institution from 2013 to 2018. Participants were divided into four groups: chronic hypertension (CHTN), gestational hypertension (GHTN), preeclampsia (PE) without severe features, and PE with severe features. The CD rate was compared between AMA and non-AMA women, stratified by HDP group. Differences were evaluated by chi-square test or t test, and logistic regression was utilized to adjust for confounders, with significance at P&lt;.05. This study was institutional review board‒approved. RESULTS: We identified 1,625 women with HDP, of whom 450 (28%) were AMA. CD rate was highest in PE with severe features compared to all other groups (P&lt;.001). In AMA women, the CD rate also varied significantly by HDP, with the highest CD rate in PE with severe features compared to all other groups (P=.008). AMA was associated with increased odds of CD (OR, 1.6; 95% CI, 1.3–2.0; P&lt;.001), and this association remained significant after adjustment for race-ethnicity, BMI, gestational age, parity, diabetes, and prior preeclampsia (aOR, 1.7; 95% CI, 1.0–2.7; P=.03). CONCLUSION: CD rates vary by severity of HDP and are significantly higher among AMA women with HDP compared to non-AMA women. This data may impact delivery counseling for AMA women, especially those with PE with severe features.

Selective autophagic degradation of ACLY (ATP citrate lyase) maintains citrate homeostasis and promotes oocyte maturation

ABSTRACT Macroautophagy/autophagy is a cellular and energy homeostatic mechanism that contributes to maintain the number of primordial follicles, germ cell survival, and anti-ovarian aging. However, it remains unknown whether autophagy in granulosa cells affects oocyte maturation. Here, we show a clear tendency of reduced autophagy level in human granulosa cells from women of advanced maternal age, implying a potential negative correlation between autophagy levels and oocyte quality. We therefore established a co-culture system and show that either pharmacological inhibition or genetic ablation of autophagy in granulosa cells negatively affect oocyte quality and fertilization ability. Moreover, our metabolomics analysis indicates that the adverse impact of autophagy impairment on oocyte quality is mediated by downregulated citrate levels, while exogenous supplementation of citrate can significantly restore the oocyte maturation. Mechanistically, we found that ACLY (ATP citrate lyase), which is a crucial enzyme catalyzing the cleavage of citrate, was preferentially associated with K63-linked ubiquitin chains and recognized by the autophagy receptor protein SQSTM1/p62 for selective autophagic degradation. In human follicles, the autophagy level in granulosa cells was downregulated with maternal aging, accompanied by decreased citrate in the follicular fluid, implying a potential correlation between citrate metabolism and oocyte quality. We also show that elevated citrate levels in porcine follicular fluid promote oocyte maturation. Collectively, our data reveal that autophagy in granulosa cells is a beneficial mechanism to maintain a certain degree of citrate by selectively targeting ACLY during oocyte maturation. Abbreviations: 3-MA: 3-methyladenine; ACLY: ATP citrate lyase; AMA: advanced maternal age; CG: cortical granule; CHX: cycloheximide; CQ: chloroquine; CS: citrate synthase; COCs: cumulus-oocyte-complexes; GCM: granulosa cell monolayer; GV: germinal vesicle; MII: metaphase II stage of meiosis; PB1: first polar body; ROS: reactive oxygen species; shRNA: small hairpin RNA; SQSTM1/p62: sequestosome 1; TCA: tricarboxylic acid; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; UBA: ubiquitin-associated domain; Ub: ubiquitin; WT: wild-type

Prevention of perinatal mental disorders in women of advanced maternal age with pregnancy resulted from assisted reproduction

Women of advanced maternal age (AMA) with pregnancies resulting from assisted reproductive technology (ART) have a high risk of the onset and progression of anxious and depressive disorders, associated with adverse obstetric and perinatal outcomes.&#x0D; The aim. To improve the mental well-being of pregnant AMA women after ART using the developed algorithm of preventive psychological support.&#x0D; Materials and methods. The prospective study comprised 150 patients divided into three equal groups of 50 nulliparous women aged 35–45 years with a singleton pregnancy in the cephalic presentation: the main group consolidated of pregnant women after ART who have got routine psychological support; patients with a pregnancy after ART included to the comparison group and patients with a spontaneous pregnancy from the control group were not consulted routinely.&#x0D; To estimate the psychological condition of the patients the level of maternal anxiety using the Spielberg State-Trait Anxiety Inventory (STAI); sleep quality using Pittsburgh Sleep Quality Index (PSQI); the presence of depressive manifestations using Edinburgh Postnatal Depression Scale (EPDS) were assessed.&#x0D; Results. We did not observe a significant difference in trait (TA) and state anxiety (SA) levels between the main and comparison groups at terms of 22–24 weeks of gestation; however, these values were significantly lower in the control group. The numbers of patients with high TA and SA levels in the main and comparison groups were also significantly higher than in the control group (p&lt;0.05). We observed no significant increase in TA and SA levels in the main group at gestational terms of 35–37 weeks, in contrast to the comparison and control group. The number of patients with high TA and SA levels in the main group remained significantly lower than in the comparison group. A gradual decrease in TA and SA levels in all groups was observed in the postpartum period, but the differences between the groups remained consistent.&#x0D; We did not observe a significant difference in sleep quality score between the study groups at terms of 22–24 weeks of gestation. Patients of all study groups reported sleep disturbance with the pregnancy progression, but average PSQI values at terms of 35–37 weeks of gestation and 6-8 weeks after delivery were significantly lower in the main group compared to the comparison group.&#x0D; The incidence and severity of postnatal depressive symptoms, along with the number of patients at high risk of developing depression in the postpartum, were significantly lower in the main group than in the comparison group.&#x0D; Conclusions. AMA patients after ART formed a high-risk group for developing anxious and depressive disorders during the pregnancy and postpartum. High anxiety levels compromised sleep patterns have leaded to poorer quality of life of women. Preventive psychological support for patients during the pregnancy and postpartum enabled early detection and correction of depressive symptoms; validly reduced anxiety levels, improved sleep quality and consequently improved the quality of life of women and prevented adverse obstetric, perinatal, and psychiatric outcomes

Down-regulation of long non-coding RNAs in reproductive aging and analysis of the lncRNA-miRNA-mRNA networks in human cumulus cells.

Long non-coding RNAs (lncRNAs) control gene expression at multiple levels. By interacting with microRNAs (miRNAs), they regulate their mRNA targets creating dynamic regulatory networks involved in different cellular processes. Their role in follicle development and oocyte maturation has recently emerged. lncRNA deregulation has been found associated with different pathological conditions. In this study, we identified differentially expressed lncRNAs in cumulus cells (CCs) isolated from MII oocytes of advanced maternal age women and proposed ceRNA-networks involved in signaling pathways crucial in ovarian folliculogenesis and female germ cell maturation. We performed a high-throughput analysis of the expression profile of 68 lncRNAs from CCs of aged and young women by using NanoString technology. By miRNet, TarPmiR, miRTarBase, OKdb, and KEGG we predicted some ceRNA-networks involving the differentially expressed (DE) lncRNAs, miRNA interactors, and their mRNA target genes. We identified 28 lncRNAs down-regulated in CC samples from aged women. The analysis revealed that the miRNAs binding 11 of the DE lncRNAs and their mRNA targets are included in ceRNA-networks involved in the regulation of the PI3K-Akt, FOXO, and p53 signaling pathways. We proposed that the lncRNA down-regulation in CCs from aged women could influence the expression of genes encoding proteins deregulated in reproductive aging. A better understanding of the interplay of lncRNA-miRNA-mRNA networks in human CCs could increase our knowledge about the mechanisms of regulation of gene expression involved in aging, lead to the development of novel therapeutics, and improve reproductive outcomes in aged women.

Clinical outcomes after elective double-embryo transfer in frozen cycles for women of advanced maternal age: A retrospective cohort study.

We aimed to determine the clinical outcome of double cleavage-stage embryo transfers in frozen-thawed embryo transfer cycles for older women.This study analyzed a total of 8189 cleavage-stage frozen-thawed embryo transfer cycles between January 2013 and December 2017 at Sir Run Run Shaw Hospital. All cycles were sorted into 3 groups based on patient age: ≤35 years (Group A), 36 to 37 years (Group B), and ≥38 years (Group C). The clinical pregnancy rate (CPR), implantation rate (IR), live birth rate (LBR), miscarriage rate, multiple pregnancy rate (MPR), preterm birth rate, and low-birth-weight rate were compared between the 3 groups.Significant differences in CPR, IR, LBR, MPR, and premature birth rate were found among the 3 groups. The CPR, IR, LBR, and MPR in Group A were higher than those in Group C. Transfers of 2 high-quality embryos resulted in significant differences in CPR, IR, LBR, MPR, and neonatal weight among the 3 groups, but no differences in premature birth and abortion rates were observed. Transfers with 1 high-quality and 1 fair-quality embryo resulted in significant differences in CPR, IR, and LBR among the 3 groups. Comparison of transfers of 2 high-quality embryos with 1 high-quality and 1 fair-quality embryo showed that the CPR and LBR were significantly lower for the latter in Groups A and C, but Group B had no salient changes.Higher IR and LBR and lower MPR may be achieved by selection of optimal embryo types for patients of different ages. Two high-quality embryos need to be transferred in women older than 38 years. For women aged 36 to 37 years, 1 high-quality embryo or 1 high-quality plus 1 fair-quality embryo should be singled out for transfer. For women younger than 35 years, a single high-quality embryo should be selected for transfer.

Live Birth With or Without Preimplantation Genetic Testing for Aneuploidy

(Abstracted from N Engl J Med 2021;385:2047–2058) To optimize live birth rate per transfer in in vitro fertilization (IVF), morphologic score based on visualization and genetic status based on preimplantation genetic testing for aneuploidy (PGT-A) are used to select the highest quality embryos. Although some studies suggest an increased live birth rate among women of advanced maternal age, it is less clear whether PGT-A in women with good prognosis for live birth experience a similar benefit.

Year-end academic review of 2021: Advances in the field of birth defect prevention and control in China as of 2021

Year-end academic review of 2021: Advances in the field of birth defect prevention and control in China as of 2021

Risk factors for obstetric anal sphincter injury among nulliparous of advanced maternal age

Objective Data regarding the risk factors for obstetrical anal sphincter injury (OASI) among nulliparous advanced maternal age (AMA) women are scarce. We aimed to evaluate the risk factors and the rate of OASI in this population. Methods A retrospective case-control study of nulliparous women aged ≥35 who delivered vaginally between March 2011 and August 2021. The study cohort included nulliparous AMA women, aged 35 years or older, delivering vaginally a singleton, vertex neonate. We excluded cases with missing data. Maternal and intrapartum characteristics were compared between OASI and no-OASI groups. We matched groups to the earliest gestational age in which OASI has occurred. Results A total of 3,635 women met inclusion criteria. Mean age of the participants was 38 years (range 35–56, interquartile range 36–39). The oldest age in which an OASI was diagnosed was 45. A total of 55 (1.5%) cases of OASI were diagnosed. Gestational age at delivery was higher in the OASI group compared to the no-OASI group (mean 396/7±12/7 vs. 391/7±23/7 weeks respectively, p=.039). The rate of induction of labor, oxytocin and epidural analgesia, prolonged second stage, mode of delivery, and rate of blood transfusion did not vary between groups. Estimated fetal weight was higher in the OASI group (3,324 ± 308 vs. 3,114 ± 566 g, p<.001). Sonographic abdominal circumference was higher in the OASI group (338 ± 13 vs. 328 ± 28 mm, p<.001). Mean birthweight was higher in the OASI group (3,286 ± 400 vs. 3,059 ± 541 g, p=.002) and the birthweight centile was higher as well (60 ± 26 vs. 52 ± 25, p=.024). In a multivariable regression analysis including birthweight, gestational age, operative vaginal delivery, epidural anesthesia, and hypertensive disorders–birthweight and hypertensive disorder were positively associated with an OASI odds ratio [OR 95% CI 1.6 (1.1–2.32) for every 500 g increase; 2.42 (1.006–5.82), respectively]. Epidural anesthesia was negatively associated with OASI [OR 95% CI 0.49) 0.27–0.87)]. Conclusions Epidural anesthesia is the only modifiable risk factor and is protective against OASI among nulliparous AMA women. Birthweight and hypertensive disorders are also independent predictors of OASI in this population.

Female Reproductive Ageing and Chromosomal Abnormalities in a Large Series of Women Undergoing IVF

Chromosomal abnormalities are often detected in women with reproductive problems. This study aimed to investigate the presence and type of chromosomal aberrations in peripheral blood of women undergoing in vitro fertilization (IVF) and their possible association with advanced maternal age (AMA). A total of 1,837 women undergoing IVF between 2016 and 2019 were enrolled in the study. Women were further divided in AMA (≥35 years) and younger women (<35 years). Chromosomal abnormalities were detected by peripheral blood karyotyping using standard cytogenetic techniques. Chromosomal abnormalities were detected in 13.5% of the enrolled women; 1.1% had autosomal abnormalities including reciprocal translocations, inversions, Robertsonian translocations, and a supernumerary marker chromosome, while 12.4% had X chromosome abnormalities. The frequency of chromosomal abnormalities was significantly higher in AMA women than in younger ones (17.4% vs. 3.9%, p < 0.05). Women of AMA exhibited X chromosome mosaicism with a frequency of 16.1%, and mosaic karyotypes with 2 and 3 aneuploid cell lines were more frequently detected. X chromosome mosaicism is the most common karyotypic aberration in women undergoing IVF and has 6-fold increased incidence in AMA women compared to younger ones. The present study verifies previous observations that low-level peripheral blood X chromosome mosaicism and the number of aneuploid cell lines observed in women of AMA could be an indication of aneuploidy and poor quality of oocytes contributing to infertility.