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The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.

Background This study aims to investigate differences in pregnancy outcomes and potential risk factors between women of advanced maternal age (AMA, 35–39 years) and those of very advanced maternal age (vAMA, 40 years and older). Methods This retrospective cohort study included women (age ≥ 35) who were single pregnancy and delivered at a tertiary comprehensive hospital in China between 2014 and 2020 at a major urban Chinese medical center. Patient medical records were reviewed, and relevant clinical data were collected and organized into a structured data spreadsheet for analysis. Categorical variables were compared using chi-square analyses, while continuous variables were compared using either the Student t-test or Wilcoxon tests, depending on the data distribution. Logistic regression was employed to identify and evaluate risk factors. Results This study encompassed 19,560 pregnant, and divided into two groups: the AMA group with 16,131 patients and the vAMA group with 3,429 patients. A lower rate of gravidity and parity were observed in the vAMA group ( P  < 0.001). Preexisting hypertension, diabetes, and assisted reproductive technologies (ART) were more prevalent. The AMA group exhibited an increased rate of spontaneous deliveries, and precipitated labor ( P  < 0.001), while the vAMA group had a higher rate of cesarean delivery (CD) ( P  < 0.001). Additionally, the vAMA group had a significantly shorter gestational age at delivery ( P  < 0.001). Differences in birth outcomes between the AMA and vAMA groups were primarily observed in very preterm births (28–34 weeks) ( P  = 0.004) and low birth weight (LBW, 1,500-2,500 g) ( P  < 0.001). Incidences of gestational hypertension, pre-eclampsia, gestational diabetes, placenta previa, and adherent placenta were all significantly higher in the vAMA group ( P  < 0.001). Logistic regression analysis identified that gestational hypertension and placenta previa are risk factors for adverse birth outcomes in AMA women, while gestational hypertension and adherent placenta are in vAMA women. Conclusions Our study suggests that vAMA women have an increased risk of developing gestational hypertension, gestational diabetes, CD, placenta previa, and adherent placenta compared to women of AMA. Gestational hypertension, placenta previa, and adherent placenta were identified as the most important risks for preterm birth and LBW in AMA and vAMA women. Subgroup analysis of birth outcomes suggests that gestational diabetes is a risk factor for LBW and moderate preterm birth in AMA women. These results provide valuable data for prenatal counseling of patients with advanced maternal age.

Background Advanced maternal age (AMA), defined as pregnancy in people aged ≥ 35 years, is associated with an increased risk of adverse perinatal outcomes. Although the outcomes of AMA pregnancies have been reported, detailed information on the specific outcomes in pregnant individuals aged ≥ 45 years, particularly those reaching full term, remains limited. Therefore, this study aimed to investigate the perinatal outcomes of full-term pregnant individuals aged ≥ 45 years. Methods We conducted a retrospective cohort study involving full-term pregnant individuals aged ≥ 35 years who attempted vaginal delivery at our facility between January 2019 and December 2023. Participants were categorized into the AMA (35–39 years, n  = 947), moderate AMA (40–44 years, n  = 387), and very AMA (≥ 45 years, n  = 34) groups. The primary outcomes included maternal outcomes, such as intrapartum cesarean delivery (CD) rate and indications, blood loss, and additional interventions (e.g., uterine artery embolization [UAE]). Secondary outcomes included neonatal outcomes such as birth weight, Apgar score, umbilical artery pH, need for respiratory support, and neonatal intensive care unit (NICU) admission within 24 h of birth. Results The intrapartum CD rate increased significantly with age (AMA: 17.0%, moderate AMA: 27.1%, very AMA: 35.3%; p  < 0.01). However, more than half of the deliveries were vaginal, even in the very AMA group. No significant differences in intrapartum CD indications were found between the groups. The amount of blood loss was significantly higher in the moderate AMA group than in the other groups ( p  < 0.001). UAE and cesarean hysterectomy incidences showed no significant differences across the groups ( p  = 0.52 and p  = 0.78, respectively). Regarding neonatal outcomes, no significant differences in birth weight were observed, along with low Apgar score, low umbilical artery pH, need for respiratory support, or NICU admission within 24 h of birth between the groups ( p  = 0.61, p  = 0.62, p  = 0.52, p  = 1.00, and p  = 0.44, respectively). Conclusions Although the risk of intrapartum CD increases in pregnant individuals aged ≥ 45 years, those delivering at full term have neonatal outcomes similar to those of younger AMA pregnancies. Importantly, nearly two-thirds of this cohort achieved vaginal delivery. This information may be helpful for consultations with pregnant individuals aged ≥ 45 years in the clinical setting.

Background Women of advanced maternal age (AMA) are a growing population, with higher obstetric risks. The Mediterranean population has specific characteristics different from other areas. Thus, the objective of this study was to establish a cut-off to define AMA in a selected mediterranean population coming from a tertiary referral private/mutual health hospital in Barcelona. Methods Retrospective cohort of euploid singleton pregnancies delivered from January 2007 to June 2017. Main maternal outcomes were: gestational diabetes, preeclampsia, placenta previa, c-section and prolonged hospitalization (≥ 7 days). Main adverse perinatal outcomes were: stillbirth, prematurity, preterm prelabor rupture of membranes, low birth weight, need of admission at a neonatal intensive care unit and perinatal mortality. Adjustment for confounding factors (smoking, previous comorbilities, parity, assisted reproductive techniques (ART) and obesity) was performed. Results A total of 25054 pregnancies were included. Mean maternal age was 34.7 ± 4.2 years, with 2807 patients in the group of age between 40 and 44 years (11.2%) and 280 patients ≥45 years (1.1%). Women at AMA had higher incidence of previous comorbilities (compared to the reference group of women < 30 years): prior c-section, chronic hypertension and obesity. In addition, they were more likely to use ART. After adjusting for confounding factors, maternal age was an independent and statistically significant risk factor for gestational diabetes (OR 1.66/2.80/3.14) for ages 30–39, 40–44 and ≥ 45 years respectively, c-section (OR 1.28/2.41/7.27) and placenta previa (OR 2.56/4.83) for ages 40–44 and ≥ 45 years respectively, but not for preeclampsia (neither early-onset nor late-onset). Risk of emergency c-section was only increased in women ≥45 years (OR, 2.03 (95% CI, 1.50–2.74). In the other groups of age, the increase in c-section rate was because of elective indications. Age ≥ 45 years was associated with iatrogenic prematurity < 37 weeks (OR 2.62, 95% CI 1.30–5.27). No other relevant associations between AMA and maternal or neonatal outcomes were found. Conclusions Maternal age is an independent risk factor for adverse obstetric outcomes. Age ≥ 40 years was associated to relevant increased risks and reveals to be an adequate cut-off to define AMA in our population.

We utilized an updated nationally representative database to examine associations between maternal age and prevalence of maternal morbidity during complications of labor and delivery. We used hospital inpatient billing data from the 2009 United States Nationwide Inpatient Sample, part of the Healthcare Cost and Utilization Project. To determine whether the likelihood that maternal morbidity during complications of labor and delivery differed among age groups, separate logistic regression models were run for each complication. Age was the main independent variable of interest. In analyses that controlled for demographics and clinical confounders, we found that complications with the highest odds among women, 11–18 years of age, compared to 25–29 year old women, included preterm delivery, chorioamnionitis, endometritis, and mild preeclampsia. Pregnant women who were 15–19 years old had greater odds for severe preeclampsia, eclampsia, postpartum hemorrhage, poor fetal growth, and fetal distress. Pregnant women who were ≥35 years old had greater odds for preterm delivery, hypertension, superimposed preeclampsia, severe preeclampsia, and decreased risk for chorioamnionitis. Older women (≥40 years old) had increased odds for mild preeclampsia, fetal distress, and poor fetal growth. Our findings underscore the need for pregnant women to be aware of the risks associated with extremes of age so that they can watch for signs and symptoms of such complications.

Natural ovarian aging is one of the major causes for declining fertility in female animals, which has become an insurmountable issue in human reproduction clinics and assisted reproductive technology procedures. Nevertheless, the molecular basis of oocyte aging remains poorly understood, and feasible improvement strategies are unavailable. In the present study, in vivo supplementation of pyrroloquinoline-quinone effectively elevated the fecundity of reproductively aged mice by balancing hormonal secretion, harmonizing the estrus cycle, and eliminating ovarian fibrosis. Moreover, oocyte quality also increased in aged mice after pyrroloquinoline-quinone administration from various aspects, including nuclear and cytoplasmic maturation competency, fertilization capacity, and pre-implantation embryonic development potential. Transcriptomic analysis identified target pathways that might mediate pyrroloquinoline-quinone’s effects in aged oocytes. Specifically, it was demonstrated that pyrroloquinoline-quinone supplementation restored the mitochondrial dynamics and lysosomal function to remove excessive reactive oxygen species and suppress apoptosis in aged oocytes. Jointly, these findings demonstrate pyrroloquinoline-quinone administration is an efficacious method to restore the compromised ovary function and damaged oocyte quality in reproductively aged mice, which might be a potential clinical therapy for women of advanced maternal age with infertility.

Advanced maternal age (AMA) pregnancies are rapidly increasing and are associated with aberrant trophoblast cell function, poor placentation, and unfavorable pregnancy outcomes, presumably due to premature placental senescence. SIRT1 is an NAD+‐dependent deacetylase with well‐known antiaging effects, but its connection with placental senescence is unreported. In this study, human term placentas and first‐trimester villi were collected from AMA and normal pregnancies, and a mouse AMA model was established by cross breeding young and aged male and female C57 mice. SIRT1 expression and activity in HTR8/SVneo cells were genetically or pharmacologically manipulated. Trophoblast‐specific Sirt1‐knockout (KO) mouse placentas were generated by mating Elf5‐Cre and Sirt1fl/fl mice. Trophoblast cell mobility was assessed with transwell invasion and wound‐healing assays. SIRT1‐binding proteins in HTR8/SVneo cells and human placental tissue were identified by mass spectrometry. We identified SIRT1 as the only differentially expressed sirtuin between AMA and normal placentas. It is downregulated in AMA placentas early in the placental life cycle and is barely impacted by paternal age. SIRT1 loss upregulates P53 acetylation and P21 expression and impairs trophoblast invasion and migration. Sirt1‐KO mouse placentas exhibit senescence markers and morphological disruption, along with decreased fetal weight. In trophoblasts, SIRT1 interacts with vimentin, regulating its acetylation. In conclusion, SIRT1 promotes trophoblast epithelial−mesenchymal transition (EMT) to enhance invasiveness by modulating vimentin acetylation. AMA placentas are associated with premature senescence during placentation due to SIRT1 loss. Therefore, SIRT1 may be an antiaging therapeutic target for improving placental development and perinatal outcomes in AMA pregnancies. Both the first‐trimester villi and full‐term placentas from pregnancies of advanced maternal age (AMA) are associated with the significant downregulation of SIRT1 and accumulation of P53, P21, and β‐galactosidase in trophoblasts, where SIRT1 directly interacts with vimentin and modulates the acetylation status of vimentin, thus affecting the EMT process and ultimately influencing the invasiveness and mobility of trophoblasts. Both P53–P21 axis‐dependent cellular senescence and vimentin acetylation‐induced EMT suppression may orchestrate premature placental senescence and eventually lead to a variety of adverse pregnancy outcomes.

Background Advanced maternal age generally denotes age after 35 years during the time of delivery. Despite the fact that being pregnant at any reproductive age is not risk-free, older gravidity usually culminates with adverse outcomes both to the mother and fetus or neonate. This study aimed to determine the association of adverse obstetrical and perinatal outcomes with advanced maternal age pregnancy. The study was conducted in Ayder comprehensive specialized hospital, north Ethiopia, from 2015 to 2017. Methods chart review comparative cross-sectional study was employed. Data were retrieved from medical charts of 752 pregnant mothers (376 each for both the study;> 35-year-old and reference group;20-34 year old). Data was collected using a pretested and structured checklist using systematic sampling and data was entered & analyzed using SPSS version 20. Binary and multivariable logistic regression was run to determine the association of independent variables with dependent variables. Results This study revealed that advanced maternal age pregnancy was significantly associated with pregnancy induced hypertension [AOR 4.15, 95% CI (2.272–7.575), p  <  0.001], ante partum hemorrhage [AOR 2.54, 95% CI (1.32–4.91), P  = 0.005] & cesarean delivery [AOR 2.722, 95% CI (1.777–4.170), p  <  0.001]. Furthermore, advanced maternal age pregnancy was also increasingly associated with adverse perinatal outcomes like preterm delivery [AOR 3.622, 95% CI (1.469–8.930), p  = 0.005], low birth weight [ AOR 3.137, 95% CI (1.324–7.433), p  = 0.009], perinatal death [AOR 2.54, 95% CI (1.141–5.635), p  = 0.022] and low fifth minute APGAR score [AOR 7.507, 95% CI (3.134–17.98), p <  0.001]. Notwithstanding this, maternal age was not found to be associated with amniotic fluid disturbances, premature rupture of membranes and post-term pregnancy. Conclusions Advanced maternal age is markedly linked with adverse obstetrical and perinatal outcomes. Therefore, it is better for health care providers to counsel couples, who seek to have a child in their later ages, about the risks of advanced maternal age pregnancy. In addition, health care workers need to emphasize on how to improve advanced age mothers’ health through the utilization of contraception to reduce pregnancy in this age group.

Aneuploidy in human eggs is the leading cause of pregnancy loss and Down’s syndrome. Aneuploid eggs result from chromosome segregation errors when an egg develops from a progenitor cell, called an oocyte. The mechanisms that lead to an increase in aneuploidy with advanced maternal age are largely unclear. Here, we show that many sister kinetochores in human oocytes are separated and do not behave as a single functional unit during the first meiotic division. Having separated sister kinetochores allowed bivalents to rotate by 90 degrees on the spindle and increased the risk of merotelic kinetochore-microtubule attachments. Advanced maternal age led to an increase in sister kinetochore separation, rotated bivalents and merotelic attachments. Chromosome arm cohesion was weakened, and the fraction of bivalents that precociously dissociated into univalents was increased. Together, our data reveal multiple age-related changes in chromosome architecture that could explain why oocyte aneuploidy increases with advanced maternal age. Older women are more likely to experience a miscarriage or give birth to a child who has a developmental disorder. This occurs because age increases the chances that a woman’s egg cells will have the wrong number of chromosomes. If a sperm fertilizes an egg with too many or too few copies of a chromosome, the resulting embryo will have the wrong number of copies for many genes. Many of these embryos fail to develop and die, but some are born with developmental conditions like Down's syndrome and Turner syndrome. New egg cells develop from immature egg cells that are present in a woman from birth. In an immature egg cell, chromosomes that came from the woman’s father are paired up with the matching chromosomes from the woman’s mother and the handle-like structures on each chromosome (called the kinetochores) are fused. Just before the immature egg cell divides, a molecular machine called ‘the spindle’ attaches to the chromosome handles. The spindle then separates these pairs of chromosomes such that each new cell receives only one copy of each chromosome. However, while it is known that this process sometimes goes wrong, it is not clear why mistakes happen more often in older women. Now, Zielinska et al. used powerful microscopes to observe cell division in over 200 preserved or living immature egg cells donated by women between the ages of 23 and 46. First, the experiments examined over 1,000 chromosomes in preserved immature egg cells that were about to divide. This revealed that the chromosome handles that were supposed to be fused had often disconnected in women over 35 years old. Chromosome pairs without correctly fused handles were also prone to rotating during the division process, and sometimes the pairs simply fell apart too soon. Further experiments with living immature egg cells then revealed that the spindle struggled to grip and separate the chromosomes correctly, possibly because the chromosome handles were not properly fused. These events increased the likelihood of a new egg cell receiving too many or too few chromosomes. Finally, Zielinska et al. found that immature egg cells lack a robust control mechanism that can detect when these problems occur. Together these findings help to explain why miscarriages and chromosome abnormalities are more common in the children of older women. Research building on these findings may in the future help women in their late 30s and early 40s to increase their chances of having a family.

PurposeTo report the effects of blastocyst stage aneuploidy testing on clinical, gestational, and neonatal outcomes for patients of advanced maternal age undergoing IVF.MethodsThis is a single-center observational-cohort study with 2 years follow-up. The study includes a total of 2538 couples undergoing 2905 egg collections (control group), 308 (PGT-A), and 106 (drop-out group, consenting for PGT-A but withdrawing due to poor embryological outcome)ResultsCompared with control group, PGT-A showed improved clinical outcomes (live-birth rate per transferred embryo, LBR 40.3% vs 11.0%) and reduced multiple pregnancy rate (MPR, 0% vs 11.1%) and pregnancy loss (PL, 3.6% vs 22.6%). Drop-out group showed the worst clinical outcomes suggesting that abandoning PGT-A due to poor response to ovarian stimulation is not a favorable option. Cytogenetic analysis of product of conceptions and CVS/amniocentesis showed higher aneuploid pregnancy rates for control group regardless of embryo transfer strategy (0%, 17.9%, and 19.9%, for PGT-A, control day 5 and day 3, respectively). Multivariate analysis showed no negative impact of PGT-A-related interventions on cumulative delivery rate (26.3%, 95% CI 21.5–31.6 vs 24.0%, 95% CI 22.5–25.6 for PGT-A and control, respectively) and on neonatal outcomes.ConclusionPGT-A improves clinical outcomes, particularly by reducing pregnancy loss and chromosomally abnormal pregnancy for patients of advanced maternal age, with no major impact on cumulative live-birth rate (CLBR) per egg retrieval.