Advanced maternal age (AMA) and pregnancy: a feasible but problematic event.

This narrative review aimed to summarize all adverse outcomes of pregnancy in advanced maternal age (AMA) to assess the age of the mother as a potentially crucial risk factor. AMA refers to women older than 35 years. While expectations and the role of women in society have undergone significant changes today, the biology of aging remains unchanged. Various pathologic changes occur in the human body with age, including chronic noncommunicable diseases, as well as notable changes in reproductive organs, that significantly affect fertility. Despite substantial advancements in technology and medicine, pregnancy in AMA remains a formidable challenge. Although there are some advantages to postponing childbirth, they primarily relate to maternal maturity and economic stability. However, regrettably, there are also many adverse aspects of pregnancy at advanced ages. These include complications affecting both the mother and the fetus. Pregnants in AMA were more prone to suffer from gestational diabetes mellitus, preeclampsia, and eclampsia during pregnancy compared to younger women. In addition, miscarriages and ectopic pregnancies were more prevalent. Delivery was more frequently completed via cesarean section, and postpartum complications and maternal mortality were also higher. Unfortunately, there were also complications concerning the fetus, such as chromosomal abnormalities, premature birth, low birth weight, admission to the neonatal intensive care unit, and stillbirth.

IVF and obstetric outcomes among women of advanced maternal age (≥45 years) using donor eggs.

RESEARCH QUESTION: Does very advanced maternal age (VAMA; age ≥45 years) influence obstetric outcomes among women using donor oocytes in IVF? DESIGN: This retrospective cohort study analysed data from a nationwide IVF registry in Taiwan, focusing on IVF cycles involving women aged 45 years and older using donated oocytes between 2007 and 2016. The study assessed cumulative live birth rates (CLBR) and secondary outcomes such as clinical pregnancy, miscarriage, live birth and twin pregnancy rates, alongside perinatal outcomes such as Caesarean section rates, pre-eclampsia, gestational diabetes and birthweight. RESULTS: The study included 1226 embryo transfer cycles from 745 women, with a stable live birth rate of about 40% across the study period. The CLBR was slightly lower in women aged 50 years and older (54.2%) compared with those aged 45-46 years (58.0%), but these differences were not statistically significant (P = 0.647). Secondary outcomes and perinatal outcomes did not significantly differ across age groups. Regression analysis suggested a non-significant trend towards a decrease in live birth rate and birthweight with increasing maternal age. The study also found that single-embryo transfer (SET) minimized the risk of twin pregnancies without significantly affecting live birth rates. CONCLUSIONS: IVF with donor oocytes remains a viable option for women of VAMA, with consistent live birth rates across age groups. However, the study underscores the importance of elective SET to reduce the risk of twin pregnancies and associated adverse outcomes. Further research is needed to explore the impact of other factors such as paternal age and embryo development stage on IVF success in this population.

The effect of postpartum nursing guidance on early pelvic floor dysfunction recovery in women of advanced maternal age: a randomized controlled trial.

Objective: This study aimed to investigate the efficacy of postpartum nursing guidance in the treatment of early pelvic floor dysfunction (PFD) in women of advanced maternal age. Methods: A total of 146 patients of advanced maternal age admitted to our hospital between January and December 2021 were enrolled in this study and randomly divided into two groups: the control group and the experimental group, with 73 patients in each group. Parturients in the control group received routine pelvic floor rehabilitation treatment, whereas those in the experimental group were given individualized postpartum nursing guidance alongside routine pelvic floor rehabilitation treatment. The recovery of pelvic floor muscle (PFM) strength, the incidence of PFD diseases and nursing satisfaction were compared between the two groups after 3 months of treatment. Results: The enhancement of PFM strength in the experimental group significantly surpassed that in the control group. Furthermore, the experimental group exhibited a notably lower overall occurrence of PFD and significantly greater maternal satisfaction compared with the control group, and the difference was statistically significant (p < 0.05). Conclusion: Combining postpartum nursing guidance with pelvic floor rehabilitation for women of advanced maternal age represents a treatment regimen deserving of clinical endorsement, as it offers numerous advantages, including substantial improvement in PFM strength, decreased incidence of PFD and enhanced patient satisfaction.

Multilevel modelling of the determinants of low birth weight in frontier, outermost and underdeveloped regions: Evidence from the Indonesian National Socioeconomic Survey (2019-2021).

BACKGROUND: The prevalence of low-birthweight infants is increasing in Indonesia. A low birth weight can have a negative effect on a child's development. Understanding the factors influencing low birth weight may enable preventative actions. AIM: To analyse the determinant factors of low-birthweight infants in frontier, outermost and underdeveloped regions in Indonesia. METHODS: A cross-sectional study was conducted using a secondary dataset from the Indonesian National Socioeconomic Survey, 2019-2021. The sample included 27,678 inhabitants aged 16-64 years. The Indonesian regions of Nusa Tenggara Timur, Nusa Tenggara Barat, Sulawesi Tengah, Sulawesi Tenggara, Gorontalo, Maluku, Maluku Utara, Papua and Papua Barat were included. A multilevel logistic regression was conducted to determine the relationship between variables. p < 0.05 was considered to indicate significance in the fixed-effects model findings. FINDINGS: Women who lived in a rural area [OR 1.176, 95 % confidence interval (CI) 0.088-0.235] and had never used contraception (OR 1.227, 95 % CI 0.096-0.313) were more likely to have low-birthweight infants. In contrast, water resources, social assistance/welfare, maternal age and gross domestic product per capita had no significant effect on the prevalence of low-birthweight infants. DISCUSSION AND CONCLUSION: Living in a rural area and lifetime non-use of contraception were found to be significant risk factors for low birth weight in frontier, outermost and underdeveloped regions in Indonesia. Increasing health facilities in rural areas and establishing programmes on the use of contraception may be positive strategies to reduce the prevalence of low-birthweight infants.

[Humoral Immunity Abnormalities in Advanced Maternal-Age Women With Recurrent Spontaneous Abortion: A Single Center Study]. / é«˜é¾„å¤å‘æ€§æµäº§æ‚£è€ ä½“æ¶²å ç–«å¼‚å¸¸çš„å•ä¸­å¿ƒç ”ç©¶.

Objective: To determine the humoral immunity in advanced maternal-age women with recurrent spontaneous abortion (RSA). Methods: A retrospective study was performed between January 2022 and October 2023 in the Department of Reproductive Immunity of Shanghai First Maternity and Infant Hospital. Women with RSA were recruited and multiple autoantibodies were tested. Multivariate logistic regression was performed to compare the associations between different age groups (20 to 34 years old in the low maternal-age group and 35 to 45 years in the advanced maternal-age group) and multiple autoantibodies, while controlling for three confounding factors, including body mass index (BMI), previous history of live birth, and the number of spontaneous abortions. Then, we investigated the differences in the humoral immunity of advanced maternal-age RSA women and low maternal-age RSA women. Result: A total of 4009 women with RSA were covered in the study. Among them, 1158 women were in the advanced maternal-age group and 2851 women were in the low maternal-age group. The prevalence of antiphospholipid syndrome, systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, and undifferentiated connective tissue disease was 15.6% and 14.1%, 0.0% and 0.1%, 0.9% and 0.9%, 0.3% and 0.0%, and 23.7% and 22.6% in the advanced maternal-age group and low maternal-age group, respectively, showing no statistical difference between the two groups. The positive rates of antiphospholipid antibodies (aPLs), antinuclear antibody (ANA), extractable nuclear antigen (ENA) antibody, anti-double stranded DNA (dsDNA) antibody, anti single-stranded DNA (ssDAN) antibody, antibodies against alpha-fodrin (AAA), and thyroid autoimmunity (TAI) were 19.1% and 19.5%, 6.6% and 6.6%, 9.2% and 10.5%, 2.0% and 2.0%, 2.2% and 1.2%, 5.1% and 4.9%, and 17.8% and 16.8%, respectively. No differences were observed between the two groups. 1.6% of the women in the advanced maternal-age group tested positive for lupus anticoagulant (LA), while 2.7% of the women in the low maternal-age group were LA positive, with the differences being statistically significant (odds ratio=0.36, 95% confidence interval: 0.17-0.78). In the 4008 RSA patients, the cumulative cases tested positive for the three antibodies of the aPLs spectrum were 778, of which 520 cases were positive for anti-ß2 glycoprotein Ⅰ antibodies (ß2GPⅠ Ab)-IgG/IgM, 58 were positive for aCL-IgG/IgM, 73 were positive for LA, 105 were positive for both ß2GPⅠ Ab-IgG/IgM and aCL-IgG/IgM, 17 were positive for both ß2GPⅠ Ab-IgG/IgM and LA, 2 were positive for both aCL-IgG/IgM and LA, and 3 were positive for all three antibodies. Conclusion: Our study did not find a difference in humoral immunity between RSA women of advanced maternal age and those of low maternal age.

[Mechanisms of the Effect of Maternal Age-Related Oocyte Aging on Fertility: Transcriptomic Sequencing Analysis of a Zebrafish Model]. / æ¯ä½“å¹´é¾„ç›¸å ³çš„åµæ¯ç»†èƒžè€åŒ–å¯¹ç”Ÿè‚²åŠ›çš„å½±å“æœºåˆ¶ï¼šæ–‘é©¬é±¼æ¨¡åž‹çš„è½¬å½•ç»„å­¦æµ‹åºåˆ†æž.

Objective: Female fertility gradually decreases with the increase in women's age. The underlying reasons include the decline in the quantity and quality of oocytes. Oocyte aging is an important manifestation of the decline in oocyte quality, including in vivo oocyte aging before ovulation and in vitro oocyte aging after ovulation. Currently, few studies have been done to examine oocyte aging, and the relevant molecular mechanisms are not fully understood. Therefore, we used zebrafish as a model to investigate oocyte aging. Three different age ranges of female zebrafish were selected to mate with male zebrafish of the best breeding age. In this way, we studied the effects of maternal age-related oocyte aging on fertility and investigated the potential molecular mechanisms behind maternal age-related fertility decline. Methods: Eight female zebrafish aged between 158 and 195 d were randomly selected for the 6-month age group (180±12) d, 8 female zebrafish aged between 330 and 395 d were randomly selected for the 12-month age group (360±22) d, and 8 female zebrafish aged between 502 and 583 d were randomly selected for the 18-month age group (540±26) d. Male zebrafish of (180±29) d were randomly selected from zebrafish aged between 158 and 195 d and mated with female zebrafish in each group. Each mating experiment included 1 female zebrafish and 1 male zebrafish. Zebrafish embryos produced by the mating experiments were collected and counted. The embryos at 4 hours post-fertilization were observed under the microscope, the total number of embryos and the number of unfertilized embryos were counted, and the fertilization rate was calculated accordingly. The numbers of malformed embryos and dead embryos were counted 24 hours after fertilization, and the rates of embryo malformation and mortality were calculated accordingly. The primary outcome measure was the embryo fertilization rate, and the secondary outcome measures were the number of embryos per spawn (the total number of embryos laid within 1.5 hours after the beginning of mating and reproduction of the zebrafish), embryo mortality, and embryo malformation rate. The outcome measures of each group were compared. The blastocyst embryos of female zebrafish from each group born after mating with male zebrafish in their best breeding period were collected for transcriptomics analysis. Fresh oocytes of female zebrafish in each group were collected for transcriptomics analysis to explore the potential molecular mechanisms of maternal age-related fertility decline. Results: Compared with that of the 6-month group (94.9%±3.6%), the embryo fertilization rate of the 12-month group (92.3%±4.2%) showed no significant difference, but that of the 18-month group (86.8%±5.5%) decreased significantly (P<0.01). In addition, the fertilization rate in the 18-month group was significantly lower than that in the 12-month group (P<0.05). Compared with that of the 6-month group, the embryo mortality of the female zebrafish in the 12-month group and that in the 18-month group were significantly higher than that in the 6-month group (P<0.000 1, P<0.001). There was no significant difference in the number of embryos per spawn or in the embryo malformation rate among the three groups. The results of the transcriptomics analysis of blastocyst embryos showed that some genes, including dusp5, bdnf, ppip5k2, dgkg, aldh3a2a, acsl1a, hal, mao, etc, were differentially expressed in the 12-month group or the 18-month group compared with their expression levels in the 6-month group. According to the KEGG enrichment analysis, these differentially expressed genes (DEGs) were significantly enriched in the MAPK signaling pathway, the phosphatidylinositol signaling system, and the fatty acid degradation and histidine metabolism pathway (P<0.05). The analysis of the expression trends of the genes expressed differentially among the three groups (the 6-month group, the 12-month group, and the 18-month group in turn) showed that the gene expression trends of fancc, fancg, fancb, and telo2, which were involved in Fanconi anemia pathway, were statistically significant (P<0.05). In the results of oocyte transcriptomics analysis, the genes that were differentially expressed in the 12-month group or the 18-month group compared with the 6-month group were mainly enriched in cell adhesion molecules and the protein digestion and absorption pathway (P<0.05). The results of the trends of gene expression in the zebrafish oocytes of the three groups (the 6-month group, the 12-month group, and the 18-month group in turn) showed that three kinds of gene expression trends of declining fertility with growing maternal age had significant differences (P<0.05). Further analysis of the three significantly differential expression trends showed 51 DEGs related to mitochondria and 5 DEGs related to telomere maintenance and DNA repair, including tomm40, mpc2, nbn, tti1, etc. Conclusion: With the increase in the maternal age of the zebrafish, the embryo fertilization rate decreased significantly and the embryo mortality increased significantly. In addition, with the increase in the maternal age of the zebrafish, the expression of mitochondria and telomere-related genes, such as tomm40, mpc2, nbn, and tti1, in female zebrafish oocytes decreased gradually. Maternal age may be a factor contributing to the decrease in oocyte fertilization ability and the increase in early embryo mortality. Maternal age-related oocyte aging affects the fertility and embryo development of the offspring.

Basal FSH values are positively associated with aneuploidy incidence in pre-advanced maternal age (AMA) but not in AMA patients.

PURPOSE: To assess the impact of maternal age on the association between maternal basal FSH and aneuploidy. METHODS: A retrospective study including data from 1749 blastocysts diagnosed as euploid or aneuploid by PGT-A (preimplantation genetic testing for aneuploidy). Aneuploidy incidence was compared between embryos from mothers with high vs. low basal FSH levels (above and below the group median, respectively) in total, pre-AMA (advanced maternal age; < 35 years, 198 embryos) and AMA (≥ 35 years, 1551 embryos) patient groups, separately. To control for the interference of potentially confounding variables, the association between aneuploidy and high basal FSH levels was assessed by multivariate logistic analysis in overall, pre-AMA and AMA patient groups. RESULTS: Overall, aneuploidy rate was 9% higher (p = 0.02) in embryos from patients with high basal FSH (63.7%) compared to those with low basal FSH (58.4%). In the pre-AMA subgroup, aneuploidy incidence was 35% higher (p = 0.04) in embryos from patients with high basal FSH (53.5%) compared to those with low basal FSH (39.4%). Differently, aneuploidy occurrence did not vary between embryos from AMA patients with low (61.0%) and high (64.8%) basal FSH (p = 0.12). The multivariate analysis revealed that, in pre-AMA embryos, the association between aneuploidy occurrence and high basal FSH is independent of potential confounding variables (p = 0.04). CONCLUSION: Maternal basal FSH values are associated with embryo aneuploidy in pre-AMA but not in AMA patients. The present findings suggest that basal FSH is a useful parameter to assess aneuploidy risk in pre-AMA patients and reinforce the hypothesis that excessive FSH signalling can predispose to oocyte meiotic errors.

Effects of maternal age and environmental enrichment on learning ability and brain size.

It is well known that maternal age at reproduction affects offspring lifespan and some other fitness-related traits, but it remains understudied whether maternal senescence affects how offspring respond to their environments. Early environment often plays a significant role in the development of an animal's behavioral phenotype. For example, complex environments can promote changes in cognitive ability and brain morphology in young animals. Here, we study whether and how maternal effect senescence influences offspring plasticity in cognition, group behavior, and brain morphology in response to environmental complexity. For this, juvenile 3-spined sticklebacks from young and old mothers (i.e. 1-yr and 2-yr-old) were exposed to different levels of environmental enrichment and complexity (i.e. none, simple, and complex), and their behavior, cognitive ability, and brain size were measured. Exposing fish to enriched conditions improved individual learning ability assessed by a repeated detour-reaching task, increased the size of the whole brain, and decreased aggressive interactions in the shoal. Maternal age did not influence the inhibitory control, learning ability, and group behavioral responses of offspring to the experimental environmental change. However, maternal age affected how some brain regions of offspring changed in response to environmental complexity. In offspring from old mothers, those exposed to the complex environment had larger telencephalons and cerebellums than those who experienced simpler environments. Our results suggest that maternal effect senescence may influence how offspring invest in brain functions related to cognition in response to environmental complexity.

Preconception underweight and the risk of offspring congenital heart diseases in young pregnant women: Evidence from the China Birth Cohort Study.

OBJECTIVE: Maternal obesity is a highly suggestive risk factor of offspring congenital heart diseases (CHD). However, the risk of offspring CHD associated with maternal underweight has rarely been mentioned. Therefore, this study aimed to explore the effect of preconception underweight on offspring CHD. METHODS: From November 2017 to August 2021, 132 386 pregnant women were enrolled in a birth cohort study in China in early pregnancy, and completed follow-up until delivery (or miscarriage/termination). Offspring CHD was diagnosed by prenatal ultrasound examination in both live births and stillbirths. Log-binomial regression and restricted cubic spline were used to estimate the risk of offspring CHD associated with preconception body mass index (BMI). A generalized additive model was used to explore the modification effect of maternal age on the association between preconception BMI and offspring CHD. RESULTS: A total of 129 096 pregnant women were included in the analysis. The incidence of CHD in the underweight, normal weight, overweight, and obesity groups were 117/17 313 (0.68%), 556/85 695 (0.65%), 128/19 936 (0.64%), 47/6152 (0.76%), respectively. Both underweight and obesity before pregnancy marginally increased the risk of offspring CHD. The association between preconception BMI and offspring CHD varied by maternal age, with low preconception BMI associated with a significantly higher risk of offspring CHD in women <24 years (RR 2.32, 95% CI: 1.07-5.01 for 17 vs 21 kg/m2). CONCLUSION: Preconception underweight was associated with an increased risk of offspring CHD in young pregnant women. Therefore, weight gain is important to prevent offspring CHD, especially for young women with low preconception BMI.

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.

Introduction: 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. Materials and Methods: 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. Results: 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. Conclusions: 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.

Infertility following trisomic pregnancies: A nationwide cohort study.

OBJECTIVE: To study whether gynecologic or reproductive disorders show association with trisomic conceptions. METHODS: This nationwide cohort study utilized the Registry of Congenital Malformations to identify women who had a trisomic pregnancy (n = 5784), either with trisomy 13 (T13; n = 351), trisomy 18 (T18; n = 1065) or trisomy 21 (T21; n = 4369) from 1987 to 2018. We used the Finnish Maternity cohort to match the cases to population controls (n = 34 422) on the age, residence, and timing of pregnancy. These data were cross-linked to the ICD-10 diagnoses of the national Care Registry for Health Care data on specialized health care in Finland during 1996 to 2019. Both inflammatory (ICD-10 diagnoses: N70-N77) and noninflammatory disorders of the genital tract (N80-N98) were studied. Crude odds ratios (ORs) with 95% CIs were calculated for associations between diagnoses and trisomic conceptions. RESULTS: The diagnosis of female infertility (N97) at any time was associated with trisomic conceptions (OR: 1.19, 95% CI: 1.08-1.32). In the subgroup analysis, this association was found for T18 (OR: 1.29, 95% CI: 1.03-1.61) and T21 (OR: 1.17, 95% CI: 1.04-1.32), but not for T13 (OR: 1.15, 95% CI: 0.75-1.72). When restricting the timing of the diagnosis of female infertility, an elevated OR was found only after the index pregnancy (OR: 1.81, 95% CI: 1.56-2.09). These increased odds for infertility after trisomic conceptions were observed both in women <35 years (T18 OR: 1.91, 95% CI: 1.21-3.00; T21 OR: 1.68, 95% CI: 1.31-2.14) and in women ≥35 years (T18 OR: 2.17, 95% CI: 1.40-3.33; T21 OR: 1.87; 95% CI: 1.47-2.39), but not after T13 conceptions. CONCLUSION: Our observational data suggest a link between trisomic conceptions and subsequent diagnoses of infertility but do not demonstrate causality. These data implicate that partially similar mechanisms might predispose to trisomy and infertility, regardless of maternal age.

Establishing a risk score for prediction of intrapartum cesarean delivery among older women: A retrospective cohort study.

OBJECTIVE: To determine risk factors and to develop a risk prediction score for intrapartum cesarean delivery (CD) in women over 40 years old. STUDY DESIGN: A retrospective cohort study, in a single university-affiliated tertiary medical center. All women aged 40 years or more who planned a trial of labor between 2012 and 2022. Women who opted for an elective CD and those with non-viable fetuses were excluded. Maternal and neonatal characteristics of women who delivered vaginally were compared to those who underwent an intrapartum CD. Risk factors were examined using univariate and multivariate analysis. A score was developed to predict the need for intrapartum CD. We assessed a receiver operating characteristic curve to evaluate the performance of our model. MAIN OUTCOME MEASURE: An unplanned intrapartum cesarean section. RESULTS: During the study period, 122,583 women delivered at our center, of whom 6122 (4.9 %) aged 40 years or more attempted a trial of labor. Of them, 428 (7 %) underwent intrapartum CD. Several independent risk factors were identified, including nulliparity, regional anesthesia, induction of labor, use of antibiotics during labor, multiple gestation, previous cesarean delivery, and the presence of gestational diabetes or preeclampsia. A risk score model, employing a cut-off of 7, demonstrated successful prediction of intrapartum CD, with an area under the curve of 0.86. CONCLUSION: The score model for intrapartum CD can be used by caregivers to offer a more informed consultation to women aged 40 years or more deciding on the mode of delivery.

Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial.

STUDY QUESTION: Does luteal estradiol (E2) pretreatment give a similar number of retrieved oocytes compared to no-pretreatment in advanced-aged women stimulated with corifollitropin alfa in an antagonist protocol? SUMMARY ANSWER: Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38-42 years. WHAT IS KNOWN ALREADY: Programming antagonist cycles with luteal E2 pretreatment is a valuable tool to organize the IVF procedure better and is safe without any known impact on cycle outcome. However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise. STUDY DESIGN, SIZE, DURATION: This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38-42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1-2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20-24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8. MAIN RESULTS AND THE ROLE OF CHANCE: Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of -0.1 oocyte 95% CI [-1.5; 1.3] P = 0.004 in the PP population and a mean difference of -0.44 oocyte [-1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively). LIMITATIONS, REASONS FOR CAUTION: Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. Finally, the absence of placebo for pretreatment could also introduce possible bias. WIDER IMPLICATIONS OF THE FINDINGS: Programming antagonist cycles with luteal E2 pretreatment seems a useful tool in advanced age women to better schedule oocyte retrievals on working days. However, the potential benefit of the number of collected oocytes remains to be demonstrated in a larger population displaying the characteristics of decreased ovarian reserve encountered in Poseïdon classification. STUDY FUNDING/COMPETING INTEREST(S): Research grant from (MSD) Organon, France. I.C., S.D., B.B., X.M., S.G., and C.J. have no conflict of interest with this study. I.C.D. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA and participation on advisory board from Merck KGaA. I.C.D. also declares consulting fees, and travel and meeting support from Merck KGaA. N.M. declares grants paid to their institution from MSD (Organon, France); consulting fees from MSD (Organon, France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. N.C. declares grants from IBSA Pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA Pharma, Merck KGaG, MSD (Organon, France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. A.G.L. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02884245. TRIAL REGISTRATION DATE: 29 August 2016. DATE OF FIRST PATIENT'S ENROLMENT: 4 November 2016.

Clinical parameters that predict a premature LH rise in patients undergoing ovarian stimulation for IVF.

Background: Normal reproductive function requires adequate regulation of follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion. During ovarian stimulation for in-vitro fertilization (IVF), some patients will demonstrate an early rise in LH despite being treated with a gonadotropin releasing-hormone (GnRH) antagonist, sometimes necessitating cycle cancellation. Previous studies have demonstrated a possible link between a premature LH rise with ovarian response to gonadotropins. We sought to determine what clinical parameters can predict this premature LH rise and their relative contribution. Methods: A retrospective study of 382 patients who underwent IVF treatment at Rambam Medical Center. The patients were stratified into age groups. A model predicting premature LH rise based on clinical and demographic parameters was developed using both multiple linear regression and a machine-learning-based algorithm. Results: LH rise was defined as the difference between pre-trigger and basal LH levels. The clinical parameters that significantly predicted an LH rise were patient age, BMI, LH levels at stimulation outset, LH levels on day of antagonist administration, and total number of stimulation days. Importantly, when analyzing the data of specific age groups, the model's prediction was strongest in young patients (age 25-30 years, R2 = 0.88, p < .001) and weakest in older patients (age > 41 years, R2 = 0.23, p = .003). Conclusions: Using both multiple linear regression and a machine-learning-based algorithm of patient data from IVF cycles, we were able to predict patients at risk for premature LH rise and/or LH surge. Utilizing this model may help prevent IVF cycle cancellation and better timing of ovulation triggering.

Association between interpregnancy interval and the labor curve.

BACKGROUND: Both short and long interpregnancy intervals are associated with adverse pregnancy outcomes; however, the impact of interpregnancy intervals on labor progression is unknown. OBJECTIVE: We examined the impact of interpregnancy intervals on the labor curve, hypothesizing that those with a longer interpregnancy intervals would have slower labor progression. STUDY DESIGN: This is a retrospective cohort study of patients with a history of one prior vaginal delivery admitted for induction of labor or spontaneous labor with a singleton gestation ≥37 weeks at an academic medical center between 2004 and 2015. Repeated measures regression was used to construct labor curves, which were compared between patients with short interpregnancy intervals, defined as <3 years since the last delivery, and long interpregnancy intervals, defined as >3 years since the last delivery. We chose this interval as it approximates the median birth interval in the United States. Interval-censored regression was used to estimate the median duration of labor after 4 centimeters of dilation, stratified by type of labor (spontaneous vs induced). Multivariate analysis was used to adjust for potential confounders. RESULTS: Of the 1331 patients who were included in the analysis, 544 (41%) had a long interpregnancy interval. Among the entire cohort, there were no significant differences in first or second-stage progression between short and long interpregnancy interval groups. In the stratified analysis, first-stage progression varied between groups on the basis of labor type: long interpregnancy interval was associated with a slower active phase among those being induced and a quicker active phase among those in spontaneous labor. The second-stage duration was similar between cohorts regardless of labor type. CONCLUSION: Multiparas with an interpregnancy interval >3 years may have a slower active phase than those with a shorter interpregnancy interval when undergoing induction of labor. Interpregnancy interval does not demonstrate an effect on the length of the second stage.

Does cleavage- versus blastocyst-stage embryo transfer improve fertility rates in women over 38 years of age undergoing assisted reproductive technology?

OBJECTIVE: To evaluate whether extending embryo culture to day 5 (D5) affects pregnancy rates in women older than 38 years undergoing in vitro fertilization (IVF). METHODS: This retrospective, observational cohort study included data from fresh IVF cycles of women over 38 years, during 2011-2021. The cohort was divided according to day 3 (D3) versus D5 embryo transfer (ET). RESULTS: A total of 346 patients (ages 38-45 years) who underwent 496 IVF cycles were included, each yielding one to six embryos. A total of 374 (75%) fresh D3 ETs were compared with 122 (25%) D5 ETs. Demographically, there were more nulliparas in the D3 group (189 [50.9%] vs 47 [38.8%], P = 0.021). Higher gonadotropin dosage was used (3512 ± 1346 vs 3233 ± 1212 IU, P = 0.045) and lower maximum estradiol levels were reached in the D3 group (1129 ± 685 vs 1432 ± 708 pg/mL, P = 0.002). Thirty-three (27%) of the D5 cycles resulted in transfer cancelation due to failure of blastocyst formation (P = 0.001). However, clinical pregnancy rates (P = 0.958), live birth rates (P = 0.988), and miscarriage rates (P = 0.710) did not differ between D3 and D5 ETs. Multivariable logistic regression for clinical pregnancy rate showed that day of transfer did not have a significant effect on the odds (P = 0.376), but maternal age (P = 0.001) and number of retrieved oocytes (P = 0.009) were significant variables. CONCLUSIONS: In older women, culturing embryos to blastocyst stage can decrease invalid ETs without reducing pregnancy rates. Cancelation rates are higher but it may avoid interventions and conserve valuable time.

Examining Cesarean Among Individuals of Advanced Maternal Age in Nurse-Midwifery Care.

INTRODUCTION: Cesarean rates are rising, especially for individuals of advanced maternal age (AMA), defined as aged 35 or older. The Robson 10-Group Classification System (TGCS) facilitates assessment and comparison of cesarean rates among individuals in different settings. In midwifery-led care, in which pregnant people are typically healthier and seek a vaginal birth, it is unknown whether individuals of AMA have different antecedents leading to cesarean compared with younger counterparts. This study aimed to examine antecedents contributing to cesarean using Robson TGCS for individuals across age groups in midwifery care. METHODS: This study was a secondary analysis of 2 cohort data sets from Oregon Health & Science University (OHSU) and University of Michigan Health Systems (UMHS) hospitals. The samples were individuals in midwifery-led care birthing at either OHSU from 2012 to 2019 or UMHS from 2007 to 2019. RESULTS: A total of 11,951 individuals were studied. Overall cesarean rates were low; however, the rate for individuals of AMA was higher than the rate of their younger counterparts (18.30% vs 15.10%). The Robson groups were similar; however, the primary contributor among AMA individuals was group 5 (multiparous with previous cesarean), followed by group 2 [nulliparous with labor induced or prelabor cesarean], and group 1 [nulliparous with spontaneous labor]. In contrast, the primary contributors for younger individuals were groups 1, 2, and 5, respectively. In addition, prelabor cesarean and induced labor partly mediated the relationship between AMA and cesarean among nulliparous individuals, whereas prelabor cesarean was the key contributor to cesarean among multiparous people. DISCUSSION: The cesarean rate in midwifery-led care was low. Using Robson TGCS provided additional insight into the antecedents to cesarean, rather than viewing cesarean as a single outcome. Future studies should continue to use Robson TGCS and investigate antecedents to cesarean, including factors influencing successful vaginal birth after cesarean in individuals of AMA.

Maternal age at transfer following autologous oocyte cryopreservation is not associated with live birth rates.

PURPOSE: Our aim was to evaluate if maternal age at transfer following autologous oocyte cryopreservation is associated with live birth rate (LBR). METHODS: We performed a retrospective cohort study of all patients who thawed autologous oocytes and then underwent a single frozen euploid embryo transfer between 2011 and 2021 at a large urban university-affiliated fertility center. Each oocyte thaw patient was matched 2:1 to in vitro fertilization (IVF) patients who underwent single embryo transfer < 1 year after retrieval. Primary outcome was LBR. Secondary outcomes included implantation rates (IR) and spontaneous abortion rates (SABR). RESULTS: A total of 169 oocyte thaw patients were matched to 338 IVF patients. As expected, oocyte thaw patients were older (median age 42.5 vs. 37.6 years, p < 0.001) and waited longer between retrieval and transfer than in vitro fertilization patients (median time 59 vs. 1 month, p < 0.001). In univariate analysis, implantation and LBR differed among oocyte thaw and IVF patients (p < 0.05), but SABR did not (p = 0.57). Transfer outcomes in oocyte thaw patients did not differ based on transfer age group (IR: p = 0.18; SABR: p = 0.12; LBR: p = 0.24). In a multiple logistic regression model, age at transfer was not predictive of live birth when controlling for age at retrieval, embryo morphology, and day of blastulation. CONCLUSIONS: Maternal age at transfer after oocyte cryopreservation is not predictive of LBR; this suggests that "an aging womb" does not impair LBR after oocyte thaw and empowers patients to return for transfer when ready for childbearing.

Risk factors for maternal near-miss in an undeveloped province in south-central China, 2012-2022.

OBJECTIVE: To explore the risk factors for maternal near-miss (MNM) using the WHO near-miss approach. METHODS: Data were obtained from the Maternal Near-Miss Surveillance System in Hunan Province, China, 2012-2022. Multivariate logistic regression analysis (method: Forward, Wald, α = 0.05) and adjusted odds ratios (aORs) were used to identify risk factors for MNM. RESULTS: Our study included 780,359 women with 731,185 live births, a total of 2461 (0.32%) MNMs, 777,846 (99.68%) non-MNMs, and 52 (0.006%) maternal deaths were identified. The MNM ratio was 3.37‰ (95%CI: 3.23-3.50). Coagulation/hematological dysfunction was the most common cause of MNM (75.66%). Results of multivariate logistic regression analysis showed risk factors for MNM: maternal age > = 30 years old (aOR > 1, P < 0.05), unmarried women (aOR = 2.21, 95%CI: 1.71-2.85), number of pregnancies > = 2 (aOR > 1, P < 0.05), nulliparity (aOR = 1.51, 95%CI: 1.32-1.72) or parity > = 3 (aOR = 1.95, 95%CI: 1.50-2.55), prenatal examinations < 5 times (aOR = 1.13, 95%CI: 1.01-1.27), and number of cesarean sections was 1 (aOR = 1.83, 95%CI: 1.64-2.04) or > = 2 (aOR = 2.48, 95%CI: 1.99-3.09). CONCLUSION: The MNM ratio was relatively low in Hunan Province. Advanced maternal age, unmarried status, a high number of pregnancies, nulliparity or high parity, a low number of prenatal examinations, and cesarean sections were risk factors for MNM. Our study is essential for improving the quality of maternal health care and preventing MNM.

Single-cell proteomics reveals decreased abundance of proteostasis and meiosis proteins in advanced maternal age oocytes.

Advanced maternal age is associated with a decline in oocyte quality, which often leads to reproductive failure in humans. However, the mechanisms behind this age-related decline remain unclear. To gain insights into this phenomenon, we applied plexDIA, a multiplexed data-independent acquisition, single-cell mass spectrometry method, to analyze the proteome of oocytes from both young women and women of advanced maternal age. Our findings primarily revealed distinct proteomic profiles between immature fully grown germinal vesicle and mature metaphase II oocytes. Importantly, we further show that a woman's age is associated with changes in her oocyte proteome. Specifically, when compared to oocytes obtained from young women, advanced maternal age oocytes exhibited lower levels of the proteasome and TRiC complex, as well as other key regulators of proteostasis and meiosis. This suggests that aging adversely affects the proteostasis and meiosis networks in human oocytes. The proteins identified in this study hold potential as targets for improving oocyte quality and may guide future studies into the molecular processes underlying oocyte aging.