Advanced maternal age alters cardiac functional and structural adaptations to pregnancy in rats.

A significant number of pregnancies occur at advanced maternal age (>35 yr), which is a risk factor for pregnancy complications. Healthy pregnancies require massive hemodynamic adaptations, including an increased blood volume and cardiac output. There is growing evidence that these cardiovascular adaptations are impaired with age, however, little is known about maternal cardiac function with advanced age. We hypothesized that cardiac adaptations to pregnancy are impaired with advanced maternal age. Younger (4 mo; ∼early reproductive maturity in humans) and aged (9 mo; ∼35 yr in humans) pregnant Sprague-Dawley rats were assessed and compared with age-matched nonpregnant controls. Two-dimensional echocardiographic images were obtained (ultrasound biomicroscopy; under anesthesia) on gestational day 19 (term = 22 days) and compared with age-matched nonpregnant rats (n = 7-9/group). Left ventricular structure and function were assessed using short-axis images and transmitral Doppler signals. During systole, left ventricular anterior wall thickness increased with age in the nonpregnant rats, but there was no age-related difference between the pregnant groups. There were no significant pregnancy-associated differences in left ventricular wall thickness. Calculated left ventricular mass increased with age in nonpregnant rats and increased with pregnancy only in young rats. Compared with young pregnant rats, the aortic ejection time of aged pregnant rats was greater and Tei index was lower. Overall, the greater aortic ejection time and lower Tei index with age in pregnant rats suggest mildly altered cardiac adaptations to pregnancy with advanced maternal age, which may contribute to adverse outcomes in advanced maternal age pregnancies.NEW & NOTEWORTHY We demonstrated that even before the age of reproductive senescence, rats show signs of age-related alterations in cardiac structure that suggests increased cardiac work. Our data also demonstrate, using an in vivo echocardiographic approach, that advanced maternal age in a rat model is associated with altered cardiac function and structure relative to younger pregnant controls.

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.

Addition of rapamycin or co-culture with cumulus cells from younger reproductive age women does not improve rescue in vitro oocyte maturation or euploidy rates in older reproductive age women.

Both spontaneously conceived pregnancies and those achieved using assisted reproduction decline with advancing maternal age. In this study, we tested if rapamycin and/or cumulus cells (CCs) from young donors could improve oocyte maturation and euploidy rates of germinal vesicle (GV) stage oocytes obtained from older women of reproductive age. A total of 498 GVs from 201 women >38 years (40.6 ± 1.8, mean ± SD) were included. GVs were randomly assigned into five groups for rescue IVM: control (with no CCs and no rapamycin); with autologous CCs; with autologous CCs and rapamycin; with CCs from young women (<35 years); and with CCs from young women and rapamycin. After 24 h of culture, the first polar body (PB) was biopsied in metaphase II oocytes, and the cytogenetic constitution was assessed using next-generation sequencing for both oocytes and PBs. Comparable maturation rates were found (56.2%, 60.0%, 46.5%, 51.7%, and 48.5% for groups 1-5, respectively; P = 0.30). Similarly, comparable euploidy rates were observed in the five groups (41.5%, 37.8%, 47.2%, 43.6%, and 47.8% for Groups 1-5, respectively; P = 0.87). Our findings indicate that rescue IVM is effective for obtaining mature euploid oocytes in older women of reproductive age, and that incubation with rapamycin or CCs obtained from young donors does not improve the maturation or euploidy rate.

Livebirth rates are influenced by an interaction between male and female partners' age: analysis of 59 951 fresh IVF/ICSI cycles with and without male infertility.

STUDY QUESTION: Does advanced male partner's age impact live birth rates (LBRs) in IVF treatment when female partner's age is factored in? SUMMARY ANSWER: In fresh IVF cycles LBRs decline with male partner's age ≥40 years when the female partner is aged 35-39 years, irrespective of the presence or absence of male factor; but not when the female partner is <35 years or ≥40 years of age; this decline is not observed in ICSI cycles. WHAT IS KNOWN ALREADY: Advanced paternal age is associated with declining sperm parameters, impaired embryo development, compromised pregnancy outcomes, and abnormalities in the offspring in IVF/ICSI cycles. However, data on the interaction between maternal and paternal age on IVF outcomes are very limited and inconsistent. No significant effect of male partner's age on pregnancy outcomes has been noted in donor oocyte cycles. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of all eligible autologous IVF/ICSI cycles with oocyte retrieval and intended fresh embryo transfer (ET) from the UK's national anonymized registry, published online by the Human Fertilisation and Embryology Authority (HFEA). There were 59 951 cycles that qualified the inclusion criteria in the study period: 1 January 2017 to 31 December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples underwent IVF (n = 27 226) or ICSI (n = 32 725) treatment with partner's sperm followed by fresh ET due to unexplained (n = 31 846), tubal (n = 6605), or male infertility (n = 22 905). Treatment cycles with endometriosis (n = 5563), ovulatory disorders (n = 9970), female partner aged >44 years (n = 636), and PGT (n = 280) were excluded. Women were stratified by age in the following groups: <35, 35-39, 40-42, and 43-44 years; male partner's age as <35 (reference group), 35-37, 38-39, 40-42, 43-44, 45-50, 51-55, 55-60, and >55 years as presented by the HFEA. Some age-groups were merged in the analysis to increase the population size. Chi-square test was used to compare binominal data; and multiple logistic regression to find any association between male and female age-groups on live birth adjusting for other confounders that had a significant effect on this outcome. MAIN RESULTS AND THE ROLE OF CHANCE: LBRs per oocyte retrieval as well as per ET were no different across the male partners' age-groups when the female partners were aged <35 years or in 40- to 44-year age-group, whether male-factor infertility was included or excluded and whether it was IVF or ICSI cycle. However, when IVF was the method of insemination in the female partner's age-group of 35-39 years, LBRs per oocyte retrieval dropped significantly from 27.0% in the male age-group of <35 years (reference group) to 22.9% (P = 0.002), 22.0% (P = 0.006), and 18.8% (P = 0.004) in 40-44, 45-50, and >50 years age-group, respectively in population that included male-factor infertility. Likewise, LBR per retrieval declined from 27.6% in 35 years age-group to 23.5% (P = 0.002) and 22.2% (P = 002) in 40-44 years and older groups, respectively in cycles without male infertility. However, there was no impact of male age on LBR in any female partner's age-group when ICSI was performed in either the presence or the absence of male infertility. A similar decline in the LBR per retrieval and per ET was observed in female age-group of 35-39 years in the analyses with IVF and ICSI cycles combined. The inference remained unchanged when only the first treatment cycle was included (per patient analysis) or when single blastocyst transfer cycles were analysed, eliminating the impact of the number and stage of embryo transferred. After adjusting for confounders including male age, female age, number of previous treatment cycles, previous live birth, insemination method (IVF or ICSI), number of embryos transferred, and day (stage) of ET, male partner's age remained significantly associated with LBR in the female age-group of 35-39 years, but not when women were in <35 years or 40- to 44-year age-group, in population including as well as excluding male infertility. Miscarriage rates per single ET trended to rise (non-significantly) in IVF as well as ICSI cycle only when men were over 55 years and female partners aged <40 years, particularly when male infertility was excluded. LIMITATIONS, REASONS FOR CAUTION: Information on ovarian reserve and stimulation protocols was not available. This probably would have had little impact, given the large size of the population studied. The ages of female and male partners were given in groups necessitating taking them as ordinal variable in the regression analysis. Cumulative LBRs could not be determined as the information on subsequent frozen-thawed ET cycles could not be traced and the severity or cause of abnormal semen parameters were not present in the HFEA database. Some age-groups with small number of patients were merged to obtain a reliable result. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest clinical data to support the laboratory evidence of the ability of oocytes from young women to reverse the age-related deterioration of sperm quality. As the ageing oocytes lose this reparatory mechanism, the ageing sperm exert a detrimental effect on the LBR. The message of this study is important in counselling of patients and planning out treatment. Further research on interaction between male and female age will increase our understanding of this matter and help to establish whether ICSI procedure is more appropriate for older male partners even when there is no apparent semen abnormality. STUDY FUNDING/COMPETING INTEREST(S): No funding was required. There is no competing interest. TRIAL REGISTRATION NUMBER: N/A (retrospective analysis).

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.

Gonadotropin elevation is ootoxic to ovulatory oocytes and inhibits oocyte maturation, and activin decoy receptor ActRIIB:Fc therapeutically restores maturation.

BACKGROUND: Elevated FSH often occurs in women of advanced maternal age (AMA, age ≥ 35) and in infertility patients undergoing controlled ovarian stimulation (COS). There is controversy on whether high endogenous FSH contributes to infertility and whether high exogenous FSH adversely impacts patient pregnancy rates. METHODS: The senescence-accelerated mouse-prone-8 (SAMP8) model of female reproductive aging was employed to assess the separate impacts of age and high FSH activity on the percentages (%) of viable and mature ovulated oocytes recovered after gonadotropin treatment. Young and midlife mice were treated with the FSH analog equine chorionic gonadotropin (eCG) to model both endogenous FSH elevation and exogenous FSH elevation. Previously we showed the activin inhibitor ActRIIB:Fc increases oocyte quality by preventing chromosome and spindle misalignments. Therefore, ActRIIB:Fc treatment was performed in an effort to increase % oocyte viability and % oocyte maturation. RESULTS: The high FSH activity of eCG is ootoxic to ovulatory oocytes, with greater decreases in % viable oocytes in midlife than young mice. High FSH activity of eCG potently inhibits oocyte maturation, decreasing the % of mature oocytes to similar degrees in young and midlife mice. ActRIIB:Fc treatment does not prevent eCG ootoxicity, but it restores most oocyte maturation impeded by eCG. CONCLUSIONS: FSH ootoxicity to ovulatory oocytes and FSH maturation inhibition pose a paradox given the well-known pro-growth and pro-maturation activities of FSH in the earlier stages of oocyte growth. We propose the FOOT Hypothesis ("FSH OoToxicity Hypothesis), that FSH ootoxicity to ovulatory oocytes comprises a new driver of infertility and low pregnancy success rates in DOR women attempting spontaneous pregnancy and in COS/IUI patients, especially AMA women. We speculate that endogenous FSH elevation also contributes to reduced fecundity in these DOR and COS/IUI patients. Restoration of oocyte maturation by ActRIB:Fc suggests that activin suppresses oocyte maturation in vivo. This contrasts with prior studies showing activin A promotes oocyte maturation in vitro. Improved oocyte maturation with agents that decrease endogenous activin activity with high specificity may have therapeutic benefit for COS/IVF patients, COS/IUI patients, and DOR patients attempting spontaneous pregnancies.

Identifying key predictive features for live birth rate in advanced maternal age patients undergoing single vitrified-warmed blastocyst transfer.

BACKGROUND: Infertility affects one in six couples worldwide, with advanced maternal age (AMA) posing unique challenges due to diminished ovarian reserve and reduced oocyte quality. Single vitrified-warmed blastocyst transfer (SVBT) has shown promise in assisted reproductive technology (ART), but success rates in AMA patients remain suboptimal. This study aimed to identify and refine predictive factors for live birth following SVBT in AMA patients, with the goal of enhancing clinical decision-making and enabling personalized treatment strategies. METHODS: This retrospective cohort study analyzed 1,168 SVBT cycles conducted between June 2016 and December 2022 at the First Affiliated Hospital of Guangxi Medical University and Nanning Maternity and Child Health Hospital. Nineteen machine-learning models were applied to identify key predictive factors for live birth. Feature selection and 10-fold cross-validation were employed to validate the models. RESULTS: The most significant predictors of live birth included inner cell mass quality, trophectoderm quality, number of oocytes retrieved, endometrial thickness, and the presence of 8-cell blastomeres on day 3. The stacking model demonstrated the best predictive performance (AUC: 0.791), followed by Extra Trees (AUC: 0.784) and Random Forest (AUC: 0.768). These models outperformed traditional methods, achieving superior accuracy, sensitivity, and specificity. CONCLUSION: Leveraging advanced machine-learning models and identifying critical predictive factors can improve the accuracy of live birth outcome predictions for AMA patients undergoing SVBT. These findings offer valuable insights for enhancing clinical decision-making and managing patient expectations. Further research is needed to validate these results in larger, multi-center cohorts and to explore additional factors, including fresh embryo transfers, to broaden the applicability of these models in clinical practice.

Biodemographic Characteristics of Children with Down Syndrome, Their Siblings, and Their Parents in Moroccan Population.

OBJECTIVE: In this study, we present the results of biodemographic characteristics of households and associated factors with Down syndrome (DS) birth in Morocco. METHODS: We conducted a retrospective survey between 2014 and 2017 addressed to 277 families with 925 siblings and at least one child with DS (279 with DS). The data are collected using a standardized questionnaire in Marrakech-Safi region. Data were entered and analyzed using the statistical program SPSS statistics software for Windows (version 20.0). χ2 and student t tests were used for testing statistical significance. Differences were considered significant when the p value <0.05. RESULTS: The binary logistic regression analysis between DS and non-DS children in their biodemographic characteristics studied (sex, breastfeeding, duration of exclusive breastfeeding, birth weight, maternal age at birth, paternal age at birth, oral contraceptive use, duration of oral contraceptive use before pregnancy, child age, and rank of birth) showed that only maternal age and paternal age at birth, duration of exclusive breastfeeding, birth weight, and child age were associated with DS birth (odds ratio [OR] = 1.08; 95% Cl: 1.04-1.13, OR = 1.04; 95% Cl: 1.00-1.08, OR = 0.95; 95% Cl: 0.92-0.98, OR = 0.31; 95% Cl: 0.22-0.44, and OR = 0.90; 95% CI: 0.87-0.93, respectively). In the other hand, the comparison between some of socio- and biodemographic characteristics of households studied with data from National Population Survey and Family Health (2018) showed a higher level of education in women and men in our sample in comparison with the general population. Similar results were shown in proportion of men and women in paid employment, the proportion of smoking and alcohol consumption among men, and the rate of oral contraceptive use before pregnancy among women. CONCLUSION: Highlighting the biodemographic characteristics of people with DS will help families to take good care of this group.

Pregnancy history and estradiol influence spatial memory, hippocampal plasticity, and inflammation in middle-aged rats.

Pregnancy and motherhood can have long-term effects on cognition and brain aging in both humans and rodents. Estrogens are related to cognitive function and neuroplasticity. Estrogens can improve cognition in postmenopausal women, but the evidence is mixed, partly due to differences in age of initiation, type of menopause, dose, formulation and route of administration. Additionally, past pregnancy influences brain aging and cognition as a younger age of first pregnancy in humans is associated with poorer aging outcomes. However, few animal studies have examined specific features of pregnancy history or the possible mechanisms underlying these changes. We examined whether maternal age at first pregnancy and estradiol differentially affected hippocampal neuroplasticity, inflammation, spatial reference cognition, and immediate early gene activation in response to spatial memory retrieval in middle-age. Thirteen-month-old rats (who were nulliparous (never mothered) or previously primiparous (had a litter) at three or seven months) received daily injections of estradiol (or vehicle) for sixteen days and were tested on the Morris Water Maze. An older age of first pregnancy was associated with impaired spatial memory but improved performance on reversal training, and increased number of new neurons in the ventral hippocampus. Estradiol decreased activation of new neurons in the dorsal hippocampus, regardless of parity history. Estradiol also decreased the production of anti-inflammatory cytokines based on age of first pregnancy. This work suggests that estradiol affects neuroplasticity and neuroinflammation in middle age, and that age of first pregnancy can have long lasting effects on hippocampus structure and function.

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.

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

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

Very young and advanced maternal age strongly elevates the occurrence of nonchromosomal congenital anomalies: a systematic review and meta-analysis of population-based studies.

BACKGROUND: Nonchromosomal congenital anomalies (NCAs) are the most common cause of infant mortality and morbidity. The role of maternal age is well known, although the specifics are not thoroughly elucidated in the literature. OBJECTIVE: To evaluate the role of maternal age in the incidence of NCAs and to pinpoint age groups at higher risk to refine screening protocols. STUDY DESIGN: A systematic review and meta-analysis were conducted following the PRISMA 2020 guidelines and Cochrane Handbook. Searches were performed on October 19, 2021, across MEDLINE (via PubMed), Cochrane Library (CENTRAL), and Embase. Population-based studies assessing the impact of maternal age on the incidence of NCAs in pregnant women were included, without restrictions on age range, country, or comorbidities. A random-effects model was used for pooling effect sizes, considering the heterogeneity across studies. RESULTS: From 15,547 studies, 72 were synthesized. Maternal age >35 showed an increased NCA risk (risk ratio [RR]: 1.31, confidence interval [CI]: 1.07 -1.61), rising notably after>40 (RR: 1.44, CI: 1.25 -1.66). The latter changes to 1.25 (CI: 1.08 -1.46) if the co-occurrence of chromosomal aberrations is excluded. Specific anomalies like cleft lip/palate (>40, RR: 1.57, CI: 1.11 -2.20) and circulatory system defects (>40, RR: 1.94, CI: 1.28 -2.93) were significantly associated with advanced maternal age. Conversely, gastroschisis was linked to mothers <20 (RR: 3.08, CI: 2.74 -3.47). CONCLUSION: The study confirms that both very young and advanced maternal ages significantly increase the risk of NCAs. There is a pressing need for age-specific prenatal screening protocols to better detect these anomalies, especially considering the current trend of delayed childbearing. Further research is required to fully understand the impact of maternal age on the prevalence of rarer NCAs.

An analysis of risk factors for spontaneously occurring type 2 diabetes mellitus in rhesus macaques (Macaca mulatta).

BACKGROUND: Type 2 Diabetes Mellitus (T2D) is a chronic disease with a high prevalence worldwide. Human literature suggests factors beyond well-known risk factors (e.g., age, body mass index) for T2D: cytomegalovirus serostatus, season of birth, maternal age, birth weight, and depression. Nothing is known, however, about whether these variables are influential in primate models of T2D. METHODS: Using a retrospective methodology, we identified 22 cases of spontaneously occurring T2D among rhesus monkeys at our facility. A control sample of n = 1199 was identified. RESULTS: Animals born to mothers that were ≤5.5 years of age, and animals that showed heightened Activity and Emotionality in response to brief separation in infancy, had a greater risk for development of T2D in adulthood. CONCLUSIONS: Knowledge of additional risk factors for T2D could help colony managers better identify at-risk animals and enable diabetes researchers to select animals that might be more responsive to their manipulations.

Evaluating neonatal mortality in Malta compared with other EU countries: Exploring the influence of congenital anomalies and maternal risk factors.

BACKGROUND: Globally, 240,000 babies die in the neonatal period annually due to congenital anomalies (CA). Malta reports the highest neonatal mortality rate (NMR) among EU (European Union) Countries, constituting a public health concern. OBJECTIVES: This study describes the contribution of CA to NMR in Malta, investigating possible associations with known maternal risk factors of maternal age, nationality, and education. Additionally, it provides an update on the contribution of CA to neonatal deaths in Malta and other EU countries. METHODS: Anonymous data for births and neonatal deaths were obtained for 2006-2020 from the National Obstetrics Information System (NOIS) in Malta. Regression analyses adjusting for maternal risk factors were run on this data to explore possible associations with NMR. NMRs published by EUROSTAT 2011-2020 were used to compare mortality by underlying cause of death (CA or non-CA causes) for Malta and other EU countries. RESULTS: Between 2006 and 2020, 63,890 live births with 283 neonatal deaths were registered in Malta, (NMR 4.4 per 1000 live births). CA accounted for 39.6% of neonatal deaths. No time trends were observed in either total NMR, NMR attributed to CA or mortality due to non-CA causes. Adjusted variables revealed associations for women hailing from non-EU, low-income countries. Malta registered high NMRs compared to EU countries, most marked for deaths attributed to CA. CONCLUSIONS: Between 2006 and 2020, Malta's NMR remained stable. Maternal Nationality, from non-EU low-income countries, was associated with higher neonatal mortality. The influx of such migrants may play a partial role in the high NMRs experienced. Malta's high NMR was primarily driven by early neonatal deaths, which included high proportions of deaths due to CA and is linked to the fact that termination of pregnancy is illegal in Malta.

Major postpartum haemorrhage after frozen embryo transfer: A population-based study.

OBJECTIVE: To investigate the effect on major postpartum haemorrhage (PPH) of mode of conception, differentiating between naturally conceived pregnancies, fresh embryo in vitro fertilisation (fresh-IVF) and frozen embryo transfer (frozen-IVF). DESIGN: Retrospective cohort study. SETTING: The French Burgundy Perinatal Network database, including all deliveries from 2006 to 2020, was linked to the regional blood centre database. POPULATION OR SAMPLE: In all, 244 336 women were included, of whom 240 259 (98.3%) were singleton pregnancies. METHODS: The main analyses were conducted in singleton pregnancies, including 237 608 naturally conceived, 1773 fresh-IVF and 878 frozen-IVF pregnancies. Multivariate logistic regression models adjusted on maternal age, body mass index, smoking, parity, induction of labour, hypertensive disorders, diabetes, placenta praevia and/or accreta, history of caesarean section, mode of delivery, birthweight, birth place and year of delivery, were used. MAIN OUTCOME MEASURES: Major PPH was defined as PPH requiring blood transfusion and/or emergency surgery and/or interventional radiology. RESULTS: The prevalence of major PPH was 0.74% (n = 1749) in naturally conceived pregnancies, 1.92% (n = 34) in fresh-IVF pregnancies, and 3.30% (n = 29) in frozen-IVF pregnancies. The risk of major PPH was higher in frozen-IVF pregnancies than in both naturally conceived pregnancies (adjusted odds ratio [aOR] 2.63, 95% CI 1.68-4.10) and fresh-IVF pregnancies (aOR 2.78, 95% CI 1.44-5.35). CONCLUSIONS: We found that frozen-IVF pregnancies have a higher risk of major PPH and they should be subject to increased vigilance in the delivery room.

Risk of major congenital heart disease in pregestational maternal diabetes is modified by hemoglobin A1c.

OBJECTIVES: The association between pregestational diabetes mellitus (PDM) and risk of congenital heart disease (CHD) is well recognized; however, the importance of glycemic control and other coexisting risk factors during pregnancy is less clear. We sought to determine the relative risk (RR) of major CHD (mCHD) among offspring from pregnancies complicated by PDM and the effect of first-trimester glycemic control on mCHD risk. METHODS: We determined the incidence of mCHD (requiring surgery within 1 year of birth or resulting in pregnancy termination or fetal demise) among registered births in Alberta, Canada. Linkage of diabetes status, maximum hemoglobin A1c (HbA1c) at < 16 weeks' gestation and other covariates was performed using data from the Alberta Perinatal Health Program registry. Risk of mCHD according to HbA1c was estimated as an adjusted RR (aRR), calculated using log-binomial modeling. RESULTS: Of 1412 cases of mCHD in 594 773 (2.37/1000) births in the study period, mCHD was present in 48/7497 with PDM (6.4/1000; RR, 2.8 (95% CI, 2.1-3.7); P < 0.0001). In the entire cohort, increased maternal age (aRR, 1.03 (95% CI, 1.02-1.04); P < 0.0001) and multiple gestation (aRR, 1.37 (95% CI, 1.1-1.8); P = 0.02) were also associated with mCHD risk, whereas maternal prepregnancy weight > 91 kg was not. The stratified risk for mCHD associated with HbA1c ≤ 6.1%, > 6.1-8.0% and > 8.0% was 4.2/1000, 6.8/1000 and 17.1/1000 PDM/gestational diabetes mellitus births, respectively; the aRR of mCHD associated with PDM and HbA1c > 8.0% was 8.5 (95% CI, 5.0-14.4) compared to those without diabetes and 5.5 (95% CI, 1.6-19.4) compared to PDM with normal HbA1c (≤ 6.1%). CONCLUSIONS: PDM is associated with a RR of 2.8 for mCHD, increasing to 8.5 in those with HbA1c > 8%. These data should facilitate refinement of referral indications for high-risk pregnancy screening. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Association between maternal age and sex-based neonatal free triiodothyronine levels.

BACKGROUND: Advanced maternal age may affect the intrauterine environment and increase the risk of neurodevelopmental disorders in offspring. Thyroid hormones are critical for fetal neurological development but whether maternal age influences fetal thyroid hormone levels in euthyroid mothers is unknown. OBJECTIVE: This study evaluated the association between cord blood thyroid hormones and maternal age, fetal sex, maternal thyroid function, and other perinatal factors. METHODS: The study population consisted of 203 healthy women with term singleton pregnancies who underwent elective cesarean section. Maternal levels of free T3 (fT3), free T4 (fT4) and TSH before delivery, and cord levels of fT3, fT4 and TSH were measured. Spearman's correlation coefficient and multiple linear regression analyses were performed to determine the correlation between cord thyroid hormone parameters and maternal characteristics. RESULTS: There were no significant differences in maternal serum or cord blood thyroid hormone levels between male and female births. In multivariate linear regression analysis, maternal age and maternal TSH values were negatively associated with the cord blood levels of fT3 in all births, after adjusting for confounding factors. Maternal age was more closely associated with the cord blood levels of fT3 in female than in male births. CONCLUSION: The inverse association between maternal age and cord blood levels of fT3 in euthyroid pregnant women suggested an impact of maternal aging on offspring thyroid function.

Mothers' school starting age and infant health.

We study the effects of women's school starting age on the infant health of their offspring. In Spain, children born in December start school a year earlier than those born the following January, despite being essentially the same age. We follow a regression discontinuity design to compare the health at birth of the children of women born in January versus the previous December, using administrative, population-level data. We find small and insignificant effects on average weight at birth, but, compared to the children of December-born mothers, the children of January-born mothers are more likely to have very low birthweight. We then show that January-born women have the same educational attainment and the same partnership dynamics as December-born women. However, they finish school later and are (several months) older when they have their first child. Our results suggest that maternal age is a plausible mechanism behind our estimated impacts of school starting age on infant health.

Does the Fraternal Birth Order Effect Influence Handedness?

The fraternal birth order effect (FBOE) is the phenomenon whereby the probability that a man has a same-sex sexual orientation in adulthood increases with each biological older brother. Several studies have found evidence that the FBOE is limited to right-handed men, and left-handed men do not show an FBOE. Recent debates about the appropriate methods for quantifying the FBOE center on distinguishing the FBOE from other effects, such as the female fecundity effect (FFE), whereby mothers more prone to bearing gay sons are also more fecund. The FBOE and FFE are confounded in that a real FFE will result in data consistent with the FBOE under some analyses. Here, we applied some recent proposed analytic methods for the FBOE to the property of handedness. A straightforward application of Khovanova's technique to the binary trait of handedness yielded support for a fraternal birth order effect consistent with the maternal immune hypothesis, in that the ratios of handedness differed between men with one older brother only, and men with one younger brother only, while no such effect was seen in women. This effect was not seen, however, when the confounding effects of parental age were controlled for. Models including factors to simultaneously test multiple posited effects find significant female fecundity effects, as well as paternal age and birth order effects on handedness in men, but no FBOE. The effects seen in women were different, with no fecundity or parental age effects, but birth order and sex of older siblings had effects. We conclude, based on this evidence, that many of the factors thought to contribute to sexual orientation in men may also have an influence on handedness, and further note that parental age is a potential confound which may be overlooked by some analyses of the FBOE.

Unplanned cesarean sections in advanced maternal age: A predictive model.

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