Plasma membrane repair defect in Alzheimer's disease neurons is driven by the reduced dysferlin expression.

Alzheimer's disease (AD) is the most common neurodegenerative disease, and a defect in neuronal plasma membrane repair could exacerbate neurotoxicity, neuronal death, and disease progression. In this study, application of AD patient cerebrospinal fluid (CSF) and recombinant human Aß to otherwise healthy neurons induces defective neuronal plasma membrane repair in vitro and ex vivo. We identified Aß as the biochemical component in patient CSF leading to compromised repair capacity and depleting Aß rescued repair capacity. These elevated Aß levels reduced expression of dysferlin, a protein that facilitates membrane repair, by altering autophagy and reducing dysferlin trafficking to sites of membrane injury. Overexpression of dysferlin and autophagy inhibition rescued membrane repair. Overall, these findings indicate an AD pathogenic mechanism where Aß impairs neuronal membrane repair capacity and increases susceptibility to cell death. This suggests that membrane repair could be therapeutically targeted in AD to restore membrane integrity and reduce neurotoxicity and neuronal death.

Both reduced ovarian reserve and severe semen alterations are overrepresented in couples seeking assisted reproductive technology treatment for the first time: a cross-sectional study.

BACKGROUND: Once a mate choice decision has been made, couples that fail to reach a live birth in natural and/or intrauterine insemination (IUI) cycles will likely visit fertility clinics seeking assisted reproductive technology (ART) treatment. During the more or less prolonged period of infertility experienced, those couples with mild/moderate reproductive anomalies would have advantage over couples displaying more severe reproductive alterations in achieving a natural or IUI conception. Thus, we can expect to find a progressive increase in the proportion of couples with more severe reproductive anomalies as duration of infertility rises. In this study, we aim to ascertain whether there is an association between male and female infertility diagnoses and duration of infertility in couples seeking ART treatment for the first time. METHODS: A cross-sectional analysis of 1383 infertile couples that sought ART treatment for the first time. Forward-stepwise binary logistic regression analyses were applied to calculate exponentiated regression coefficients. RESULTS: Men suffering from any combination of oligo-, astheno-, and teratozoospermia (ACOAT) exhibited higher odds of having a duration of infertility > 2 years compared with non-ACOAT men [odds ratio (95% confidence interval): 1.340 (1.030-1.744)]. Women from ACOAT couples displaying a duration of infertility > 2 years presented shorter menstrual cycles (P ≤ 0.047) and lower antral follicular count (AFC) values (P ≤ 0.008) and serum anti-Müllerian hormone (AMH) levels (P ≤ 0.007) than women from non-ACOAT couples exhibiting > 2 years of infertility. Likewise, AFC values (P ≤ 0.013) and serum AMH levels (P ≤ 0.001) were decreased when compared with women from ACOAT couples displaying ≤ 2 years of infertility. A relative low but significant percentage of ACOAT couples displaying > 2 years of infertility stood out for their smoking habits. CONCLUSIONS: Couples consisting of ACOAT men and women with a relative low ovarian reserve are overrepresented in couples seeking ART treatment for the first time after experiencing > 2 years of infertility. This outcome leads us to develop a general hypothesis proposing that the origin of couple's infertility is a consequence of a process of positive assortative mating shaped by sexual selection forces.

Accuracy and precision of responses to visual analog scales: Inter- and intra-individual variability.

Visual analog scales (VASs) are gaining popularity for collecting responses in computer administration of psychometric tests and surveys. The VAS format consists of a line marked at its endpoints with the minimum and maximum positions that it covers for respondents to place a mark at their selected location. Creating the line with intermediate marks along its length was discouraged, but no empirical evidence has ever been produced to show that their absence does any good. We report a study that asked respondents to place marks at pre-selected locations on a 100-unit VAS line, first when it only had numerical labels (0 and 100) at its endpoints and then when intermediate locations (from 0 to 100 in steps of 20) were also labeled. The results show that settings are more accurate and more precise when the VAS line has intermediate tick marks: The average absolute error decreased from 3.02 units without intermediate marks to 0.82 units with them. Provision of intermediate tick marks also reduced substantially inter- and intra-individual variability in accuracy and precision: The standard deviation of absolute error decreased from 0.87 units without tick marks to 0.25 units with them and the standard deviation of signed distance to target decreased from 1.16 units without tick marks to 0.24 units with them. These results prompt the recommendation that the design of VASs includes intermediate tick marks along the length of the line.

mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis.

BACKGROUND: Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models. OBJECTIVE: To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants. METHODS: Randomized, double-blind, parallel group, placebo-controlled clinical trial at the New York University of patients with probable MSA randomly assigned (3:1) to sirolimus (2-6 mg daily) for 48 weeks or placebo. Primary endpoint was change in the Unified MSA Rating Scale (UMSARS) total score from baseline to 48 weeks. (ClinicalTrials.gov NCT03589976). RESULTS: The trial was stopped after a pre-planned interim analysis met futility criteria. Between August 15, 2018 and November 15, 2020, 54 participants were screened, and 47 enrolled and randomly assigned (35 sirolimus, 12 placebo). Of those randomized, 34 were included in the intention-to-treat analysis. There was no difference in change from baseline to week 48 between the sirolimus and placebo in UMSARS total score (mean difference, 2.66; 95% CI, -7.35-6.91; P = 0.648). There was no difference in UMSARS-1 and UMSARS-2 scores either. UMSARS scores changes were similar to those reported in natural history studies. Neuroimaging and blood biomarker results were similar in the sirolimus and placebo groups. Adverse events were more frequent with sirolimus. Analysis of 1-year biomarker trajectories in all participants showed that increases in blood neurofilament light chain (NfL) and reductions in whole brain volume correlated best with UMSARS progression. CONCLUSIONS: Sirolimus for 48 weeks was futile to slow the progression of MSA and had no effect on biomarkers compared to placebo. One-year change in blood NfL and whole brain atrophy are promising biomarkers of disease progression for future clinical trials. © 2022 International Parkinson and Movement Disorder Society.

Efficacy of capacitive resistive monopolar radiofrequency in the physiotherapeutic treatment of chronic pelvic pain syndrome: A randomized controlled trial.

AIM: To evaluate the efficacy of adjuvant, capacitive resistive monopolar radiofrequency (CRMRF, INDIBA) treatment at 448 kHz together with physiotherapeutic techniques compared to a sham treatment with the same techniques, for pain reduction and quality of life (QoL) improvements in patients with chronic pelvic pain syndrome (CPPS). METHODS: A triple-blind, randomized controlled trial (RCT) including patients with CPPS randomly allocated (1:1) to a CRMRF-activated group (intervention) or a CRMRF-deactivated one (control). Both groups received physiotherapeutic techniques and pain education weekly for 10 consecutive weeks. Data from a visual analogical scale and the SF-12 questionnaire were collected at trial commencement and repeated at the 5th and 10th sessions. Pain intensity was considered the main outcome. For the comparisons between variables, the χ2 and Student's t test were used. Superiority was analyzed by estimating the mean change (95% confidence interval). Analysis was performed for the per-protocol and the intention-to-treat populations. The statistical significance level was set at p < 0.05. RESULTS: Eighty-one patients were included (67.9% women) with a mean age of 43.6 years (SD 12.9). CRMRF lessened pain scores by more than 2 points and improved QoL by 5 points. There were no relevant side effects and overall adherence to the treatment was 86.4%. CONCLUSIONS: This is the first RCT that evaluates the efficacy of CRMRF (INDIBA) compared to a sham treatment, and demonstrates its superiority in decreasing pain and improving QoL. Such results may lead to greater prescribing of CRMRF when treating CPPS patients.

Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

Are physiological and behavioural responses to stressors displayed concordantly by wild urban rodents?

Understanding wild animal responses to stressors underpins effective wildlife management. In order for responses to stressors to be correctly interpreted, it is critical that measurements are taken on wild animals using minimally invasive techniques. Studies investigating wild animal responses to stressors often measure either a single physiological or behavioural variable, but whether such responses are comparable and concordant remains uncertain. We investigated this question in a pilot study that measured responses of wild-caught urban brown and black rats (Rattus norvegicus, Rattus rattus) to fur-based olfactory cues from a predator, the domestic cat (Felis catus); a novel herbivore, the koala (Phascolarctos cinereus); and a familiar herbivore and competitor, the common brushtail possum (Trichosurus vulpecula). Physiological responses, measured by assaying faecal glucocorticoid metabolites, were compared to behavioural responses observed via video recordings. We found that physiological and behavioural responses to stressors were expressed concordantly. There was no sizeable physiological response observed, and the behavioural response when considered across the night was negligible. However, the behavioural response to the predator and competitor cues changed across the observation period, with activity increasing with increasing hours of exposure. Our results indicate that responses of wild rodents to cues are nuanced, with stress responses modulated by behaviour changes that vary over time according to the severity of the perceived threat as animals gather further information. If the physiological response alone had been assessed, this moderated response may not have been evident, and in terms of wildlife management, vital information would have been lost.

Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement.

PURPOSE: The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. METHODS: Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations. RESULTS: The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. CONCLUSIONS: Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment.

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal-curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of ß-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.

Cumulative probabilities of live birth across multiple complete IVF/ICSI cycles: a call for attention.

PURPOSE: To call attention to the fact that cumulative live birth (LB) proportions exhibit an inverted pattern to that displayed by each individual oocyte retrieval cycle (ORC-specific LB proportions) as well as when grouping together all the ORCs undergone by a woman (TNORC-specific LB proportions). METHODS: A retrospective study of 1433 infertile women that had a LB using autologous fresh or frozen embryos and/or dropped out of IVF/ICSI treatment after completing a maximum number of three treatment cycles. Generalized Estimating Equations (GEE) and standard and landmark Kaplan-Meier survival analyses were applied. RESULTS: A standard Kaplan-Meier analysis indicated that cumulative LB proportions rose as number of ORCs increased (0.320, 0.484, and 0.550 at ORC 1, 2, and 3, respectively). In contrast, landmark ORC-specific LB proportions showed an inverted pattern (0.320, 0.242, and 0.127 at ORC 1, 2, and 3, respectively). GEE models revealed that women's clinical outcomes decreased as TNORCs increased. In particular, compared to women that experienced just one ORC, women that underwent two and three ORCs displayed higher incidences of cycle cancellations before either oocyte retrieval or embryo transfer, and clinical pregnancy losses, and lower odds of LB. CONCLUSION: Infertile women should be informed that cumulative LB probabilities exhibit an inverted pattern to that displayed by each individual ORC as well as when grouping together all the ORCs undergone by a woman.

A predictive model for women's assisted fecundity before starting the first IVF/ICSI treatment cycle.

PURPOSE: To introduce a prognostic model for women's assisted fecundity before starting the first IVF/ICSI treatment cycle. METHODS: In contrast to previous predictive models, we analyze two groups of women at the extremes of prognosis. Specifically, 708 infertile women that had either a live birth (LB) event in the first autologous IVF/ICSI cycle ("high-assisted-fecundity women", n = 458) or did not succeed in having a LB event after completing three autologous IVF/ICSI cycles ("low-assisted-fecundity women", n = 250). The initial sample of 708 women was split into two sets in order to develop (n = 531) and internally validate (n = 177) a predictive logistic regression model using a forward-stepwise variable selection. RESULTS: Seven out of 32 initially selected potential predictors were included into the model: women's age, presence of multiple female infertility factors, number of antral follicles, women's tobacco smoking, occurrence of irregular menstrual cycles, and basal levels of prolactin and LH. The value of the c-statistic was 0.718 (asymptotic 95% CI 0.672-0.763) in the development set and 0.649 (asymptotic 95% CI: 0.560-0.738) in the validation set. The model adequately fitted the data with no significant over or underestimation of predictor effects. CONCLUSION: Women's assisted fecundity may be predicted using a relatively small number of predictors. This approach may complement the traditional procedure of estimating cumulative and cycle-specific probabilities of LB across multiple complete IVF/ICSI cycles. In addition, it provides an easy-to-apply methodology for fertility clinics to develop and actualize their own predictive models.

Correction to: a predictive model for women's assisted fecundity before starting the first IVF/ICSI treatment cycle.

The original article unfortunately contained a mistake. In Table 2, the headers "Development set" and "Validation set" were not aligned to to their sub-headers.

Order effects in two-alternative forced-choice tasks invalidate adaptive threshold estimates.

Adaptive psychophysical methods are widely used for the quick estimation of percentage points (thresholds) on psychometric functions for two-alternative forced-choice (2AFC) tasks. The use of adaptive methods is supported by numerous simulation studies documenting their performance, which have shown that thresholds can be reasonably estimated with them when their founding assumptions hold. One of these assumptions is that the psychometric function is invariant, but empirical evidence is mounting that human performance in 2AFC tasks needs to be described by two different psychometric functions, one that holds when the test stimulus is presented first in the 2AFC trial and a different one that holds when the test is presented second. The same holds when presentations are instead simultaneous at two spatial locations rather than sequential. We re-evaluated the performance of adaptive methods in the presence of these order effects via simulation studies and an empirical study with human observers. The simulation study showed that thresholds are severely overestimated by adaptive methods in these conditions, and the empirical study corroborated these findings. These results question the validity of threshold estimates obtained with adaptive methods that incorrectly assume the psychometric function to be invariant with presentation order. Alternative ways in which thresholds can be accurately estimated in the presence of order effects are discussed.

Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD.

Few animal models exist that successfully reproduce several core associative and non-associative behaviours relevant to post-traumatic stress disorder (PTSD), such as long-lasting fear reactions, hyperarousal, and subtle attentional and cognitive dysfunction. As such, these models may lack the face validity required to adequately model pathophysiological features of PTSD such as CNS grey matter loss and neuroinflammation. Here we aimed to investigate in a mouse model of PTSD whether contextual fear conditioning associated with a relatively high intensity footshock exposure induces loss of neuronal dendritic spines in various corticolimbic brain regions, as their regression may help explain grey matter reductions in PTSD patients. Further, we aimed to observe whether these changes were accompanied by alterations in microglial cell number and morphology, and increased expression of complement factors implicated in the mediation of microglial cell-mediated engulfment of dendritic spines. Adult male C57Bl6J mice were exposed to a single electric footshock and subsequently underwent phenotyping of various PTSD-relevant behaviours in the short (day 2-4) and longer-term (day 29-31). 32 days post-exposure the brains of these animals were subjected to Golgi staining of dendritic spines, microglial cell Iba-1 immunohistochemistry and immunofluorescent staining of the complement factors C1q and C4. Shock exposure promoted a lasting contextual fear response, decreased locomotor activity, exaggerated acoustic startle responses indicative of hyperarousal, and a short-term facilitation of sensorimotor gating function. The shock triggered loss of dendritic spines on pyramidal neurons was accompanied by increased microglial cell number and complexity in the medial prefrontal cortex and dorsal hippocampus, but not in the amygdala. Shock also increased expression of C1q in the pyramidal layer of the CA1 region of the hippocampus but not in other brain regions. The present study further elaborates on the face and construct validity of a mouse model of PTSD and provides a good foundation to explore potential molecular interactions between microglia and dendritic spines.

Allogeneic hematopoietic stem-cell transplantation from haploidentical donors using 'ex-vivo' T-cell depletion in pediatric patients with hematological malignancies: state of the art review.

PURPOSE OF REVIEW: Nowadays, T-cell-depleted haploidentical transplantation is considered a valid approach for children lacking a human leukocyte antigen (HLA) identical donor for allogeneic transplantation. This kind of allogeneic transplant is now widely used especially for pediatric patients with high-risk hematological malignancies. However, relapsing disease and life-threatening viral infections are still relevant clinical problems as a consequence of delayed immune reconstitution. Adoptive cell therapies have been proposed to overcome this problem. RECENT FINDINGS: After initial clinical approach using CD34+ selection as method for T-cell depletion (TCD), it was observed that immune reconstitution was delayed and it resulted on high incidence of opportunistic infections and nonrelapse mortality. It is now evident that development over time of graft manipulation techniques for TCD, have provide clinicians a useful tool for overcoming transplant complication such as graft failure, severe graft-vs.-host disease and opportunistic infections. As such, several procedures of almost total or partial TCD have been developed including CD3/CD19 depletion, T cell receptor αß/CD19 depletion and more recently CD45RA+ depletion. Recent studies showed that immune reconstitution is associated with transplant outcomes. Based on this, haploidentical transplantation is now been explored as platform for cellular therapy to prevent disease recurrence or to treat clinical complications. SUMMARY: Allogeneic transplantation still remains a standard of care for pediatric patients with high-risk hematological malignancies. In absence of an HLA identical donor, T-cell-depleted haploidentical transplant is now considered a valid option and provide a platform for cellular therapy to prevent relapse disease or to treat opportunistic infections.

Nonparametric tests for equality of psychometric functions.

Many empirical studies measure psychometric functions (curves describing how observers' performance varies with stimulus magnitude) because these functions capture the effects of experimental conditions. To assess these effects, parametric curves are often fitted to the data and comparisons are carried out by testing for equality of mean parameter estimates across conditions. This approach is parametric and, thus, vulnerable to violations of the implied assumptions. Furthermore, testing for equality of means of parameters may be misleading: Psychometric functions may vary meaningfully across conditions on an observer-by-observer basis with no effect on the mean values of the estimated parameters. Alternative approaches to assess equality of psychometric functions per se are thus needed. This paper compares three nonparametric tests that are applicable in all situations of interest: The existing generalized Mantel-Haenszel test, a generalization of the Berry-Mielke test that was developed here, and a split variant of the generalized Mantel-Haenszel test also developed here. Their statistical properties (accuracy and power) are studied via simulation and the results show that all tests are indistinguishable as to accuracy but they differ non-uniformly as to power. Empirical use of the tests is illustrated via analyses of published data sets and practical recommendations are given. The computer code in MATLAB and R to conduct these tests is available as Electronic Supplemental Material.

Hematopoietic stem cell transplantation for infantile osteopetrosis.

We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated, or mismatched unrelated donor transplantation. The 5- and 10-year probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (P = .01 and P = .002, respectively). Graft failure was the most common cause of death, accounting for 50% of deaths after HLA-matched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (P = .49). The median age of surviving patients is 7 years. Of evaluable surviving patients, 70% are visually impaired; 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors >5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%. Though allogeneic transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed.

Note of clarification: Potential risks to offspring of intrauterine exposure to maternal age-related obstetric complications.

Several hypotheses have been proposed to explain the negative effects of delayed motherhood on an offspring's morbidity later in life. However, these hypotheses are not supported by clinical and epidemiological evidence. Because advanced maternal age is associated with increased risk of obstetric complications, the aim of the present study was to ascertain whether the negative effects on offspring of intrauterine exposure to maternal age-related obstetric complications may explain the reported negative effects of delayed motherhood on offspring. To this end, a literature search was performed to identify relevant publications up to March 2016 on PubMed; references cited in relevant articles were also searched. There was a direct correlation between the risks to offspring conferred by intrauterine exposure to at least one of the obstetric complications present at the time of delivery in women aged ≥35 years and the risks to offspring of delayed motherhood. This correlation was not observed when comparing the risks to offspring of delayed motherhood and the risks associated with maternal transmission of defective mitochondria, chromosomal anomalies or DNA double-strand breaks. Most of the effects on offspring of intrauterine exposure to maternal age-related obstetric complications may be induced by epigenetic DNA reprogramming during critical periods of embryo or fetal development. Women wanting to enrol in a fertility preservation program to offset age-related declines in fertility should be informed not only about their chances of pregnancy and the percentage of live births, but also about the risks to themselves and their prospective offspring of delaying motherhood.

Potential risks to offspring of intrauterine exposure to maternal age-related obstetric complications.

Several hypotheses have been proposed to explain the negative effects of delayed motherhood on an offspring's morbidity later in life. However, these hypotheses are not supported by clinical and epidemiological evidence. Because advanced maternal age is associated with increased risk of obstetric complications, the aim of the present study was to ascertain whether the negative effects on offspring of intrauterine exposure to maternal age-related obstetric complications may explain the reported negative effects of delayed motherhood on offspring. To this end, a literature search was performed to identify relevant publications up to March 2016 on PubMed; references cited in relevant articles were also searched. There was a direct correlation between the risks to offspring conferred by intrauterine exposure to at least one of the obstetric complications present at the time of delivery in women aged ≥35 years and the risks to offspring of delayed motherhood. This correlation was not observed when comparing the risks to offspring of delayed motherhood and the risks associated with maternal transmission of defective mitochondria, chromosomal anomalies or DNA double-strand breaks. Most of the effects on offspring of intrauterine exposure to maternal age-related obstetric complications may be induced by epigenetic DNA reprogramming during critical periods of embryo or fetal development. Women wanting to enrol in a fertility preservation program to offset age-related declines in fertility should be informed not only about their chances of pregnancy and the percentage of live births, but also about the risks to themselves and their prospective offspring of delaying motherhood.

Obstetric and offspring risks of women's morbid conditions linked to prior anticancer treatments.

BACKGROUND: Literature shows the effects of type of cancer and/or anticancer treatment on live birth percentages and/or pregnancy and neonatal complications in female cancer survivors. However, studies analyzing the obstetric and offspring risks of the morbid conditions associated with previous anti-cancer treatments are missing. The present review aims to uncover these risks. METHODS: A literature search based on publications up to March 2016 identified by PubMed and references cited in relevant articles. RESULTS: The morbid conditions associated with prior anticancer treatments including chemotherapy, radiotherapy, surgery, and/or hematopoietic stem-cell transplant may induce not only obstetric and neonatal complications but also long-term effects on offspring. Whereas some risks are predominantly evidenced in untreated women others are observed in both treated and untreated women. These risks may be superimposed on those induced by the current women's trend in Western societies to postpone maternity. CONCLUSIONS: Medical professionals should be aware and inform female cancer survivors wishing to have a child not only of the short- and long-term risks to themselves and their prospective offspring of previous anticancer treatments, fertility-preservation technologies, and pregnancy itself, but also of those risks linked to the morbid conditions induced by prior anticancer treatments. Once female cancer survivors wishing to have a child have been properly informed about the risks of reproduction, they will be best placed to make decisions of whether or not to have a biological or donor-conceived child. In addition, when medical professionals be aware of these risks, they will be also best placed to provide appropriate treatments before/during pregnancy in order to prevent or alleviate the impact of these morbid conditions on maternal and offspring health.