Early Life Oxidative Stress and Long-Lasting Cardiovascular Effects on Offspring Conceived by Assisted Reproductive Technologies: A Review.
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SUBMITTER: Yang H
PROVIDER: S-EPMC7432066 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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Early Life Oxidative Stress and Long-Lasting Cardiovascular Effects on Offspring Conceived by Assisted Reproductive Technologies: A Review.
Yang Huixia H Kuhn Christina C Kolben Thomas T Ma Zhi Z Lin Peng P Mahner Sven S Jeschke Udo U von Schönfeldt Viktoria V
International journal of molecular sciences 20200722 15
Assisted reproductive technology (ART) has rapidly developed and is now widely practised worldwide. Both the characteristics of ART (handling gametes/embryos in vitro) and the infertility backgrounds of ART parents (such as infertility diseases and unfavourable lifestyles or diets) could cause increased oxidative stress (OS) that may exert adverse influences on gametogenesis, fertilisation, and foetation, even causing a long-lasting influence on the offspring. For these reasons, the safety of AR ...[more]
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Project description:The cardiometabolic health of children conceived by assisted reproductive technologies (ART) compared with children conceived without medical assistance is unclear. Although the majority of published studies evaluating height, weight, and body mass index have not found differences by method of conception, some studies have indicated differences in adiposity by more direct measures such as skinfolds and dual X-ray absorptiometry. Far fewer studies have investigated other cardiometabolic characteristics, such as blood pressure and measures of lipid and glucose metabolism. Of these studies, some indications of increased blood pressure and recent findings of vascular dysfunction among children conceived by ART compared with children conceived without ART warrant further investigation. Epigenetic differences may be the global mechanism at work, resulting from different aspects of ART treatment, such as ovarian stimulation, in vitro culture, and manipulation of sperm, among other considerations. Fetal growth and placental development may serve as mediators of these effects. Future studies should consider recruiting sufficient numbers of ART and non-ART conceived multiples and collect information on indicators of cardiometabolic health in the parents. Despite some advantages of sibling cohorts in developmental origins research, its feasibility and utility for investigating health of children conceived by ART remains debatable.
| S-EPMC3612937 | biostudies-literature
Project description:IntroductionAssisted reproductive technologies (ART), namely in vitro fertilisation and intracytoplasmic sperm injection, have become widely used to treat infertility. Although the use of ART is generally considered favourable, there are ongoing concerns about the prenatal and perinatal risks as well as long-term risks for the child. Epidemiological studies have demonstrated an association between pathological events during fetal development and future cardiovascular risk, raising concerns about cardiovascular remodelling in fetuses conceived by ART. The authors hypothesise fetuses conceived by ART present signs of cardioventricular dysfunction, which can be detected by deformation analysis. To address these issues, we will assess comprehensive cardiovascular structure and function in ART offspring and explore the role of speckle-tracking in myocardial deformation.Methods and analysisThis prospective observational cohort study will include 100 singleton pregnancies conceived by ART and 100 controls identified in fetal life and followed up to 6 months old. At inclusion, a baseline assessment of the mothers and ART characteristics will be recorded by interview and review of medical records. Between 28 and 32 weeks gestation, a detailed fetal echography will be performed, including an assessment of estimated fetal weight, fetoplacental Doppler, fetal echocardiography and fetal abdominal artery ultrasound. On delivery, maternal and neonatal characteristics will be assessed. Within 60 days of birth, the first postnatal cardiovascular assessment will be conducted which will include echocardiography and abdominal artery ultrasound. At 6 months of age, the second infants' follow-up evaluation will include the weight and length of the infant, echocardiography and abdominal artery ultrasound. Data will be presented as mean±SD, median or percentages where appropriate. A p<0.05 will be considered statistically significant.Ethics and disseminationEthical approval has been obtained from the Ethics Committee of Shengjing Hospital of China Medical University. Findings will be disseminated through scientific publications and conference presentations.Trial registration numberChiCTR1900021672.
| S-EPMC6830675 | biostudies-literature
Project description:Since the first report in 1978, the number of individuals conceived by Assisted Reproductive Technologies (ART) has grown incessantly. In parallel, with the recent emergence of possible underlying mechanisms of ART-induced epigenetic changes in the renin-angiotensin system, the cardiovascular repercussions of ART in mice and human offspring (including arterial hypertension, vascular dysfunction, and cardiac remodeling) have become increasingly recognized. Here, we hypothesized that ART may increase arterial responsiveness to angiotensin II (ANG II) by epigenetically modifying the expression of its receptors. To test this hypothesis, we assessed the vasoconstrictor responsiveness to ANG II in isolated aortas from ART and control mice. We also examined ANG II receptor (ATR) type 1 and 2 expression and the promoter methylation of the At1aR, At1bR and At2R genes. We found that the vasoconstrictor response to ANG II was markedly increased in ART mice compared to controls. This exaggerated vasoconstrictor responsiveness in ART mice correlated with a significant increase in the ANG II receptor (ATR) type 1 to ATR type 2 protein expression ratio in the aorta; this was mainly driven by an increase in AT1R expression, and by hypomethylation of two CpG sites located in the At1bR gene promoter leading to increased transcription of the gene. We conclude that in mice, ART increase the vasoconstrictor response to ANG II in the aorta by epigenetically causing an imbalance between the expression of vasoconstrictor (AT1R) and vasodilator (AT2R) ANG II receptors. Unbalanced expression of AT1R and AT2R receptors seems to be a novel mechanism contributing to ART-induced arterial hypertension in mice.
| S-EPMC9654033 | biostudies-literature
Project description:Worldwide, over 8 million children and adults are conceived following assisted reproductive technologies (ART), and their long-term health is of consequential public health interest. The objective of this paper is to describe the Growing up Healthy Study (GUHS) cohort in detail, publicise it and invite collaboration. Combining the data collected in the GUHS with other cohorts or databases will improve the much-needed knowledge about the effects of ART, and allow for better understanding of the long-term health outcomes of offspring conceived after ART. The GUHS cohort is a prospective observational study of adolescents and young adults conceived after assisted reproductive technologies (ART). It was established to determine if the long-term health of offspring conceived by ART differs from that of the general population. This was investigated by comparing a substantial number of health parameters to those of a representative population of offspring conceived without ART. The n = 303 GUHS participants were born between 1991-2001 in the two fertility clinics operating at the time in Perth, Western Australia, and undertook assessments at ages 14, 17 and 20, replicating the pre-defined study protocols from the reference cohort-the Raine Study. Participants were comprehensively phenotyped through detailed questionnaires, anthropometry, biochemical analyses, as well as age-specific assessments (asthma, atopy, cardiometabolic health, body composition, mental health, thyroid function, epigenetics and vision). To date the GUHS cohort has been used to study the methylation, cardiometabolic, and thyroid profiles, as well as respiratory and mental health. To summarise, the GUHS cohort provides a valuable addition to the limited knowledge of the long-term health outcomes of ART-conceived offspring.
| S-EPMC9307151 | biostudies-literature
Project description:Study questionWhat are the factors influencing the occurrence of monozygotic (MZ) twins in offspring conceived by assisted reproductive technology (ART)?Summary answerParental ages, the transfer of fresh versus frozen embryos, and the grade of blastocysts are all related to MZ twinning in ART offspring.What is known alreadyOffspring conceived by ART have significantly increased risk of MZ twins, which may be due to the characteristics of the infertile population. The objective of this study was to explore the incidence of monozygotic (MZ) twins after ART and to clarify the risk factors for MZ twinning.Study design size durationA total of 255 monozygotic twins were enrolled in this cohort study, and then matched with singletons at a ratio of 1:4 randomly (with 1020 in the control group). All offspring were conceived by single embryo transfer.Participants/materials setting methodsThe collected data were divided into the following three aspects for analysis: characteristics of the infertile population, gamete or embryo manipulations, and factors related to embryo development.Main results and the role of chanceThe incidence of MZ twins was 1.638% (255 out of 15 567 pregnancies after single embryo transfers). Compared to singleton births, a significantly lower rate of frozen embryo transfers (FET; 78.0% vs 86.1% P = 0.002) was seen amongst the MZ twins. Amongst fresh ETs, the rate of blastocyst transfers in the MZ twins group was higher compared to that in the control group (92.9% vs 75.4%, P = 0.005). We also found that certain grades of blastocysts in terms of trophectoderm (TE) development, inner cell mass + TE development and the classification of 'top-quality' embryos were associated with the incidence of MZ twinning (P = 0.025, P = 0.012, P = 0.020, respectively). Logistic regression analysis revealed that higher paternal age (odds ratio (OR) = 0.94, 95% CI = 0.89-1.00, P = 0.029) and FET (OR = 0.48, 95% CI = 0.33-0.68, P = 0.001) may be protective factors against MZ twinning. However, higher maternal age (OR = 1.07, 95% CI = 1.01-1.13, P = 0.027) and the transfer of blastocysts (OR = 4.31, 95% CI = 1.46-12.73, P = 0.008) appeared to be associated with an increased risk of MZ twinning. Amongst blastocyst transfers, a C grade TE may be protective factor against MZ twinning (B: OR = 1.90, 95% CI = 1.18-3.07, P = 0.009; A: OR = 1.58, 95% CI = 0.93-2.67, P = 0.089).Limitations reasons for cautionFirst, our definition of MZ twins was based on twins' birth after single embryo transfers (SET), rather than ultrasound examination during early pregnancy. Second, the parental characteristics of the two groups were homogenous, so it was difficult to find any associations between infertility factors and the incidence of MZ twins.Wider implications of the findingsThis multifaceted analysis of the risk factors for MZ twinning provides some information for clinical interventions in high-risk populations.Study funding/competing interestsThis study was supported by the National Key Technology Research and Developmental Program of China (2022YFC2704404), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), Taishan Scholars Program for Young Experts of Shandong Province (tsqn201909195), the Basic Science Center Program (31988101), and the Shandong Provincial Key Research and Development Program (2020ZLYS02). All authors have no conflicts of interest to declare.Trial registration numberN/A.
| S-EPMC10570986 | biostudies-literature
Project description:Background: In the last 40 years, assisted reproductive techniques (ARTs) have emerged as potentially resolving procedures for couple infertility. This study aims to evaluate whether ART is associated with epigenetic dysregulation in the offspring. Methods. To accomplish this, we collected all available data on methylation patterns in offspring conceived after ART and in spontaneously conceived (SC) offspring. Results. We extracted 949 records. Of these, 50 were considered eligible; 12 were included in the quantitative synthesis. Methylation levels of H19 CCCTC-binding factor 3 (CTCF3) were significantly lower in the ART group compared to controls (SMD -0.81 (-1.53; -0.09), I2 = 89%, p = 0.03). In contrast, H19 CCCTC-binding factor 6 (CTCF6), Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1OT1), Paternally-expressed gene 3 (PEG3), and Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) were not differently methylated in ART vs. SC offspring. Conclusion: The methylation pattern of the offspring conceived after ART may be different compared to spontaneous conception. Due to the lack of studies and the heterogeneity of the data, further prospective and well-sized population studies are needed to evaluate the impact of ART on the epigenome of the offspring.
| S-EPMC9457481 | biostudies-literature
Project description:BackgroundGestational age is a useful proxy for assessing developmental maturity, but correct estimation of gestational age is difficult using clinical measures. DNA methylation at birth has proven to be an accurate predictor of gestational age. Previous predictors of epigenetic gestational age were based on DNA methylation data from the Illumina HumanMethylation 27 K or 450 K array, which have subsequently been replaced by the Illumina MethylationEPIC 850 K array (EPIC). Our aims here were to build an epigenetic gestational age clock specific for the EPIC array and to evaluate its precision and accuracy using the embryo transfer date of newborns from the largest EPIC-derived dataset to date on assisted reproductive technologies (ART).MethodsWe built an epigenetic gestational age clock using Lasso regression trained on 755 randomly selected non-ART newborns from the Norwegian Study of Assisted Reproductive Technologies (START)-a substudy of the Norwegian Mother, Father, and Child Cohort Study (MoBa). For the ART-conceived newborns, the START dataset had detailed information on the embryo transfer date and the specific ART procedure used for conception. The predicted gestational age was compared to clinically estimated gestational age in 200 non-ART and 838 ART newborns using MM-type robust regression. The performance of the clock was compared to previously published gestational age clocks in an independent replication sample of 148 newborns from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restrictions (PREDO) study-a prospective pregnancy cohort of Finnish women.ResultsOur new epigenetic gestational age clock showed higher precision and accuracy in predicting gestational age than previous gestational age clocks (R2 = 0.724, median absolute deviation (MAD) = 3.14 days). Restricting the analysis to CpGs shared between 450 K and EPIC did not reduce the precision of the clock. Furthermore, validating the clock on ART newborns with known embryo transfer date confirmed that DNA methylation is an accurate predictor of gestational age (R2 = 0.767, MAD = 3.7 days).ConclusionsWe present the first EPIC-based predictor of gestational age and demonstrate its robustness and precision in ART and non-ART newborns. As more datasets are being generated on the EPIC platform, this clock will be valuable in studies using gestational age to assess neonatal development.
| S-EPMC8056641 | biostudies-literature
Project description:BackgroundThe births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the safety issue regarding ARTs has drawn growing attention with accumulating observations of rising health risks, and underlying epigenetic mechanisms are largely uncharacterized.MethodsIn order to clarify epigenetic risks attributable to ARTs, we profiled DNA methylome on 137 umbilical cord blood (UCB) and 158 parental peripheral blood (PPB) samples, histone modifications (H3K4me3, H3K4me1, H3K27me3 and H3K27ac) on 33 UCB samples and transcriptome on 32 UCB samples by reduced representation bisulfite sequencing (RRBS), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq), respectively.FindingsWe revealed that H3K4me3 was the most profoundly impacted by ICSI and freeze-thawing operation compared with the other three types of histone modifications. IVF-ET seemed to introduce less disturbance into infant epigenomes than IVF-FET or ICSI-ET did. ARTs also decreased the similarity of DNA methylome within twin pairs, and we confirmed that ART per se would introduce conservative changes locally through removal of parental effect. Importantly, those unique and common alterations induced by different ART procedures were highly enriched in the processes related to nervous system, cardiovascular system and glycolipid metabolism etc., which was in accordance with those findings in previous epidemiology studies and suggested some unexplored health issues, including in the immune system and skeletal system.InterpretationDifferent ART procedures can induce local and functional epigenetic abnormalities, especially for DNA methylation and H3K4me3, providing an epigenetic basis for the potential long-term health risks in ART-conceived offspring.Funding sourcesThis study was funded by National Natural Science Foundation of China (81730038; 81521002), National Key Research and Development Program (2018YFC1004000; 2017YFA0103801; 2017YFA0105001) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020703). Yang Wang was supported by Postdoctoral Fellowship of Peking-Tsinghua Center for Life Science.
| S-EPMC7585147 | biostudies-literature
Project description:BackgroundThe mental health of children conceived using Assisted Reproductive Technologies (ARTs) such as In-Vitro-Fertilization (IVF) is a subject of significant controversy. Existing studies suggest children conceived through ART meet physical and cognitive developmental milestones at similar rates to their spontaneously conceived peers, however, a significant number of studies have connected ART conception with mental health conditions, particularly depression and attention-deficit hyperactivity disorder (ADHD) in adolescence. This study, therefore, aimed to determine whether maternal use of ARTs to achieve pregnancy is associated with an increased risk of mental disorders in these children, and whether these effects are sex-dependent or confounded by known covariates in the ART population.MethodsSecondary data analysis was performed using Growing Up in Australia: The Longitudinal Study of Australian Children (LSAC) data; a nationally representative population-based cross-sequential cohort study. Multivariate logistic regression models examined the impact of ART (including IVF and other fertility drugs, from LSAC wave-1 and wave-2 conducted in 2004 and 2006, respectively) on mental health outcomes (i.e., autism, ADHD, anxiety and/or depression, from LSAC waves 8 conducted in 2018) in Australian adolescents aged 18-19 years in 2018 (n = 1735). Known sociological and obstetric covariates including maternal age, birth weight, smoking and drinking alcohol during pregnancy, maternal gestational diabetes, postnatal depression, hypertension, and socioeconomic status were considered to generate an adjusted logistic model. Variables with a p-value of <0.05 in the regression models were considered statistically significant.ResultsOf the 1735 mother-child dyads analysed, the maternal mean age was 35.6 years (Standard deviation = ±4.75), approximately 5% of mothers (n = 89) used ART to become pregnant, and 22% of adolescents (n = 384) had a mental disorder. Longitudinal analysis revealed no relationship between ART and children developing a mental disorder in the LSAC population.ConclusionThese results should reassure parents considering ART that there is no increased risk of psychological or neurodevelopmental problems in their ART conceived offspring.
| S-EPMC11210819 | biostudies-literature
Project description:ImportanceThe use of assisted reproductive technologies (ARTs) is steadily increasing worldwide. The outcomes associated with treatment for an individual's long-term health, including risk of cardiovascular disease (CVD), remain largely unknown, due to the small number of studies and their limited follow-up time.ObjectiveTo study whether the risk of CVD is increased among individuals who have given birth after ART compared with those who have given birth without ART.Design, setting, and participantsA registry-based cohort study was conducted using nationwide data from Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1985-2015). Data analysis was conducted from January to August 2022. A total of 2 496 441 individuals with a registered delivery in the national birth registries during the study period were included, and 97 474 (4%) of these gave birth after ART.ExposuresData on ART conception were available from ART quality registries and/or medical birth registries.Main outcomes and measuresInformation on CVD was available from patient and cause of death registries. The risk of CVD was estimated with Cox proportional hazards regression, adjusting for age, calendar year of start of follow-up, parity, diagnosis of polycystic ovary syndrome, diabetes, chronic hypertension, and country.ResultsMedian follow-up was 11 (IQR, 5-18) years. The mean (SD) age of women with no use of ART was 29.1 (4.9) years, and the age of those who used ART was 33.8 (4.7) years. The rate of any CVD was 153 per 100 000 person-years. Individuals who gave birth after using ART had no increased risk of CVD (adjusted hazard ratio [AHR], 0.97; 95% CI, 0.91-1.02), with evidence of heterogeneity between the countries (I2 = 76%; P = .01 for heterogeneity). No significant differences in the risk of ischemic heart disease, cerebrovascular disease, stroke, cardiomyopathy, heart failure, pulmonary embolism, or deep vein thrombosis were noted with use of ART. However, there was a tendency for a modest reduction in the risk of myocardial infarction (AHR, 0.80; 95% CI, 0.65-0.99), with no notable heterogeneity between countries.Conclusions and relevanceThe findings of this study suggest that women who gave birth after ART were not at increased risk of CVD over a median follow-up of 11 years compared with those who conceived without ART. Longer-term studies are needed to further examine whether ART is associated with higher risk of CVD.
| S-EPMC10413220 | biostudies-literature