Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight.
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ABSTRACT:
SUBMITTER: Mertens J
PROVIDER: S-EPMC10858059 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight.
Mertens Joke J Belva Florence F van Montfoort Aafke P A APA Regin Marius M Zambelli Filippo F Seneca Sara S Couvreu de Deckersberg Edouard E Bonduelle Maryse M Tournaye Herman H Stouffs Katrien K Barbé Kurt K Smeets Hubert J M HJM Van de Velde Hilde H Sermon Karen K Blockeel Christophe C Spits Claudia C
Nature communications 20240209 1
Children conceived through assisted reproductive technologies (ART) have an elevated risk of lower birthweight, yet the underlying cause remains unclear. Our study explores mitochondrial DNA (mtDNA) variants as contributors to birthweight differences by impacting mitochondrial function during prenatal development. We deep-sequenced the mtDNA of 451 ART and spontaneously conceived (SC) individuals, 157 mother-child pairs and 113 individual oocytes from either natural menstrual cycles or after ova ...[more]
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Project description:BackgroundPrevious research has documented that children conceived through medically assisted reproduction (MAR) are at increased risk of poor birth outcomes, such as low birthweight (LBW), which are risk factors for stunted longer-term cognitive development. However, parents who undergo MAR to conceive have, on average, advantaged socioeconomic backgrounds which could compensate for the negative effects of being born LBW. Previous studies have not analysed whether the negative effects of LBW are attenuated among MAR conceived children.MethodsWe draw on the UK Millennium Cohort Study (sweeps 1-6) which contains a sub-sample of (N = 396) MAR-conceived children. The dependent variable measures cognitive ability at around ages 3, 5, 7, 11 and 14. We examine the cognitive development of four groups of children: MAR-conceived low birthweight (MAR LBW); MAR-conceived non-low birthweight (MAR NLBW); naturally conceived low birthweight (NC LBW); naturally conceived non-low birthweight (NC NLBW). We estimate the two following linear regression models for each sweep: (i) a baseline model to examine the unadjusted association between cognitive development and low birthweight by mode of conception; and (ii) a model adjusted by socio-demographic family characteristics.ResultsIn baseline models, MAR LBW children [age 3: β = 0.021, 95% confidence interval (CI): -0.198, 0.241; age 5: β = 0.21, 95% CI: 0.009, 0.418; age 7: β = 0.163, 95% CI: -0.148, 0.474; age 11: β = 0.003, 95% CI: -0.318, 0.325; age 14: β = 0.156, 95% CI: -0.205, 0.517], on average perform similarly in cognitive ability relative to NC NLBW at all ages, and display higher cognitive scores than NC LBW children until age 7. When we account for family characteristics, differences are largely attenuated and become close to zero at age 14.ConclusionsDespite the higher incidence of LBW among MAR compared with NC children, they do not seem to experience any disadvantage in their cognitive development compared with naturally conceived children. This finding is likely explained by the fact that, on average, MAR children are born to socioeconomically advantaged parents.
| S-EPMC8580276 | biostudies-literature
Project description:Study questionAre there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children?Summary answerIn this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children.What is known alreadyDNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day.Study design, size, durationThis observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (<35 years of age at conception) and older fathers (>45 years of age at conception).Participants/materials, setting, methodsWhole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing.Main results and the role of chanceNo significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10-7), with on average 71 DNMs in the genomes of children born to young fathers (<35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (>45 years of age).Limitations, reasons for cautionThis is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results.Wider implications of the findingsThis pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort.Study funding/competing interest(s)This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare.Trial registration numberN/A.
| S-EPMC9156847 | biostudies-literature
Project description:PurposeProprotein convertase subtilisin/kexin type 9 (PCSK9) and lipoprotein (a) (Lp[a]) levels are associated with cardiovascular risk. To investigate PCSK9 and Lp(a) levels of children born after assisted reproduction technologies (ART) compared with naturally conceived (NC) controls.MethodsIn this exposure-matched cohort study, 73 racial-, sex-, and age-matched children (mean age 98 ± 35 months) of ART (intracytoplasmic sperm injection [ICSI] n = 33, classic in vitro fertilization [IVF] n = 40) and 73 NC children were assessed. Blood lipid profile, including PCSK9 and Lp(a) levels, was measured. Children were grouped according to age (< 8 years, 8-10 years, ≥ 10 years).ResultsIn the overall population, PCSK9 levels were related to total cholesterol, low-density lipoprotein, and systolic blood pressure, while Lp(a) levels were related to age, apolipoprotein-B, birth weight, height, waist-to-hip ratio, insulin resistance, insulin, and high-sensitivity C-reactive protein. No significant differences were observed regarding lipid biomarkers between ART and NC children. However, a significant interaction was found between age groups and conception method (p < 0.001) showing that PCSK9 levels increase with age in ART children, while they decline with age in NC offspring. IVF children showed higher levels of adjusted mean Lp(a) than ICSI (13.5 vs. 6.8 mg/dl, p = 0.010) and NC children (12.3 vs. 8.3 mg/dl, p = 0.048).ConclusionsWe show that PCSK9 levels increase with age in ART children, indicating a gradual deterioration of lipidemic profile that could lead to increased cardiovascular risk. Moreover, our results indicate that ART method may be of importance given that classic IVF is associated with higher levels of Lp(a).
| S-EPMC6603255 | biostudies-literature
Project description:Ovarian aging is characterized by a decline in both the total number and overall quality of oocytes, the latter of which has been experimentally tied to mitochondrial dysfunction. Clinical studies in the late 1990s demonstrated that transfer of cytoplasm aspirated from eggs of young female donors into eggs of infertile women at the time of intracytoplasmic sperm injection improved pregnancy success rates. However, donor mitochondria were identified in offspring, and the United States Food and Drug Administration raised questions about delivery of foreign genetic material into human eggs at the time of fertilization. Accordingly, heterologous cytoplasmic transfer, while promising, was in effect shut down as a clinical protocol. The recent discovery of adult oogonial (oocyte-generating) stem cells in mice, and subsequently in women, has since re-opened the prospects of delivering a rich source of pristine and patient-matched germline mitochondria to boost egg health and embryonic developmental potential without the need for young donor eggs to obtain cytoplasm. Herein we overview the science behind this new protocol, which has been patented and termed autologous germline mitochondrial energy transfer, and its use to date in clinical studies for improving pregnancy success in women with a prior history of assisted reproduction failure.
| S-EPMC5545901 | biostudies-other
Project description:Research questionStudies in rodents have shown that paternal folate intake prior to conception is associated with pregnancy and offspring outcomes. The aim of this study was to assess whether those associations might apply to humans as well.DesignBetween 2007 and 2017, the study prospectively analysed data from 108 couples participating in a preconception cohort of couples undergoing fertility treatment using their own gametes, whose treatment resulted in 113 pregnancies during the course of the study. Paternal and maternal preconception folate intake was assessed using a validated food frequency questionnaire. Linear mixed models were used to assess whether paternal preconception folate intake was associated with gestational age at delivery and gestational age-specific birthweight, while accounting for correlated data and potential confounders.ResultsIn a multivariable-adjusted model, a 400 μg/day increase in preconception paternal folate intake was associated with a 2.6-day longer gestation (95% confidence interval 0.8-4.3) after adjusting for potential confounders, including maternal folate intake. Similar associations were found for folate from food and supplements. Maternal folate intake was not associated with gestational age at delivery. Neither paternal nor maternal folate intake was associated with gestational-age-specific birthweight.ConclusionsHigher paternal preconception folate intake was associated with slightly longer gestation among live births achieved through assisted reproduction. The results suggest that preconception exposures of the father may have an impact on the health of his offspring, and therefore that preconception care should shift from a woman-centric to a couple-based approach.
| S-EPMC6848767 | biostudies-literature
Project description:To what extent do financial, demographic and cultural determinants explain the vast cross-national differences in ART treatments in Europe?The normative cultural acceptance of ART is a major driver of ART treatments in Europe, above and beyond differences in country wealth, demographic aspects and religious composition.There are vast differences in the number of ART treatments across European countries, which are to some extent related to country affluence, regulation, and insurance coverage and costs. The role and impact of cultural and normative factors has not been explored in a larger cross-national comparison.A descriptive and comparative cross-national analysis of ART treatment prevalence in over 30 European countries in 2010, with the outcome defined as the total number of ART cycles per million women of reproductive age (15-44 years). Data is drawn from multiple sources (ICMART, US Census Bureau Library, World Bank, Barro-Lee Educational Attainment Dataset, IFFS Surveillance reports, European Values Study and World Religion Database).Our sample includes data from 35 European countries, where we describe the associations between demographic and cultural factors and the prevalence of ART treatments. Bivariate correlation and ordinary least squares multiple regression analysis serves to establish the relationships between predictor variables and the number of ART treatments per million women aged 15-44 years in a country.A one-percent increase in national GDP is associated with 382 (95% CI: 177-587) additional ART procedures per million women of reproductive age, yet this effect is reduced to 99 (-92 to 290) treatments once cultural values and demographic factors are accounted for. In our fully adjusted model, normative cultural values measuring the acceptability of ART are the strongest predictor of ART usage, with a one-point increase of average approval in a country associated with 276 (167-385) additional ART treatments per million women of reproductive age.Findings are based on a cross-sectional, cross-national analysis, making formal tests of causality impossible and prohibiting inferences to the individual level.Results indicate that reproductive health policy should openly acknowledge the importance of cultural norms in informally shaping and regulating the wider availability of ART treatment.Funding for this project was provided by the European Union's Seventh Framework Program (FP7 2007-2013) (No. 320116 Families and Societies), European Research Council for the SOCIOGENOME Consolidator Grant (ERC-2013-CoG-615603) and the Wellcome Trust Institutional Strategic Support Fund (all to M.C.M.). The authors have no conflicts of interest to declare.N/A.
| S-EPMC5850226 | biostudies-literature
Project description:Preeclampsia is a complex genetic disorder with an incompletely understood pathogenesis. Its phenotype may be better elucidated by integrating symptoms. This study aimed to identify symptoms by gestational age and associations with novel preeclampsia candidate genes. Women with a history of preeclampsia recruited from The Preeclampsia Registry completed clinical/demographic, symptom surveys and provided medical records. DNA extracted from saliva was processed with multiplexed assays for eight single-nucleotide polymorphisms (SNPs) selected to tag candidate genes and/or located in symptom susceptibility regions. Groups with versus without symptoms were compared using χ2. Associations between SNPs and symptoms were analyzed as genotype categories and presence/absence of the variant allele. Logistic regression modeling was conducted with exploratory p = .05. In 114 participants, 113 reported at least 1 of the 18 symptoms. Symptoms varied by trimester. Nine symptoms were associated with seven SNPs. Visual disturbances were associated with three SNPs and nausea/vomiting with two SNPs. Modeling adjustment for maternal age and parity resulted in 15 associations between 9 symptoms and 8 SNPs. Medical records demonstrated 100% concordance with self-reported diagnosis and 48% concordance with reported severity. Findings indicated novel symptom-genotype associations in preeclampsia. The small sample was self-selected, but results support future studies including medical records review. When validated, these results may lead to holistic phenotyping of women to characterize subsets of preeclampsia. This approach may optimize health in pregnancy and later life for mothers and offspring through prediction, prevention, and precision nursing care.
| S-EPMC5942529 | biostudies-literature
Project description:Selected human sperms with ART technique demonstrate many changes in the genetic and epigenetic aspects. There are many evidances shown that DNA damange and histone retention ratio have significant improved after selection with different methods. These changes may relate with DNA epigenetic changes, however no evidance demonstate these relevance. In this study, MeDIP-ChIP method has been employed to detect DNA methylation loci in human sperm genome processed with density selection. Results demonstrated that DNA methylation changed in specific gene location. comparison the DNA methylation site between 3 pair human sperm DNA samples before or after density selection
2016-08-01 | E-GEOD-71339 | biostudies-arrayexpress
Project description:PurposeTo generate a large cohort of children born after assisted reproductive technology (ART) in the UK between 1992 and 2009, their naturally conceived siblings (NCS) and matched naturally conceived population (NCP) controls and linking this with health outcome data to allow exploration of the effects of ART. The effects of fresh and frozen embryo transfer on birth weight (BW) were analysed to test the validity of the cohort.ParticipantsChildren recorded on the Human Fertilisation and Embryology Authority (HFEA) register as being born after ART between 1992 and 2009, their NCS and matched NCP controls linked to Office for National Statistics birth registration dataset (HFEA-ONS cohort). This cohort was further linked to the UK Hospital Episode Statistics database to allow monitoring of the child's post-natal health outcomes up to 2015 (HFEA-ONS-HES subcohort).Findings to dateThe HFEA-ONS cohort consisted of 75 348 children born after non-donor ART carried out in the UK between 1 April 1992 and 31 July 2009 and successfully linked to birth registration records, 14 763 NCS and 164 823 matched NCP controls. The HFEA-ONS-HES subcohort included 63 877 ART, 11 343 NCS and 127 544 matched NCP controls further linked to health outcome data. The exemplar analysis showed that children born after fresh embryo transfers were lighter (BW difference: -131 g, 95% CI: -140 to -123) and those born after frozen embryo transfers were heavier (BW difference: 35 g, 95% CI: 19 to 52) than the NCP controls. The within-sibling analyses were directionally consistent with the population control analyses, but attenuated markedly for the fresh versus natural conception (BW difference: -54 g; 95% CI: -72 to -36) and increased markedly for the frozen versus natural conception (BW difference: 152 g; 95% CI: 113 to 190) analyses.Future plansTo use this cohort to explore the relationship between ART conception and short-term and long-term health outcomes in offspring.
| S-EPMC8291329 | biostudies-literature
Project description:To investigate differences in gene expression between bulk NK cells from naturally cycling endometrium versus bulk NK cells from superovulated endometrium, we performed bulk RNAseq of sort-purified endometrial NK cells.
2023-09-20 | GSE222892 | GEO