Cognitive achievements in school-age children born following assisted reproductive technology treatments: A prospective study

Farhi, Adel; Gabis, Lidia V.; Frank, Shay; Glasser, Saralee; Hirsh-Yechezkel, Galit; Brinton, Louise A.; Scoccia, Bert; Ron-El, Raphaël; Orvieto, Raoul; Lerner‐Geva, Liat

doi:10.1016/j.earlhumdev.2021.105327

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…Moreover, singletons and twins of both sexes conceived by ART perform as well as SC children once they reach school ( Wagenaar et al, 2008 ; Punamäki et al, 2016 ; Norrman et al, 2018 ; Luke et al, 2020 ). Cognitive function, visual-motor ability, attention, and verbal skills of ART children were similar to SC children ( Farhi et al, 2021a ). Some reports suggested that ART does exert some negative influences on cognitive development.…”

Section: Cognitive and Neurodevelopmental Health Of Newborns And Chil...mentioning

confidence: 76%

The Consequences of Assisted Reproduction Technologies on the Offspring Health Throughout Life: A Placental Contribution

Schroêder

Badini

Sferruzzi‐Perri

et al. 2022

Front. Cell Dev. Biol.

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The use of assisted reproductive technologies (ART) worldwide has led to the conception and birth of over eight million babies since being implemented in 1978. ART use is currently on the rise, given growing infertility and the increase in conception age among men and women in industrialized countries. Though obstetric and perinatal outcomes have improved over the years, pregnancies achieved by ART still bear increased risks for the mother and the unborn child. Moreover, given that the first generation of ART offspring is now only reaching their forties, the long-term effects of ART are currently unknown. This is important, as there is a wealth of data showing that life-long health can be predetermined by poor conditions during intrauterine development, including irregularities in the structure and functioning of the placenta. In the current review, we aim to summarize the latest available findings examining the effects of ART on the cardiometabolic, cognitive/neurodevelopmental, and behavioral outcomes in the perinatal period, childhood and adolescence/adulthood; and to examine placental intrinsic factors that may contribute to the developmental outcomes of ART offspring. Altogether, the latest knowledge about life outcomes beyond adolescence for those conceived by ART appears to suggest a better long-term outcome than previously predicted. There are also changes in placenta structure and functional capacity with ART. However, more work in this area is critically required, since the potential consequences of ART may still emerge as the offspring gets older. In addition, knowledge of the placenta may help to foresee and mitigate any adverse outcomes in the offspring.

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Section: Cognitive and Neurodevelopmental Health Of Newborns And Chil...mentioning

confidence: 76%

The Consequences of Assisted Reproduction Technologies on the Offspring Health Throughout Life: A Placental Contribution

Schroêder

Badini

Sferruzzi‐Perri

et al. 2022

Front. Cell Dev. Biol.

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“…Table S2). These indirect connections with autism and neurodevelopment are particularly noteworthy, given previous reports indicating that neurodevelopmental outcomes differ in children conceived by ART 100;101 , but not always 102;103 .…”

Section: Discussionmentioning

confidence: 72%

The X-factor in ART: does the use of Assisted Reproductive Technologies influence DNA methylation on the X chromosome?

Romanowska

Nustad

Page

et al. 2022

Preprint

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Background: Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate DNAm differences on the X chromosome. Materials and Methods: The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). The replication cohort consisted of 149 ART and 58 non-ART neonates from the Australian "Clinical review of the Health of adults conceived following Assisted Reproductive Technologies" (CHART) study. The Illumina EPIC array was used to measure DNA methylation (DNAm) in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ("XWASs" hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. For replication purposes, we ran an analogous model to our main model on the CHART dataset. Results and conclusions: In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted even after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental infertility as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. Overall, genes that co-localized with the significant CpGs and DMRs are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism. These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to naturally-conceived.

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“…This promoter regulates four genes that are important in the developmental processes of various tissues, including neurons (Additional file 1 : Table S2). These indirect connections with autism and neurodevelopment are particularly noteworthy, given previous reports indicating that neurodevelopmental outcomes differ in children conceived by ART [ 101 , 102 ], but not always [ 103 , 104 ].…”

Section: Discussionmentioning

confidence: 85%

The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?

et al. 2023

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Background Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother–father–newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian ‘Clinical review of the Health of adults conceived following Assisted Reproductive Technologies’ (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies (‘XWASs’ hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset. Results In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. Conclusions Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.

show abstract

Cognitive achievements in school-age children born following assisted reproductive technology treatments: A prospective study

Cited by 11 publications

References 27 publications

The Consequences of Assisted Reproduction Technologies on the Offspring Health Throughout Life: A Placental Contribution

The Consequences of Assisted Reproduction Technologies on the Offspring Health Throughout Life: A Placental Contribution

The X-factor in ART: does the use of Assisted Reproductive Technologies influence DNA methylation on the X chromosome?

The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?

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