Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts

Caramaschi, Doretta; Jungius, James; Page, Christian M.; Novakovic, Boris; Saffery, Richard; Halliday, Jane; Lewis, Sharon; Magnus, Maria C; London, Stephanie J.; Håberg, Siri E.; Relton, Caroline L; Lawlor, Debbie A.; Elliott, Hannah R

doi:10.1093/humrep/deab137

Cited by 20 publications

(12 citation statements)

References 59 publications

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“…This is supported by our observation that differences attenuate by adjustment for birthweight and gestational age, although this should be interpreted with caution, since assumptions for such analyses and potential for collider bias makes them difficult to interpret. 25 , 26 , 28 Other possible explanations include effects of ART-induced epigenetic alterations, 29 , 30 and effects of the ovarian stimulating hormones administered prior to ART. 31 The different findings for fresh ET and FET may reflect effects of ovarian stimulation on endometrium and corpus luteum when using fresh embryos 32 or the impact of freezing on embryos.…”

Section: Discussionmentioning

confidence: 99%

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood

et al. 2022

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IMPORTANCEPeople conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population. OBJECTIVE To investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study. DESIGN, SETTING, AND PARTICIPANTS This cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022. EXPOSURES Conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction). MAIN OUTCOMES AND MEASURESThe main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups. RESULTSUp to 158 066 offspring (4329 conceived by ART) were included in each age-group metaanalysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were −0.27 (95% CI, −0.39 to −0.16) SD units at age younger than 3 months, −0.16 (95% CI, −0.22 to −0.09) SD units at age 17 to 23 months, −0.07 (95% CI, −0.10 to −0.04) SD units at age 6 to 9 years, and −0.02 (95% CI, −0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was −0.14 [95% CI, −0.20 to −0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, −0.15 to 0.15] (continued)

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Section: Discussionmentioning

confidence: 99%

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood

et al. 2022

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“…This is supported by our finding that differences attenuate by adjustment for birthweight and gestational age, though, this should be interpreted with caution since assumptions for such analyses and potential for collider bias makes them difficult to interpret (25, 26, 28). Other possible explanations include effects of ART-induced epigenetic alterations (29, 30), and effects of the ovarian stimulating hormones administered prior to ART. The different findings for fresh ET and FET may reflect effects of ovarian stimulation on endometrium and corpus luteum when using fresh embryos (31) or the impact of freezing on embryos.…”

Section: Discussionmentioning

confidence: 99%

Association of assisted reproductive technology with offspring growth and adiposity from infancy to early adulthood

Elhakeem

Taylor

Inskip

et al. 2022

Preprint

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ImportancePeople conceived using assisted reproductive technology (ART) make up an increasing proportion of the world’s population, and their numbers are expected to continue rising.ObjectiveInvestigate association of ART conception with growth and adiposity outcomes from infancy to early adulthood in offspring from a large multinational multi-cohort study.Design26 population-based cohort studies.SettingEurope, Asia-Pacific, and North AmericaParticipantsInfants, children, adolescents, and young adults born from 1984 to 2018, with mean ages at assessment of growth/adiposity outcomes ranging from 0.6 month to 27.4 years.ExposuresConception by ART (conventional in vitro fertilisation and intracytoplasmic sperm injection) versus natural conception (NC).Main Outcomes and MeasuresLength/height, weight, and body mass index (BMI). Each cohort was analysed separately with adjustment for maternal BMI, age, smoking, education, parity, ethnicity, and offspring sex and age. Cohort results were combined in random effects meta-analysis for thirteen age groups.ResultsUp to 158,066 offspring (4,329 conceived by ART) were included in each age-group meta-analysis; 47.6% to 60.6% were female. Compared with NC, ART-conceived offspring were slightly shorter, lighter, and thinner from infancy to early adolescence. The differences in growth/adiposity outcomes were largest at the youngest ages and attenuated with older child age, e.g., adjusted standardised mean differences (95% confidence intervals) in offspring weight at age ‘<3 months’, ‘17 to 23 months’, ‘6 to 9 years’, and ‘14 to 17 years’ were -0.27 standard deviation (SD) units (−0.39 to -0.16), -0.16SD (−0.22 to -0.09), -0.07SD (−0.10 to -0.04), and -0.02SD (−0.15 to 0.12), respectively. There was no evidence that results were driven by parental subfertility or of difference between conventional in vitro fertilisation and intracytoplasmic sperm injection however, smaller offspring size appeared to be limited to offspring conceived by fresh but not frozen embryo transfer, compared with NC. More marked but less precise differences were observed for body fat measurements. There was imprecise evidence that offspring conceived by ART may develop greater adiposity by early adulthood.Conclusions and RelevancePeople conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.KEY POINTSQuestionIs conception by assisted reproductive technology associated with growth and adiposity from infancy to early adulthood?FindingsIn this multi-cohort study of up to 158,066 European, Asian-Pacific, and Canadian infants, children, adolescents, and young adults, those conceived using assisted reproductive technology were on average shorter, lighter, and thinner from infancy up to early adolescence when compared with their naturally conceived peers though differences were small across all ages and reduced with older age.MeaningParents conceiving or hoping to conceive through assisted reproductive technology and their offspring should be reassured that differences in early life growth and adiposity are small and no longer apparent by late adolescence.

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“…The location of DMPs and DMRs was compared with the results of 15 other studies on genome-wide DNA methylation and ART [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. Genomic coordinates of DMPs and DMRs found in each individual study were extracted and annotated to the nearest gene.…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Analysis of DNA Methylation in Buccal Cells of Children Conceived through IVF and ICSI

Ducreux

Frappier

Bruno

et al. 2021

Genes

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Early life periconceptional exposures during assisted reproductive technology (ART) procedures could alter the DNA methylation profiles of ART children, notably in imprinted genes and repetitive elements. At the genome scale, DNA methylation differences have been reported in ART conceptions at birth, but it is still unclear if those differences remain at childhood. Here, we performed an epigenome-wide DNA methylation association study using Illumina InfiniumEPIC BeadChip to assess the effects of the mode of conception on the methylome of buccal cells from 7- to 8-year-old children (48 children conceived after ART or naturally (control, CTL)) and according to the embryo culture medium in which they were conceived. We identified 127 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) (FDR < 0.05) with low delta beta differences between the two groups (ART vs. CTL). DMPs were preferentially located inside promoter proximal regions and CpG islands and were mostly hypermethylated with ART. We highlighted that the use of distinct embryo culture medium was not associated with DNA methylation differences in childhood. Overall, we bring additional evidence that children conceived via ART display limited genome-wide DNA methylation variation compared with those conceived naturally.

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Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts

Cited by 20 publications

References 59 publications

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood

Association of assisted reproductive technology with offspring growth and adiposity from infancy to early adulthood

Genome-Wide Analysis of DNA Methylation in Buccal Cells of Children Conceived through IVF and ICSI

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