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Analyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach.

Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore. jonathan_huang@sics.a-star.edu.sg. Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore. Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore. Université de Paris, CRESS, Inserm, Paris, France. Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA. MRC Lifecourse Epidemiology Centre and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton, Southampton, UK. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore. Academic Clinical Program in Obstetrics and Gynaecology, Duke-NUS Medical School, Singapore, Singapore. University of Helsinki, Department of General Practise and Primary Health Care, Helsinki University Hospital, Helsinki, Finland. Folkhälsan Research Center, Helsinki, Finland.

Nature communications. 2021;(1):5613
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Abstract

Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (-0.5 SD [95% CI: -0.7, -0.2]), lighter (-0.6 SD [-0.9, -0.3]) and have lower skinfold thicknesses (e.g. -14% [-24%, -3%] suprailiac), and blood pressure (-3 mmHg [-6, -0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.

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Publication Type : Clinical Trial ; Observational Study

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