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

Jonathan Yinhao Huang (), Shirong Cai, Zhongwei Huang, Mya Thway Tint, Wen Lun Yuan, Izzuddin M. Aris, Keith M. Godfrey, Neerja Karnani, Yung Seng Lee, Jerry Kok Yen Chan, Yap Seng Chong, Johan Gunnar Eriksson and Shiao-Yng Chan
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Jonathan Yinhao Huang: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Shirong Cai: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Zhongwei Huang: Yong Loo Lin School of Medicine, National University of Singapore
Mya Thway Tint: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Wen Lun Yuan: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Izzuddin M. Aris: Harvard Medical School and Harvard Pilgrim Health Care Institute
Keith M. Godfrey: University of Southampton and University Hospital Southampton
Neerja Karnani: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Yung Seng Lee: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Jerry Kok Yen Chan: KK Women’s and Children’s Hospital
Yap Seng Chong: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Johan Gunnar Eriksson: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)
Shiao-Yng Chan: Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology, and Research (A*STAR)

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25899-4

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