Emma Norrman, Max Petzold, Mika Gissler, Anne Lærke Spangmose, Signe Opdahl, Anna-Karina Henningsen, Anja Pinborg, Aila Tiitinen, Annika Rosengren, Liv Bente Romundstad, Ulla-Britt Wennerholm, Christina Bergh
Abstract
Some earlier studies have found indications of significant changes in cardiometabolic risk factors in children born after assisted reproductive technology (ART). Most of these studies are based on small cohorts with high risk of selection bias. In this study, we compared the risk of cardiovascular disease, obesity, and type 2 diabetes between singleton children born after ART and singleton children born after spontaneous conception (SC).
Introduction
The use of assisted reproductive technology (ART) has increased significantly during the last decades, with more than 390,000 children born worldwide annually [1] and the total number of children born after ART now exceeding 9 million [2]. Long-term cardiovascular and metabolic risks in children born after ART have gained increased attention in both animal and human studies during the last decade. Impaired activity of enzymes related to fatty acid metabolism [3], altered glucose parameters [4,5], and elevated systolic blood pressure [6,7] have been found in studies of mice born after ART. Similarly, studies in humans have found altered glucose metabolism [8,9], elevated blood pressure [8–12], increased thickness of carotid intima–media [13,14], and suboptimal cardiac diastolic function [15,16] in children born after ART.
Methods
Study design and data collection
This was a population-based cohort study carried out in Norway, Sweden, Finland, and Denmark. Data were obtained from the CoNARTaS cohort (Committee of Nordic Assisted Reproductive Technology and Safety) and then cross-linked with data from national patient registers (NPRs), national cause of death registers (CDRs), SWEDIABKIDS (Swedish childhood diabetes register), the Swedish National Diabetes Register (NDR), the Swedish Prescribed Drug Register (SPDR), and BORIS (Swedish childhood obesity treatment register). Socioeconomic data were retrieved from the statistic bureaus in each country.
Discussion
This large, Nordic population-based cohort study included 122,429 singletons born after ART and 7,574,685 singletons born after SC and explored whether there was any difference in the risk of developing cardiovascular disease, obesity, or type 2 diabetes between the 2 groups. The main findings were that children born after ART had no increased risk of cardiovascular disease or type 2 diabetes after adjustment for measured confounders, while for obesity a small but significant increased risk was noticed. For the outcome any cardiovascular disease, the 95% CI was reasonably narrow, excluding effects of a substantial magnitude, while the 95% CI for type 2 diabetes was wide, not excluding clinically meaningful effects.
Citation: Norrman E, Petzold M, Gissler M, Spangmose AL, Opdahl S, Henningsen A-K, et al. (2021) Cardiovascular disease, obesity, and type 2 diabetes in children born after assisted reproductive technology: A population-based cohort study. PLoS Med 18(9): e1003723. https://doi.org/10.1371/journal.pmed.1003723
Editor: Ronald C. W. Ma, Chinese University of Hong Kong, CHINA
Received: November 12, 2020; Accepted: July 9, 2021; Published: September 7, 2021
Copyright: © 2021 Norrman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data cannot be shared publicly directly because use of the data from Sweden and Norway was only approved by the ethical committee for use by the Committe of Nordic ART and Safety (CoNARTaS). Approval for use for other purposes would be needed from the different countries. Data were retrieved from the following registers and where data is available: Sweden 1. National Quality Register for Assisted Reproduction: http://www.medscinet.com/qivf/ 2. Medical Birth Register: https://www.socialstyrelsen.se/statistik-och-data/register/alla-register/medicinska-fodelseregistret/
Funding: This work was funded by Sahlgrenska University Hospital, ALFGBG-70 940 (https://alfvastragotaland.se) to CB; Hjalmar Svensson Research Foundation (https://www.stiftelsemedel.se/stiftelsen-handlanden-hjalmar-svenssons-forskningsfond/) to EN and Nordforsk, project number 71450 (https://nordforsk.org) to AP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: aHR, adjusted hazard ratio; ART, assisted reproductive technology; BMI, body mass index; CDR, cause of death register; CI, confidence interval; CoNARTaS, Committee of Nordic Assisted Reproductive Technology and Safety; FET, frozen embryo transfer; HR, hazard ratio; ICD, International Statistical Classification of Diseases and Related Health Problems; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; MBR, medical birth register; NDR, Swedish National Diabetes Register; NPR, national patient register; SC, spontaneous conception; SD, standard deviation; SPDR, Swedish Prescribed Drug Register.
