Assisted reproductive technology and long-term cardiometabolic health of the offspring

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Quote: Ma RCW, Ng NYH, Cheung LP (2021) Assisted reproductive technology and long-term cardiometabolic health in offspring. PLoS Med 18 (9): e1003724. https://doi.org/10.1371/journal.pmed.1003724

Posted: September 7, 2021

Copyright: © 2021 Ma 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.

Funding: The RCWM acknowledges the support of the Research Grants Council (RGC) Research Impact Fund (R4012-18), the RGC General Research Fund (Ref. 14118718) and the Croucher Foundation. NYHN acknowledges the support of an RGC Postdoctoral Fellowship.

Competing interests: I have read the journal policy and the authors of this manuscript have the following competing interests: RCWM is a member of the editorial board of PLOS Medicine. The RCWM has received research grants for clinical trials from AstraZeneca, Bayer, MSD, Novo Nordisk, Sanofi, Tricida Inc. and fees for advice or lectures from AstraZeneca and Boehringer Ingelheim, all used to support the diabetes research at the Chinese University of Hong Kong.

Abbreviations:
ART, assisted reproduction technology; CoNARTaS, Nordic ART and Safety Committee; CVD, cardiovascular disease; DOHaD, Developmental Origins of Health and Disease; IUGR, intrauterine growth restriction; IVF, in vitro fertilization; SC, spontaneous conception; T2DM, type 2 diabetes

Since the birth of the first baby using in vitro fertilization (IVF) in July 1978, more than 9 million children have since been born using IVF or other assisted reproduction technologies (ART). Based on a report covering approximately 2/3 of global ART activity, it has been estimated that over 4.4 million ART cycles were initiated between 2008 and 2010, resulting in 1.14 million of births during this period. [1]. From 1997 to 2016, the number of registered antiretroviral treatments increased by 5.3 times in Europe, 4.6 times in the United States of America and 3.0 times in Australia and New Zealand [1]. In an accompanying study in PLOS Medicine, Emma Norrman and colleagues discuss the health of babies born after ART [2].

Although initially met with considerable skepticism and controversy, the large number of healthy babies born over the past 4 decades is a testament to the success and safety of IVF, which has transformed the lives of many couples and families. Nonetheless, given the appreciation of the Developmental Origins of Health and Disease (DOHaD) hypothesis, which postulates that insults during critical periods of development (including in utero or early life) may altering an individual’s phenotype and altering disease risk in adulthood, as as well as the previous demonstration of potential epigenetic changes following ART, there has been a renewed interest in potential long-term effects of ART on the health of the offspring [3]. In a large retrospective cohort study based on the Nordic population of all children born after ART between 1982 and 2007, there was no significant increase in overall cancer rates in children born after ART, e.g. compared to children born after spontaneous conception (SC) [4]. Questions have also been raised about the long-term cardiovascular health of offspring born after ART, as several mechanisms have been postulated to potentially contribute to impaired cardiovascular health, including suboptimal culture conditions, epigenetic changes. induced by ART, as well as indirect effects by birth weight, thus contributing to alter the cardiovascular phenotype [5] (Fig. 1). A systematic review and meta-analysis showed no evidence of an increased cardiovascular risk or diabetes in women on ART, although there was comparatively less data to address the risk to offspring. [6]. In accordance with a recent systematic review and meta-analysis [7], previous small studies have found increased adiposity, cardiometabolic risk and blood pressure in children born after antiretroviral therapy, potentially due to altered gene expression [8,9]. However, issues regarding potential selection bias were raised for the small included studies.

Fig. 1. A DOHaD perspective on the potential relationship between ART and subsequent risk of T2DM and CVD.

The putative link is highlighted by the dotted outline. ART, assisted reproduction technology; CVD, cardiovascular disease; DOHaD, Developmental Origins of Health and Disease; endocrine disruptors, chemicals disrupting the endocrine system; GD, gestational diabetes; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; NcRNA, non-coding RNA; PCOS, polycystic ovary syndrome; T2DM, type 2 diabetes. (Adapted with permission from Ma and colleagues [13]).

https://doi.org/10.1371/journal.pmed.1003724.g001

Norrman and colleagues conducted a large population-based study of the Committee of Nordic ART and Safety (CoNARTaS) cohort, which included all people born in Norway, Sweden, Finland and Denmark between 1984 and 2015, including 122,429 children born after ART, and over 7.5 million children born after SC, to study the risk of cardiovascular disease (CVD), diabetes and obesity after ART compared to SC. The offspring was followed for an average of 8.6 years in children born after ART and 14.0 years in children born after SC. Although the crude rates of CVD and type 2 diabetes (T2DM) were higher in children born after ART, there was no significant difference in the rates after adjusting for the confounders measured. The study noted a significant increase in the risk of obesity in children born on ART, although the risk was modest, with an adjusted HR of 1.14 (CI 1.06 to 1.23, p = 0.001). The study design also meant that it could not determine whether an increased risk in the offspring could be linked to maternal causes of infertility (such as polycystic ovary syndrome), rather than ART. Unlike the previous systematic review which suggested a significant increase in cardiometabolic risk factors in children on ART, the authors concluded that the cardiometabolic results in children on ART are, in general, reassuring. However, more studies with longer follow-up are needed.

The study provided vital mid-term outcome data addressing this important issue of long-term cardiometabolic risk in children born after ART. By combining high-quality Nordic registries, Norrman and colleagues were able to create a unique cohort of children on ART to compare their cardiovascular health risk with children born after SC. Such a population-based design provided a high coverage rate and high validity, so that missing data and the risk of selection bias can be minimized. However, the study had some notable limitations, including the relatively short follow-up period, especially in children born on ART. The number of clinical outcomes of interest was limited, thus limiting the statistical power to detect differences in outcomes. Although the use of national registries minimized any risk of selection bias, the definitions of the results were based on inpatient and outpatient attendance and may be associated with some determination bias, particularly with regard to capture. of obesity results. There is also a significant proportion of maternal BMI, paternal characteristics, or other missing covariates, which limited the analyzes. Another important point to note is that the impact of different ART factors on the health of the offspring has not been addressed. Over the years, ART practices and technologies have continued to evolve, for example, the increasing use of egg freezing and embryo biopsy for genetic testing and the shift from slow freezing to freezing. vitrification method for freezing gametes or embryos. Baby singletons conceived from fresh IVF embryo transfers have been shown to be associated with increased risks of low birth weight and preterm delivery, while ART involving frozen embryos is associated with increased risk of low birth weight and preterm delivery. higher incidence of large babies, macrosomia and hypertensive disorders of pregnancy. [10]. Conversely, low birth weight, intrauterine growth retardation (IUGR) as well as macrosomia have been associated with an increased risk of subsequent T2DM and CVD. [11]. These differential results illustrate that different ART techniques may have different safety profiles and exert different impacts on the long-term health of the offspring. It should be noted that the study by Norrman and colleagues included relatively few births from frozen embryos, and these were not compared to births by SC for subsequent risk of diabetes or CVD.

This important study highlights some of the challenges in determining the long-term effects of ART, or other early life exposures, for that matter. Establishing ART registers that include important exposure factors can be an important part of the way forward, especially given the long-term follow-up required. There are significant challenges, especially those related to privacy, but also increasingly diverse and complex treatment protocols, as well as innovative technologies, which may be associated with different long-term outcomes. There is currently limited understanding of the long-term results of some of these newer techniques. There are also new challenges given the globalization of healthcare delivery, with the increase of cross-border reproductive care. [12]. The increasing cryopreservation of gametes, gonadal tissues and embryos will pose new challenges for monitoring the outcome of births on ART. More long-term population-based studies are warranted, and the establishment of the infrastructure that would facilitate anonymous linking of ART registers, birth registers with national registries for diabetes and other diseases that facilitate long-term health monitoring may be a way forward. Nonetheless, given the sensitivities surrounding the data involved, such analyzes may be difficult to perform in some regions, and population-based analyzes, where possible, will continue to provide vital data for this discussion.


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