---
title: "Long-term cardiovascular risk after assisted reproductive technology and infertility: nationwide c"
id: "plos-medicine-0-long-term-risk-of-cardiovascular-disease-after-assisted-reproductive-technology"
canonical_url: "https://medichelpline.com/clinical-feed/plos-medicine-0-long-term-risk-of-cardiovascular-disease-after-assisted-reproductive-technology"
content_type: "clinical_feed_article"
specialty: "Cardiology"
source_name: "PLOS Medicine"
source_url: "https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120"
published_at: "2026-08-12T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Long-term cardiovascular risk after assisted reproductive technology and infertility: nationwide c
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-medicine-0-long-term-risk-of-cardiovascular-disease-after-assisted-reproductive-technology
- **Specialty:** [Cardiology](https://medichelpline.com/clinical-feed/cardiology.md)
- **Primary Source:** PLOS Medicine
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120)
- **Published At:** 2026-08-12T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This nationwide Swedish cohort followed 380,756 women from their first birth (1992–2002) through 2023 using linked national registers to assess long-term cardiometabolic outcomes after **assisted reproductive technology (ART)** and among women with **infertility**. - The study compared women with infertility who conceived with ART to women with infertility who conceived without ART, adjusting for age, BMI, country of origin, socioeconomic factors, pre-existing comorbidity, smoking and calendar year; it also compared women with and without infertility with similar adjustments. - Outcomes examined included acute myocardial infarction, **cerebral ischemic conditions**, intracranial hemorrhage, type 2 diabetes mellitus, heart failure, aortic aneurysm/dissection, and chronic kidney disease, with cumulative risks plotted using inverse-probability weighted Kaplan–Meier curves and risk differences/ratios at 10, 20 and 30 years. - Use of ART was not associated with an increased risk for most cardiovascular or metabolic outcomes; however, ART was associated with a higher risk of **cerebral ischemic conditions**, with a 30-year risk ratio of 1.44 (95% CI 1.09–1.90). - Compared with women without infertility, women with a history of infertility had consistently higher risk for most outcomes (notably acute myocardial infarction, type 2 diabetes mellitus and heart failure); after 30 years and adjustment for baseline covariates, infertility was associated with ~36% higher risk of acute myocardial infarction, ~34% higher risk of type 2 diabetes, and ~24% higher risk of heart failure. - Adjusting for baseline characteristics explained some but not all of the excess risks seen in women with infertility, suggesting infertility itself or related factors may mark higher long-term cardiometabolic risk. - Limitations noted by the authors include a relatively small number of women treated with ART during the early study period, limited precision for some estimates (especially early and late in follow-up), and lack of data on women who underwent ART but did not achieve a live birth. - Data access is restricted by Swedish privacy laws, but analytic code and metadata are publicly archived; funding sources and competing interests were disclosed in the original report.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosmedicine%2Farticle%3Fid%3D10.1371%2Fjournal.pmed.1005120) * * About * Browse * Publish * [](https://journals.plos.org/plosmedicine/ "PLOS Medicine") * Search [advanced search](https://journals.plos.org/plosmedicine/search) * 0 [Save](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#savedHeader) * 0 [Citation](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#citedHeader) * 28 [View](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#viewedHeader) * 0 [Share](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120#discussedHeader) Open Access Peer-reviewed Research Article # Long-term risk of cardiovascular disease after assisted reproductive technology and infertility: A cohort study * Angelo Giosuè Mezzoiuso , Roles Conceptualization, Formal analysis, Methodology, Visualization, Writing – original draft, Writing – review & editing * E-mail: angelo.giosue.mezzoiuso@ki.se Affiliation Departments of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-7667-9345 ](https://orcid.org/0000-0001-7667-9345 "ORCID Registry") ⨯ * Peter Henriksson, Roles Conceptualization, Methodology, Supervision, Writing – review & editing Affiliation Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-0633-4699 ](https://orcid.org/0000-0002-0633-4699 "ORCID Registry") ⨯ * Márta Radó, Roles Conceptualization, Funding acquisition, Methodology, Supervision, Writing – review & editing Affiliations Departments of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden, Centre Urbanisation Culture Société, Institut National de la Recherche Scientifique, Montréal, Quebec, Canada ⨯ * Kenny A. Rodriguez-Wallberg, Roles Conceptualization, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – review & editing Affiliation Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-4378-6181 ](https://orcid.org/0000-0003-4378-6181 "ORCID Registry") ⨯ * Anna Sara Oberg Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft, Writing – review & editing Affiliations Departments of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-6638-1895 ](https://orcid.org/0000-0001-6638-1895 "ORCID Registry") ⨯ # Long-term risk of cardiovascular disease after assisted reproductive technology and infertility: A cohort study * Angelo Giosuè Mezzoiuso, * Peter Henriksson, * Márta Radó, * Kenny A. Rodriguez-Wallberg, * Anna Sara Oberg ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: August 12, 2026 * * [Article](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120) * [Authors](https://journals.plos.org/plosmedicine/article/authors?id=10.1371/journal.pmed.1005120) * [Metrics](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005120) * [Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1005120) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pmed.1005120) * [Abstract](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#abstract0) * [Author summary](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#abstract1) * [Introduction](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#sec007) * [Methods](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#sec008) * [Results](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#sec017) * [Discussion](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#sec022) * [Supporting information](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#sec023) * [References](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#references) * [Reader Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1005120) * [Figures](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120) ![Accessible Data Icon](https://journals.plos.org/resource/img/accessible_data.svg)Accessible Data [ See the data ![Link Icon](https://journals.plos.org/resource/img/data_link_icon.svg) ](https://github.com/Epidemiologit/Long-term-risk-of-cardiovascular-disease-after-assisted-reproductive-technology-and-infertility-Code/releases/tag/v1.0.0) This article includes the Accessible Data icon, an experimental feature to encourage data sharing and reuse. [Find out how research articles qualify for this feature.](https://theplosblog.plos.org/2023/07/accessible-data/) [?](https://journals.plos.org/plosmedicine/s/accepted-manuscripts#loc-early-version) ## This is an uncorrected proof. ## Abstract ### Background The use of Assisted Reproductive Technology (ART) is increasing worldwide. These treatments involve ovarian stimulation to enable multiple follicle recruitment, hence inducing supraphysiological estrogen levels. While most long-term follow-up of women undergoing ART has concerned cancer incidence, the long-term safety regarding cardiovascular and metabolic diseases remains under-explored. This study was performed to assess the risk of acute myocardial infarction, cerebral ischemic conditions, intracranial hemorrhage, type 2 diabetes mellitus, heart failure, aortic aneurysm or dissection, and chronic kidney disease in women that conceived with ART, and to investigate the role of the underlying infertility and its risk factors. ### Methods and findings Swedish national registers allowed us to follow a nationwide cohort of 380,756 women from their first birth between 1992 and 2002 until the end of 2023. The safety of ART was evaluated by comparing women with infertility who conceived with and without ART, while adjusting for baseline differences in age, body mass index, country of origin, socioeconomic factors, pre-existing comorbidity, smoking and year. The role of infertility was additionally explored by comparing all women with and without infertility adjusting for age, as well as the aforementioned baseline characteristics. Cumulative risks were plotted using inverse-probability weighted Kaplan-Meier curves. To facilitate the comparison of groups, we also estimated risk differences and ratios at 10-, 20-, and 30 years of follow-up. Use of ART was not associated with cardiovascular disease except for an excess risk of cerebral ischemic conditions, with a 30-year risk ratio of 1.44 (95% Confidence Interval (CI) [1.09,1.90]). With the exception of cerebral ischemic conditions, intracranial hemorrhage, aortic dissection, and chronic kidney disease, women with a history of infertility exhibited consistently higher risk of all outcomes, and adjustment for differences in baseline characteristics explained some but not all of these elevated risks. Even though the study period was restricted with respect to the earliest years of ART implementation, the number of exposed was still low and risks calculated with limited precision, particularly at the beginning and at the end of the follow-up due to very few events and decreasing numbers at risk, respectively. ### Conclusions With the exception of ischemic cerebral conditions, the findings provide reassurance regarding the long-term cardiometabolic safety of ART use, while adding to the growing literature suggesting that infertility can act as a marker of women’s cardiovascular and metabolic disease. ## Author summary ### Why was this study done? * Assisted reproductive technology is an increasingly common infertility treatment, accounting for up to 5% of children born per year in some countries. * The treatment often exposes women to high doses of hormones, which raises concerns about potential negative effects on the cardiovascular system. * It is currently unclear whether use of assisted reproductive technology increases a woman’s long-term risk of cardiovascular diseases. ### What did the researchers do and find? * We conducted a study including all women who gave birth in Sweden from 1992 to 2002 [380,756], with ability to track the occurrence of heart disease and stroke through 2023. * We compared women who conceived with and without assisted reproductive technology after experiencing infertility, with adjustment for differences in background characteristics. We also compared overall risks to women with and without infertility. * Use of assisted reproductive technology was associated with a 44% higher risk of cerebral ischemic conditions, but not with any other studied outcomes. After 30 years follow up, women with infertility were found at 36% higher risk of acute myocardial infarction, 34% higher risk of type 2 diabetes, and 24% higher risk of heart failure, compared to women with similar background characteristics. ### What do these findings mean? * While the findings are largely reassuring with respect to long-term cardiovascular health following use of ART, an excess risk of cerebral ischemic conditions warrants further consideration. * The results suggest that women with infertility are at elevated risk of cardiovascular issues later in life. * Limitations of the study include the relatively small number of women treated with these technologies and a lack of data on women who underwent treatment which did not result in birth. ## Figures ![Fig 3](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.g003) ![Fig 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.g001) ![Table 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.t001) ![Fig 2](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.g002) ![Fig 3](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.g003) ![Fig 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.g001) ![Table 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.t001) ![Fig 2](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005120.g002) **Citation:** Mezzoiuso AG, Henriksson P, Radó M, Rodriguez-Wallberg KA, Oberg AS (2026) Long-term risk of cardiovascular disease after assisted reproductive technology and infertility: A cohort study. PLoS Med 23(8): e1005120. https://doi.org/10.1371/journal.pmed.1005120 **Academic Editor:** Peter WG Tennant, University of Leeds, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND **Received:** May 12, 2026; **Accepted:** July 28, 2026; **Published:** August 12, 2026 **Copyright:** © 2026 Mezzoiuso et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** Individual-level data from the register-linkage used in this study cannot be made publicly available or deposited in a public repository due to legal restrictions under the General Data Protection Regulation (GDPR), the Swedish Data Protection Act (SFS 2018:218), the Swedish Ethical Review Act, and the Public Access to Information and Secrecy Act. Qualified researchers who wish to replicate the study or access the data can apply for approval from the Swedish Ethical Review Authority (Etikprövningsmyndigheten). Upon receiving ethical approval, researchers can apply for data extraction directly from the respective independent register holders: the Swedish National Board of Health and Welfare (registerservice@socialstyrelsen.se) and Statistics Sweden (information@scb.se). The analytic code and all the relevant information are permanently archived on Zenodo at DOI: [10.5281/zenodo.21292155](https://10.5281/zenodo.21292155) and are publicly accessible. The live development version remains available on GitHub at . **Funding:** This work was supported by Forte – Swedish Research Council for Health, Working Life and Welfare ( ) (grant 2020-00753 to ASO and MR), Stiftelsen Riksbankens Jubileumsfond ( ) (grant P23-0640 to MR and ASO), and Karolinska Institutet KID doctoral funding ( ) (registration number XXX/2021 as salary support to AGM). PH received no specific funding. KARW is supported by grants from the Swedish Cancer Society (grant 20 0170 F) and the Radiumhemmets Research Funds for clinical researchers (2020-2026). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. **Competing interests:** I have read the journal’s policy and the authors of this manuscript have the following competing interests: KARW reports industry support and personal fees outside the submitted work (Merck, Ferring, Gedeon Richter, Roche, Pfizer, Organon, IBSA; consulting for SpringWorks Therapeutics). PH reports paid advisory work for Bayer and Abbott outside the submitted work. MR reports paid advisory work for Bayer and Abbott outside the submitted work. ASO reports advisory remuneration from Abbott and Bayer outside the submitted work. All other authors (AGM) declare no competing interests. **Abbreviations:** ART, Assisted Reproductive Technology; BMI, body mass index; CI, confidence interval; GDPR, General Data Protection Regulation; IBD, inflammatory bowel disease; ICD, International Classifications of Diseases; ICSI, intracytoplasmic sperm injection; IPTW, inverse probability of treatment weights; IVF, in vitro fertilization; MBR, Medical Birth Register; MCMC, Markov Chain Monte Carlo; RD, risk difference; RR, relative risk; SMD, standardized mean difference; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology ## Introduction Assisted reproductive technology (ART) is an increasingly utilized and effective treatment for infertility [[1](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref001)], with recent global data showing over 3.3 million ART cycles being performed across 83 countries in 2018 [[2](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref002)]. In ART, women undergo hormonal stimulation to develop several follicles from which oocytes can be retrieved for in-vitro fertilization (IVF), sometimes using intracytoplasmic sperm injection (ICSI). After a few days of culture, embryos are transferred to the uterus and/or frozen for later transfer. The full extent to which ART treatment protocols, and the controlled hyperstimulation of the ovaries, may influence women’s cardiovascular health is not clear, especially not in the long-term [[3](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref003)]. Sex hormones play a complex and still not well understood role in cardiovascular health. It has, for example, been suggested that declining estrogen after menopause [[4](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref004)], and increased androgens in conditions like polycystic ovarian syndrome could be linked to higher cardiovascular risk in women [[5](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref005)]. In the last years, growing evidence suggests that women who undergo ART are at increased risk of cardiovascular morbidity in the short term, particularly for venous thromboembolism, which has also been linked to the hyperstimulation of the ovaries [[6](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref006)–[8](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref008)]. Furthermore, a cohort study with an average follow-up of 9 years observed an elevated risk of hypertension and possibly also of stroke in women that gave birth following ART [[9](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref009)]. Seeing how hypertension contributes to cardiovascular disease through chronic exposure, extended follow-up will be necessary to observe its full consequences. Because pregnant women are a population already at risk in the short-term, it is important to understand if a treatment that further increases this risk could also affect their long-term risk of cardiovascular diseases. Until now, the long-term cardiovascular safety of ART has received limited attention in research. A recent meta-analysis on the topic included only six studies and, due to the large heterogeneity, was unable to draw conclusions beyond the necessity of more well-characterized studies [[10](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref010)]. With the exception of a recent study using Nordic register data, previous efforts have also been characterized by relatively short follow-up. As cardiovascular disease risk factors may act for long periods before disease onset, too short follow-up could underestimate the real impact and sometimes even introduce bias [[11](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005120#pmed.1005120.ref011)]. Another largely overlooked challenge is to disentangle the role of ART from that of its indication, since factors related to infertility, such as specific diseases, could be responsible for cardiovascular disease development. This distinction is crucial for accurately evaluating the safety of ART as well as understanding the overall risk to women with infertility [[12](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005
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