Association Between Assisted Reproductive Technology and Cardiac Alteration at Age 5 Years

Assisted reproductive technology (ART) has extensively permitted thousands of childbirths per year for many infertile couples throughout the world.¹ Although ART is generally considered safe, a growing body of evidence reveals the association of ART with increased risk for poorer perinatal outcomes and congenital malformations.² Furthermore, preliminary studies have indicated the presence of cardiovascular remodeling in fetuses and infants conceived with ART potentially associated with fetal cardiovascular reprogramming.^3,4 However, very little is known regarding whether cardiovascular changes occurring already in fetal life among pregnancies conceived with ART persist into childhood and retain an incremental risk of developing cardiac remodeling. On the basis of a prospective follow-up of a historic national register–based cohort study, we designed an observational study to investigate cardiac development of children conceived with ART compared with those conceived spontaneously at age 5 years.

Based on previous data,⁵ we expected a sample size of 100 participants per group to provide 80% power to detect an effect size of 0.35 with a 2-sided α of .05. The ART participants were recruited by a register-based sample from pregnancies conceived with in vitro fertilization in our center and born in the maternal fetal unit whereas age- and sex-matched control participants conceived spontaneously were recruited by a hospital-based sample from low-risk pregnancies in the same unit. The institutitonal review board of the First Affiliated Hospital of Nanjin Medical University provided approval for this study. Parents of participants provided written informed consent. All participants were free of known diseases. Blinded cardiac assessments were conducted by transthoracic conventional echocardiography and 2-dimensional speckle tracking imaging using a commercially available iE33 ultrasound unit (Philips Medical System) and QLAB 10.0 offline software (Philips Medical System) following a standardized protocol.⁶

Cardiac parameters between control participants and ART participants were compared with a paired t test before and after adjusting for baseline covariates of interest. All P values were 2-sided and considered significant if less than .05. Statistical analyses were completed in SPSS Statistics 19.0 (IBM).

Assessments showed the cardiac morphometry were similar between the 2 groups. Children conceived with ART suggested significant alteration of systolic function measured by decreases in mitral and tricuspid annular plane systolic excursions, diastolic function measured by decreases in mitral and tricuspid E deceleration time and left and right isovolumic relaxation time, and global function measured by increases in left and right myocardial performance indexes (Table 1).

Children conceived with ART demonstrated significantly lower longitudinal strain and longitudinal strain rates and radial strain and radial strain rates but similar circumferential strain and circumferential strain rates. Children conceived with ART showed alteration of systolic contraction by reduction in twisting velocity and in twist angles mainly resulting from gradual decreases in endocardial twisting and apical rotation as well as diastolic relaxation by reductions in the rate and velocity of untwisting. Concerning dyssynchrony, findings indicated the ART group had significantly larger longitudinal strain basal septal and basal lateral delays and radial strain anteroseptal to posterior delays whereas circumferential strain anteroseptal to posterior delays were similar to that of control participants (Table 2).

This study showed the presence of significant changes in both cardiac systolic and diastolic function despite the absence of significant alterations in cardiac morphometry in the ART population during childhood, indicating the potential association of ART with an increased risk and early onset of unfavorable myocardial alterations. These imaging-based parameters are relatively ideal indicators of pediatric cardiac development⁶ that can provide better insights into cardiovascular pathophysiology and suggest opportunities for early detection and potential intervention in the ART population from a public health perspective.^2,4,5

This prospective follow-up design, blinded assessment, and adjustments for a large number of potential confounders minimized the threat of biases in this study to some extent. We cannot ascertain the observed association resulting from either ART itself or other confounders beyond our currently available knowledge. The long-term consequences of ART need continued investigation in future studies.

Corresponding Author: Jie Zhou, MD, Echocardiography Group, Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Collaborative Innovation Center for Cardiovascular Disease of Translational Medicine of Jiangsu Province, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China (zhoujiegrm@sina.com).

Published Online: April 27, 2015. doi:10.1001/jamapediatrics.2015.0214.

Author Contributions: Dr Zhou had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: H. Liu, J.-Y. Liu, Zhou.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: H. Liu.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: H. Liu, Feng.

Obtained funding: H. Liu, J.-Y. Liu, Zhou, Yan.

Administrative, technical, or material support: Gu.

Study supervision: J. Liu.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants 2012CB944902 and 2012CB944903 from the National Key Basic Research Program of the Ministry of Science and Technology of China, 61020106008 and 30900749 from the National Natural Science Foundation of China, SIPO-201410311640.4 from the Invention Patents Program of State Intellectual Property Office of China, JX10231081 from the Priority Academic Program Development of Jiangsu Higher Education Institutions of China, and SJZZ20140118 from the Graduate Practice Innovation Project of Jiangsu Higher Schools of China.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Zhi-Bin Hu, MD, MPH, PhD, Changjiang Scholars Distinguished Professor, Department of Epidemiology and Biostatistics, School of Public Health, Ministry of Education Key Laboratory of Modern Toxicology, Nanjing Medical University, for the suggestion of the study design; Zhen Sun, MD, Li Gao, MD, and Yu-Gui Cui, PhD, State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical, in the recruitment and observation of the participants; and are grateful to all children and parents who participated in this study and diligently returned questionnaires. The persons named were not compensated for study assistance beyond their salaries.

Additional Information: The clinicaltrials.gov identifier for this study is NCT02190422. The ethics registration identifier in the Association for the Accreditation of Human Research Protection Program is 2012-SR-048.