Letters RESEARCH LETTER

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. Methods | 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

Table 1. Baseline Conventional Echocardiographic Characteristics of the Study Population P Value

Mean (SD) Characteristic Cardiac morphometry

ART Group

Control Participants

Crude

Adjusteda

Left atrial area, cm2

6.12 (1.85)

6.35 (1.67)

.58

.65

Right atrial area, cm2

5.45 (1.28)

5.62 (1.35)

.85

.80

Left posterior wall thickness, mm

4.86 (0.84)

4.55 (0.92)

.26

.38

Interventricular septal thickness, mm

5.17 (0.77)

5.22 (0.63)

.63

.76

Right free wall thickness, mm

4.32 (0.74)

4.41 (0.80)

.51

.40

Left end systolic volume, mL

14.50 (2.53)

15.28 (2.64)

.18

.29

Left end diastolic volume, mL

42.32 (8.36)

35.40 (9.13)

.07

.08

0.12 (0.03)

0.12 (0.02)

.88

.76

Left coronary artery/aorta Right coronary artery/aorta

0.11 (0.03)

0.11 (0.02)

.89

.82

Left sphericity index

1.70 (0.17)

1.86 (0.14)

.05

.07

Right sphericity index

1.65 (0.18)

1.82 (0.15)

.05

.06

67.32 (5.20)

68.78 (6.05)

.35

.42

2.95 (0.55)

2.83 (0.59)

.48

.56

Mitral APSE, mm

10.08(2.36)

12.76 (2.88)

.03

.05

Right ejection fraction, %

68.62 (5.23)

67.54 (5.23)

.17

.33

3.34 (0.75)

3.29 (0.81)

.56

.68

10.38 (2.34)

12.95 (2.58)

.03

.03 .06

Systolic function Left ejection fraction, % Left cardiac output, mL/min

Right cardiac output, mL/min Tricuspid APSE, mm Diastolic function Mitral E/A

1.78 (0.47)

1.61 (0.42)

.05

123.52 (15.9)

130.46 (14.0)

.04

.03

Mitral E′/A′

1.52 (0.45)

1.36 (0.52)

.04

.08

Mitral E/E′

9.85 (1.55)

9.67 (1.43)

.07

.08

Tricuspid E/A

1.73 (0.44)

1.49 (0.56)

.04

.06

128.36 (18.74)

141.58 (19.55)

.04

.05

Tricuspid E′/A′

1.78 (0.46)

1.54 (0.49)

.04

.09

Tricuspid E/E′

10.62 (1.57)

11.25 (1.71)

.08

.08

Left isovolumic relaxation time, ms

77.46 (6.84)

68.20 (6.55)

.03

.03

Right isovolumic relaxation time, ms

74.63 (7.23)

65.14 (6.96)

.02

.02

Left myocardial performance index

0.34 (0.12)

0.26 (0.11)

.02

.02

Right myocardial performance index

0.28 (0.08)

0.20 (0.07)

.02

.03

Mitral E deceleration time, ms

Tricuspid E deceleration time, ms

Global cardiac function

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Abbreviations: A, ventricular inflow during atrial contraction; A′, annular peak velocity during atrial contraction; APSE, annular plane systolic excursion; ART, assisted reproductive technology; E, ventricular inflow in early diastole; E′, annular peak velocity in early diastole. a

Adjusted for height, weight, body mass index (calculated as weight in kilograms divided by height in meters squared), bust and waist circumference, heart rate, systolic and diastolic blood pressure, leisure time physical activity (metabolic equivalent tasks in minutes/day), nutritional status (World Health Organization z score scale), parental educational level (illiterate or elementary education vs secondary education or university), parental socioeconomic level (lower vs higher vulnerability), maternal major cardiovascular risk factors before pregnancy (obesity, diabetes mellitus, hypertension, or dyslipidemia), maternal smoking status, maternal age, family history of parental cardiovascular diseases, pregnancy complications (preeclampsia, gestational diabetes mellitus, or prenatal corticoid exposure), gestational age at delivery, delivery approach (cesarean vs vaginal), and 1-minute and 5-minute Apgar scores.

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Table 2. Myocardial Mechanics Characteristics of the Study Population P Value

Mean (SD) ART Group

Control Participants

−19.42 (3.82)

−24.65 (3.55)

.03

.02

−1.53 (0.43)

−1.24 (0.38)

.03

.04

−23.54 (3.91)

−25.46 (3.77)

.31

.36

Peak circumferential strain rate, s

−1.73 (0.42)

−1.82 (0.59)

.69

.84

Peak radial strain, %

26.55 (4.17)

31.48 (3.84)

.04

.05

1.45 (0.50)

1.81 (0.46)

.02

.04

.05

Characteristic

Crude

Adjusteda

Systolic deformation Peak longitudinal strain, % Peak longitudinal strain rate, s-1 Peak circumferential strain, % -1

Peak radial strain rate, s-1 Myocardial rotation Peak rotation, degree

8.32 (2.53)

9.15 (2.60)

.04

Apical peak rotation, degree

10.37 (3.53)

13.54 (3.65)

.04

.05

Basal peak rotation, degree

−3.22 (1.54)

−4.15 (1.38)

.78

.87

Time to peak rotation, ms

94.58 (15.41)

89.36 (16.70)

.27

.28

Time to peak apical rotation, ms

82.45 (13.81)

78.66 (14.98)

.06

.05

Time to peak basal rotation, ms

93.72 (14.84)

91.52 (15.37)

.32

.43

Systolic twisting motion Peak twist angle, degree

7.42 (2.43)

9.66 (2.58)

.008

.01

Peak endocardial twist angle, degree

8.37 (2.91)

11.75 (2.44)

.02

.03

Peak epicardial twist angle, degree

4.42 (1.50)

4.56 (1.38)

.57

.49

Peak twisting velocity, degree/s

76.71 (17.43)

94.56 (16.62)

.006

.007

Time to peak twisting velocity, ms

55.54 (9.17)

48.36 (8.89)

.04

.06

Time to peak twisting angle, ms

93.22 (18.35)

88.46 (16.57)

.06

.07

61.53 (17.56)

63.62 (18.28)

.67

.79

0.53 (0.12)

0.60 (0.13)

.02

.03

−78.86 (12.55)

−83.54 (13.74)

.03

.04

92.87 (10.60)

89.79 (11.45)

.43

.50

Diastolic untwisting motion Peak untwisting, degree Untwisting rate, s-1 Peak untwisting velocity, degree/s Time to peak untwisting velocity, ms Dyssynchrony Longitudinal strain BS-BL delay, ms

23.52 (6.85)

18.47 (6.07)

.004

.005

Longitudinal strain SDt12S, ms

20.74 (5.23)

16.56 (5.29)

.02

.02

Circumferential strain AS-P delay, ms

22.55 (9.34)

19.73 (8.22)

.05

.07

Circumferential strain SDt6S, ms

14.38 (6.56)

12.92 (5.89)

.06

.07

Radial strain AS-P delay, ms

21.51 (8.63)

18.24 (8.90)

.03

.04

Radial strain SDt6S, ms

22.29 (7.55)

18.60 (6.99)

.04

.05

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). 604

Abbreviations: ART, assisted reproductive technology; AS-P, difference between time to peak systolic strain of the anteroseptal and posterior segments; BS-BL, difference between time to peak systolic strain of the basal septal and basal lateral segments; SDt6S, standard deviation of the time to peak systolic strain of 6 segments; SDt12S, standard deviation of the time to peak systolic strain of 12 segments. a

Adjusted for height, weight, body mass index (calculated as weight in kilograms divided by height in meters squared), bust and waist circumference, heart rate, systolic and diastolic blood pressure, leisure time physical activity (metabolic equivalent tasks in minutes/day), nutritional status (World Health Organization z score scale), parental educational level (illiterate or elementary education vs secondary education or university), parental socioeconomic level (lower vs higher vulnerability), maternal major cardiovascular risk factors before pregnancy (obesity, diabetes mellitus, hypertension, or dyslipidemia), maternal smoking status, maternal age, family history of parental cardiovascular diseases, pregnancy complications (preeclampsia, gestational diabetes mellitus, or prenatal corticoid exposure), gestational age at delivery, delivery approach (cesarean vs vaginal), and 1-minute and 5-minute Apgar scores.

Results | 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

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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). Discussion | 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.

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. 1. Sunderam S, Kissin DM, Crawford S, et al; Centers for Disease Control and Prevention. Assisted reproductive technology surveillance: United States, 2010. MMWR Surveill Summ. 2013;62(9):1-24.

Hong Liu, MD Yuan Zhang, MD, PhD Hai-Tao Gu, MD, PhD Qiao-Ling Feng, MD, MSc Jia-Yin Liu, MD, PhD Jie Zhou, MD Fei Yan, PhD

2. Yeung EH, Druschel C. Cardiometabolic health of children conceived by assisted reproductive technologies. Fertil Steril. 2013;99(2):318-326. 3. Valenzuela-Alcaraz B, Crispi F, Bijnens B, et al. Assisted reproductive technologies are associated with cardiovascular remodeling in utero that persists postnatally. Circulation. 2013;128(13):1442-1450.

Author Affiliations: Department of Cardiac Surgery, Clinical Center of Heart and Great Vessels, Research Institute of Heart, Lung, and Blood Vessel Diseases, First Affiliated Hospital of Nanjing Medical University, Nanjing, China (H. Liu); State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Zhang, J.-Y. Liu); Department of Pediatric Cardiothoracic Surgery, Jiangsu Women and Children Health Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Gu); Ministry of Education Key Laboratory of Clinical Diagnostic Medicine, Institute of Laboratory Medicine, Chongqing Medical University, Chongqing, China (Feng); Echocardiography Group, Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Collaborative Innovation Center for Cardiovascular Disease of Translational Medicine of Jiangsu Province, Nanjing, China (Zhou); Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China (Yan). 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 ([email protected]). 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.

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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.

4. Scherrer U, Rimoldi SF, Rexhaj E, et al. Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation. 2012;125(15):1890-1896. 5. Zhou J, Liu H, Gu HT, et al. Association of cardiac development with assisted reproductive technology in childhood: a prospective single-blind pilot study. Cell Physiol Biochem. 2014;34(3):988-1000. 6. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. J Am Soc Echocardiogr. 2011;24(3):277-313.

COMMENT & RESPONSE

Preeclampsia, Placental Insufficiency, Autism, and Antiphospholipid Antibodies To the Editor Walker et al1 published data from the Childhood Autism Risks from Genetics and Environment study in JAMA Pediatrics and concluded that fetal exposure to preeclampsia was significantly associated with autism spectrum disorder and developmental delay in children, particularly in severe presentations that involved placental insufficiency. Walker et al1 evoked a possible etiologic role for heightened maternal systemic inflammation, especially in association with maternal metabolic dysregulation, maternal infections, or autoimmune diseases. (Reprinted) JAMA Pediatrics June 2015 Volume 169, Number 6

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