Ultrasound evaluation of the cardiovascular system in offspring conceived through assisted reproductive technology

Abstract

With the widespread application of assisted reproductive technology, the health issues of offspring conceived through assisted reproductive technology have also received increasing attention. Animal experiments and clinical studies have found subclinical adverse changes in the cardiovascular system of assisted reproductive offspring. Assisted reproductive technology itself may be just one of the many factors contributing to this phenomenon, with epigenetics playing an important role. Ultrasound technology can be used to assess the morphological structure and function of the cardiovascular system in assisted reproductive offspring from the fetal stage, providing the possibility to study the potential cardiovascular damage in this large population. This review aims to explore the effects and mechanisms of assisted reproductive technology on the cardiovascular system of offspring and provide a review of the research progress in ultrasound technology in this area.

Introduction

Assisted reproductive technology (ART) encompasses all interventions involving the manipulation of human oocytes, sperm, or embryos outside the body to facilitate reproduction. This includes, but is not limited to, procedures such as artificial insemination (AI), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and embryo transfer (ET) [1]. Currently, there are over 7 million children worldwide who have been born through assisted reproductive techniques [2]. Despite the considerable advancement of ART, the health of children conceived through these techniques remains a global concern [3].

Epidemiological, clinical, and basic research evidence suggests that the maternal physiological status, diet, and lifestyle during pregnancy can influence the long-term health of offspring and increase the risk of certain diseases in adulthood. Based on this, scholars have proposed the concept of “Developmental Origins of Health and Disease” [4] which suggests that adverse environmental factors during fetal development can increase the risk of cardiovascular and metabolic diseases, cancer, and neurological impairments in offspring. ART involves direct manipulation of mature gametes and early-stage embryos [4], as well as physiological changes in the mother due to assisted reproductive techniques, such as significant hormonal fluctuations caused by ovarian stimulation [5]. Therefore, it may have an impact on the health of offspring. Current research has shown that compared to spontaneously conceived children, children conceived through ART have an increased risk of adverse perinatal outcomes, birth defects, developmental disorders, epigenetic changes, and childhood cancer [6]. In addition, the impact of ART on the cardiovascular system is also a research focus, and an increasing number of studies have found subclinical adverse changes in the cardiovascular system of ART-conceived offspring [7]. Ultrasound technology can qualitatively and quantitatively assess the structure, function, and hemodynamics of the heart, large and medium-sized blood vessels. It has the advantages of being non-invasive and cost-effective. Currently, various imaging techniques such as two-dimensional, M-mode, Doppler flow, and tissue Doppler are available. Ultrasound examination plays an important role in the diagnosis and evaluation of cardiovascular diseases and can facilitate early detection and prediction of cardiovascular diseases [8]. This provides the possibility to investigate the changes in the cardiovascular system of the relatively young population of ART-conceived offspring. This review aims to explore the effects and mechanisms of ART on the cardiovascular system of offspring and provide an overview of the research progress in ultrasound technology in this field.

Factors and mechanisms of cardiovascular damage in offspring conceived through ART

Previous studies found that fetuses and children conceived by ART performed cardiovascular remodeling and suboptimal function [3]. Cardiac impairments primarily manifest as more globular hearts, dilated cardiac chambers, reduced systolic motion, and relaxation [5]. Vascular impairments are mainly characterized by endothelial dysfunction, increased stiffness, and intima-media thickness (IMT), indicating an increased risk of atherosclerosis [9] (Fig. 1). Currently, several potential factors that may affect the health of ART-conceived offspring have been proposed by researchers, including parental factors, infertility factors, pregnancy complications, preterm birth, embryo culture conditions, and laboratory techniques [3]. The main challenge in clinical research lies in distinguishing whether the effects on the health of offspring are caused by ART or by infertility itself [3]. Animal experiments have suggested that ART itself has an impact on the offspring’s cardiovascular system, which may be related to environmental stimuli during zygote culture in vitro [10, 11]. An increasing body of research has revealed the significant role of epigenetic changes induced by these factors in the reprogramming of fetal phenotypes [3]. Epigenetic reprogramming occurs during germ cell development and early embryo development and is essential for normal fertilization and embryonic growth [12]. ART involves direct manipulation of gametes and early-stage embryos, including ovarian stimulation, exposure of gametes and embryos to the external environment, composition of culture media used during in vitro culture, variations in temperature, pH, and oxygen pressure, as well as the process of embryo cryopreservation and thawing [13]. These interventions may adversely affect the process of epigenetic reprogramming [14]. Animal experiments have revealed the role of epigenetics in the cardiovascular system damage of ART offspring, including that ART may impact the DNA methylation of the endothelial nitric oxide synthase (eNOS) gene promoter [10], hypomethylation of the angiotensin type 1 receptor gene promoter [15], and the gene expression patterns in the hearts [16].

Fig. 1.

Summary of the main content of the review. Ultrasound manifestations of cardiovascular changes in offspring conceived through assisted reproductive technology

Ultrasound evaluation of vascular changes in ART-conceived offspring

Ultrasound examination can be used for quantitative evaluation of vascular structure, endothelial function, and stiffness. Carotid intima-media thickness is commonly used to assess structural changes in the systemic vasculature and serves as an indicator for early detection of atherosclerosis and prediction of its progression [17]. Brachial artery flow-mediated vasodilation (FMD) is significantly correlated with endothelial function, and it demonstrates excellent effectiveness and accuracy in assessing endothelial function [18]. Carotid-femoral pulse wave velocity (PWV) has significant predictive value for cardiovascular events and serves as a gold standard for evaluating vascular stiffness [19].

Ultrasound evaluation of the vasculature in ART-conceived offspring primarily focuses on the postnatal period. In terms of vascular structure, Valenzuela-Alcaraz et al. [20] conducted a study on infants at 6 months of age and found that ART-conceived infants had increased carotid intima-media thickness compared to spontaneously conceived infants. Scherrer et al. [21] and Meister et al. [22] also observed an increased carotid intima-media thickness in ART-conceived children (11 years old on average) and adolescents (17 years old on average), respectively. with an average age of 11 years. In terms of vascular function, Scherrer et al. [21] found a lower brachial artery flow-mediated vasodilation and an accelerated carotid-femoral pulse wave velocity in ART-conceived children with an average age of 11 years. Similar results were obtained in ART-conceived adolescents with an average age of 17 years by Meister et al. [22] as well. These findings indicate that ART-conceived offspring experience decreased vascular endothelial function, increased stiffness, and structural changes in the vasculature. These changes partially explain the elevated systemic and pulmonary circulation pressures observed in ART-conceived offspring and suggest premature vascular aging in this population. Previous studies have indicated that ART-conceived offspring may experience early-onset atherosclerosis [21, 22]. Additionally, research has found that compared to spontaneously conceived children, 5-year-old children born through intracytoplasmic sperm injection have a significantly reduced number of retinal vascular branching points [23]. Current evidence suggests that retinal vascular changes are closely related to the extent of vascular changes in organs such as the coronary arteries and kidneys, and a lower number of branching points may indicate an increased risk of vascular disease in adulthood [24].

However, there are studies suggesting a comparable vascular status of ART offspring. Langer et al. [25] found no differences concerning circumferential strain, strain rate, and arterial distensibility of ART and SC children and adolescents with an average age of 11 years, using two-dimensional speckle tracking. Subsequent studies also did not find any differences in carotid artery intima-media thickness [26]. Halliday et al. [27] did not observe any differences in carotid artery intima-media thickness and pulse wave velocity between ART and SC adults with an age of 22–35 years. The discrepancies of research findings suggest that adverse vascular changes in ART offspring may be transient, and future studies on long-term vascular health are of great importance.

In addition to assessing the vasculature, transthoracic echocardiography can non-invasively evaluate pulmonary artery pressure. One method involves measuring the peak velocity of tricuspid regurgitation using continuous-wave Doppler and then calculating the pressure gradient between the right ventricle and right atrium using the modified Bernoulli equation. This approach is one of the standard non-invasive methods for estimating pulmonary artery pressure [21]. Scherrer et al. [21] employed this method to assess pulmonary artery pressure in children conceived spontaneously and through ART under high-altitude conditions. They found that the pulmonary artery pressure in ART-conceived children was 30% higher than in the control group.

Echocardiographic assessment of cardiac changes in offspring conceived through ART

Assessment of cardiac structure

Follow-up studies by Valenzuela-Alcaraz et al. [20] have revealed structural changes in the ART-conceived offspring observed through two-dimensional echocardiography. Compared to the control group, ART-conceived fetuses showed smaller left and right ventricular spheric indices, larger atrial areas, and thicker free walls and septa. Follow-up studies by Bi et al. [28] also found a reduced mid-segment sphere index of the left ventricle in ART-conceived fetuses, along with increased left and right ventricular areas. Due to a higher incidence of small-for-gestational-age (SGA) in ART pregnancies [29], Valenzuela-Alcaraz et al. [29] compared ART-conceived fetuses with SGA fetuses. They found that ART-conceived fetuses exhibited increased atrial area, while SGA fetuses showed increased cardiothoracic ratio. ART-conceived SGA infants displayed cardiac changes with characteristics of both groups mentioned above.

After birth, Bi et al. [28] found that only slight changes in the right ventricular wall were observed at 2 months of age, and no structural changes were observed in the infants at 6 months of age. However, Valenzuela-Alcaraz et al. [20] found an enlarged right atrium, decreased right ventricular spheric index, and increased thickness of the right ventricular free wall in ART infants at 6 months of age. These structural changes, including right atrial enlargement and decreased left and right ventricular spheric indices, persisted at 3 years of age [30]. Liu et al. [31] found decreased left and right ventricular sphere indices in 5-year-old children but did not observe an increase in atrial area. Sciuk et al. [32], using M-mode echocardiography, measured the left ventricular dimensions at end-systole and end-diastole in ART-conceived children with an average age of 13, with the mitral valve tip as a horizontal reference point on the parasternal long-axis view. They did not find any differences in the interventricular septum, left ventricular posterior wall, or left ventricular internal dimensions. Cardiac structure evaluation of ART offspring is summarized in Table 1.

Table 1.

Cardiovascular manifestations of ART fetus and offspring

Study	Subjects	Method	Sample size	Main findings (ART vs. SC)	Embryo type	Main findings (fresh ET vs. FET)
Boutet, 2021 [5]	Fetus	2D, M-mode, Doppler	100 fresh ET vs. 100 FET vs. 100 SC	Cardiac morphology: more globular ventricles, thicker myocardial walls, larger atria Cardiac function: suboptimal systolic and diastolic function	Fresh and frozen (programmed cycle)	Cardiac changes of fresh ET were more pronounced
Huluta, 2023 [47]	Fetus	2D, M-mode, Doppler	343 ART vs. 5458 SC, 112 fresh ET vs. 231 FET	Cardiac morphology: more globular ventricles Cardiac function: reduced LV systolic function	Fresh and frozen	Comparable
Valenzuela-Alcaraz, 2013 [20]	Fetus	2D, M-mode, Doppler	100 ART vs. 100 SC	Cardiac morphology: more globular heart, thicker myocardial walls, dilated atria Cardiac function: decreased longitudinal function, impaired relaxation	Not applicable	Not applicable
	Infant (6 months)			Cardiac morphology and function changes were similar to fetus Vascular changes: increased aortic intima-media thickness	Not applicable	Not applicable
Bi, 2022 [28]	Fetus	2D, M-mode, Doppler, 2D STE	88 ART vs. 85 SC, 21 fresh ET vs. 67 FET	Cardiac morphology: more globular LV, dilated LV and RV Cardiac function: decreased LV systolic deformation	Fresh and frozen	Comparable
	Infant (0–2 months)		37 ART vs. 44 SC	Comparable	Not applicable	Not applicable
	Infant (6 months)		41 ART vs. 45 SC	Comparable	Not applicable	Not applicable
Valenzuela-Alcaraz, 2019 [30]	Child (3 years)	2D, M-mode, Doppler	80 ART vs. 80 SC	Cardiac morphology: more globular ventricles, dilated atria Cardiac function: systolic dysfunction, diastolic dysfunction Vascular changes: increased aortic intima-media thickness	Not applicable	Not applicable
Liu, 2015 [31]	Child (5 years)	2D, M-mode, Doppler, 2D STE	100 ART vs. 100 SC	Cardiac morphology: comparable Cardiac function: systolic dysfunction, diastolic dysfunction	Not applicable	Not applicable
Mizrak, 2022 [51]	Child (8–9 years)	CMR	50 fresh ET vs. 50 FET vs. 50 SC	Comparable	Fresh and frozen	Comparable
Cui, 2021 [48]	Child (6–10 years)	2D, M-mode, Doppler	382 ART vs. 382 SC, 272 fresh ET vs. 107 FET	Cardiac morphology: increased LV mass index, increased relative wall thickness, increased prevalence of LV hypertrophy, high RWT and LV remodeling patterns Cardiac function: LV systolic and diastolic dysfunction	Fresh and frozen	Cardiac morphology: increased prevalence of LV hypertrophy, high RWT and LV remodeling patterns
Scherrer, 2012 [21]	Child (11 years on average)	FMD, cIMT, PWV	65 ART vs. 57 SC	Vascular changes: smaller brachial artery flow-mediated dilation, faster carotid-femoral pulse-wave velocity, increased carotid intima-media thickness	Not applicable	Not applicable
Langer, 2022 [25]	Child and adolescent (11 years of age on average)	2D ST	67 ART vs. 86 SC	Vascular changes: circumferential strain, strain rate, and arterial distensibility were comparable	Not applicable	Not applicable
Oberhoffer, 2023 [26]	Child and adolescent (11 years of age on average)	cIMT	66 ART vs. 86 SC	Vascular changes: carotid intima-media thickness was comparable	Not applicable	Not applicable
Sciuk, 2022 [32]	Child (13 years on average)	M-mode, Doppler	66 ART vs. 83 SC	Cardiac morphology: comparable Cardiac function: lower LV diastolic function, comparable when adjusted for age, birth weight percentile, and gestational age	Not applicable	Not applicable
Sciuk, 2023 [42]	Child (13 years of age on average)	M-mode, Doppler, 2D STE	64 ART vs. 83 SC	Cardiac morphology: comparable Cardiac function: lower LV diastolic function, comparable when adjusted for age, birth weight percentile, and gestational age	Not applicable	Not applicable
Meister, 2018 [22]	Adolescent (17 years on average)	FMD, cIMT, PWV	54 ART vs. 43 SC	Vascular changes: smaller brachial artery flow-mediated dilation, faster pulse-wave velocity, increased carotid intima-media thickness	Not applicable	Not applicable
Halliday, 2019 [27]	adults (22–35 years)	cIMT, PWV	193 ART vs. 86 SC	Vascular changes: carotid intima-media thickness and pulse wave velocity were comparable	Not applicable	Not applicable

ART assisted reproductive technology, SC spontaneously conceived, ET embryo transfer, FET frozen embryo transfer, LV left ventricle, RV right ventricle, 2D two dimension, 2D STE two-dimensional speckle tracking echocardiography, FMD flow-mediated vasodilation, cIMT carotid intima-media thickness, PWV pulse wave velocity, 2D ST two-dimensional speckle tracking, CMR cardiac magnetic resonance imaging

These studies indicate that cardiac remodeling in ART-conceived offspring is a different pattern from SGA. It begins during the fetal period and continues after birth. The inconsistent results of these studies can be explained by variations in the study population and differences in ART techniques, including ethnicity, preterm birth, birth weight, maternal age, embryo culture, and storage methods. Even with statistical corrections, the adjusted variables differed among the different studies.

Ultrasound examinations of ART-conceived fetuses are not only used to assess subclinical changes in cardiac structure. Previous studies have found an increased risk of congenital heart disease in ART-conceived fetuses compared to spontaneously conceived fetuses [33], and American Institute of Ultrasound in Medicine practice guideline has identified in vitro fertilization as a risk factor for congenital heart defects [34]. Authoritative organizations such as the American Heart Association also recommend fetal echocardiography for all pregnancies conceived through ART [35]. However, current practice guidelines have not reached a definitive consensus on whether ART should be considered an indication for fetal echocardiography [36]. Some studies have also suggested that routine fetal echocardiography screening in all IVF pregnancies provided limited utility without other known risk factors for congenital heart defects. Therefore, recommending fetal echocardiography for all ART pregnancies may not be necessary [37]. Some researchers recommended performing fetal echocardiography for ART pregnancies when the standard anatomic examination is unable to identify clinically relevant congenital heart defects or when ultrasound views of the fetal heart at the routine scan are suboptimal [38]. Currently, the most cost-effective approach is to perform fetal echocardiography after abnormal findings are detected during standardized obstetric ultrasound examinations, in order to diagnose and exclude congenital heart disease [36]. The recommendations for cardiac monitoring of ART group are summarized in Table 2.

Table 2.

Recommendations for cardiac monitoring of ART pregnancies and ART offspring

Study	Subjects	Main findings	Recommendations	Scan period
AIUM, 2020 [34]	ART fetus	ART were associated with an increased risk of CHD	Fetal echocardiography for CHD monitoring in ART pregnancies	Commonly 18–22 weeks of gestation
Bjorkman, 2021 [37]	ART fetus	The incidence of CHD in IVF pregnancies without other risk factors is similar to baseline population rates, and most CHDs diagnosed by fetal echocardiography in IVF pregnancies are clinically insignificant	Fetal echocardiography for CHD monitoring in ART pregnancies with other CHD risk factors
Chung, 2021 [36]	ART fetus	It costs society 5 times more to detect one additional major CHD through intensive screening of all IVF pregnancies than to pay for the neonate’s first year of care	Fetal echocardiography for CHD monitoring in ART pregnancies with abnormal cardiac findings at detailed anatomy scans
Donofrio, 2014 [39]	ART fetus	Infants conceived through IVF are in a higher risk of CHD	Fetal echocardiography for CHD monitoring in ART pregnancies	Generally 18 to 22 weeks of gestation
Kolibianakis, 2021 [38]	ART fetus	The referral of all ART pregnancies for fetal echocardiography is not cost-effective	Fetal echocardiography for CHD monitoring in ART pregnancies with other CHD risk factors, abnormal findings or suboptimal ultrasound views of the fetal heart at standardized obstetric ultrasound examinations	Second trimester, if necessary, third trimester to confirm or refute a suspected diagnosis
Scherrer, 2012 [21]	ART offspring	ART children who live at high altitude or suffer from diseases associated with chronic hypoxia are at risk for exaggerated pulmonary hypertension	Echocardiography for pulmonary hypertension monitoring in ART offspring who live at high altitude or suffer from diseases associated with chronic hypoxia
Sciuk, 2022 [32]	ART offspring	ART children born preterm might display an elevated risk of developing LV diastolic alterations	Echocardiography for cardiac function impairments monitoring in ART offspring born preterm

ART assisted reproductive technology, AIUM American Institute of Ultrasound in Medicine, CHD congenital heart defect, LV left ventricle, IVF in vitro fertilization

Evaluation of cardiac function

Currently, echocardiography offers various techniques for assessing cardiac systolic function, diastolic function, and overall function. M-mode echocardiography measures mitral and tricuspid annular plane systolic excursions, reflecting the longitudinal motion of the left and right ventricles, allowing for quantitative analysis of their systolic function. Pulse-wave Doppler can collect the diastolic flow spectra of the mitral and tricuspid valves to obtain parameters such as peak E and A velocities, E-wave deceleration time, and ventricular isovolumic relaxation time, evaluating ventricular diastolic function. Tissue Doppler imaging involves setting a sample volume to obtain tissue velocity spectra of specific myocardial regions, providing parameters such as systolic S’, early diastolic E’, and late diastolic A’ velocities and ventricular isovolumic relaxation time. This technique enables the evaluation of ventricular systolic and diastolic function and is widely used in the assessment of myocardial function disorders in children and adults. It also holds clinical value in the early detection of cardiac dysfunction [39]. Tissue Doppler imaging, in combination with blood flow Doppler parameters, allows for a comprehensive assessment of ventricular function. Previous studies have shown a significant correlation between the mitral E/E’ ratio and left ventricular diastolic function, which can be used to evaluate left ventricular filling pressure [40]. By measuring isovolumic relaxation time, isovolumic contraction time, and ejection time from Doppler spectral tracings, the myocardial performance index (MPI) can be calculated to assess the overall cardiac function.

Valenzuela-Alcaraz et al. [20] found that mitral and tricuspid annular plane systolic excursions and the E’ velocity were lower in ART-conceived fetuses compared to the control group. The E-wave deceleration time and left ventricular isovolumic relaxation time were longer in the ART group than in the control group. Similar changes were observed at 6 months [20] and 3 years of age [30], resembling the fetal period. Liu et al. [31] also discovered reduced mitral and tricuspid annular plane systolic excursions, increased mitral and tricuspid E/E’ ratios, and increased left and right ventricular myocardial performance index in 5-year-old children conceived through assisted reproduction. Sciuk et al. [32] analyzed left ventricular function in assisted reproductive children with an average age of 13 and found that left ventricular diastolic function was reduced compared to the control group. However, after adjusting for gestational age, the difference in left ventricular diastolic function between the two groups disappeared. Assisted reproductive children had significantly lower gestational age at birth, with an average gestational age of 36 weeks, indicating prematurity. This study suggests that the combination of assisted reproduction and prematurity may increase the risk of left ventricular diastolic abnormalities. These research findings suggest that changes in cardiac function in ART-conceived offspring are present during the fetal period and persist after birth.

In addition to the conventional techniques mentioned above, in recent years, studies have also used two-dimensional speckle tracking technology to evaluate cardiac function in ART-conceived offspring. Two-dimensional speckle tracking technology can track myocardial motion and obtain various parameters such as myocardial strain, enabling precise assessment of cardiac function. It has been used in the diagnosis and prognostic evaluation of various cardiac diseases [41]. Bi et al. [28] applied speckle tracking technology in the fetal period and found that assisted reproductive fetuses had reduced global longitudinal strain and strain rate in the left ventricle, consistent with the results of conventional ultrasound, demonstrating the value of this technology in the fetal period. Liu et al. [31] conducted a two-dimensional speckle tracking analysis of 5-year-old children and found that assisted reproductive children had lower longitudinal strain, longitudinal strain rate, radial strain, and radial strain rate compared to the control group. The results of functional assessment were consistent with the measurements from conventional echocardiography, demonstrating the value of this technology. Furthermore, Liu et al. [31] also discovered changes in ventricular torsion and conduction in assisted reproductive children using two-dimensional speckle tracking technology. Torsional motion was characterized by a gradual reduction in systolic endocardial rotation and apical rotation, resulting in decreased torsional velocity and torsional angle, as well as decreased diastolic untwisting velocity and untwisting rate. Conduction abnormalities were indicated by increased differences in peak times among myocardial segments. However, Sciuk et al. [42] did not find any alterations in myocardial strain in ART children with an average age of 13, using two-dimensional speckle tracking echocardiography. Cardiac function evaluation of ART offspring is summarized in Table 1.

The above research results indicate that cardiac remodeling and functional impairment in ART-conceived offspring occur in the fetal period and persist after birth. Additionally, the differences between the research results also suggest that ART is not the sole factor causing cardiac changes in offspring. When combined with certain adverse events such as being small for gestational age or premature birth, the risk of cardiac changes in the offspring increases.

Cardiac evaluation of offspring conceived through different ART

Regarding the differences in cardiac changes among offspring conceived through different ARTs, studies have compared frozen embryo transfer (FET) with fresh embryo transfer (ET). Boutet et al. [5] compared the cardiac changes in fetuses conceived through FET (programmed cycles) and fresh ET and found signs of cardiac remodeling and functional impairment in both group of fetuses, including larger atria, more globular ventricles, thicker myocardial walls, and suboptimal systolic and diastolic functions. However, the changes were more pronounced in the offspring conceived through fresh ET. One possible explanation is that during FET, the embryos undergo processes such as freezing and thawing, which can involve selection of embryos based on quality. However, direct confirmation of this hypothesis is still lacking in research. On the other hand, during fresh ET, the interval between embryo development and transfer is shorter, and the mother is in a stimulated hormonal state due to ovarian stimulation. In contrast, the condition of the mother during FET is more similar to natural conception [3]. In the opinion of some investigators, elevated estradiol levels induced by ovarian stimulation during fresh ET may cause abnormal endometrial angiogenesis, resulting in reduced implantation and abnormal placentation, which in turn can lead to low birth weight, small for gestational age, and pre-eclampsia [43]. Low birth weight, small for gestational age, and pre-eclampsia are factors associated with fetal cardiac remodeling [44]. And there have been animal experiments [45] and in vitro studies [46] to support this hypothesis. However, Huluta et al. [47] compared the cardiac function of mid-pregnancy fetuses conceived through fresh ET and FET and did not find significant differences, whereas Cui et al. [48] found cardiac remodeling and functional impairments in ART children aged 6 to 10 years, consistent with Boutet et al. [5]. Cardiac evaluation of fresh ET and FET offspring is summarized in Table 1. Although investigators have applied magnetic resonance imaging in the research of cardiovascular structure and function [49, 50], relevant studies on ART offspring are still limited. Mizrak et al. [51] compared cardiovascular function in 8–9-year-old children born through FET and fresh ET using cardiac magnetic resonance imaging and also did not find significant differences, including arterial stiffness, aortic pulse wave velocity, and left ventricular ejection fraction. The possible reasons for the discrepancies in the results of these studies are the differences in the specific protocols and procedures used for fresh and frozen embryo transfers [47]. Additionally, these studies did not specify the proportion of programmed cycles in their findings. Previous studies have indicated that compared to natural and stimulated frozen cycles, programmed frozen cycles had a higher risk of hypertensive disorders in pregnancy, postterm birth, and macrosomia [52], which could potentially influence the fetal cardiovascular parameters. In summary, compared to fresh ET, the cardiac changes in the offspring of FET may be milder. The differences in the incidence of cardiovascular diseases between the two groups of offspring still require further investigation.

Regarding the effects of different fertilization techniques on offspring, studies by Cui et al. [48] and Bi et al. [28] compared offspring conceived through in vitro fertilization with intracytoplasmic sperm injection and did not find differences in cardiac structure and function. In addition, research has compared children born through in vitro fertilization with intracytoplasmic sperm injection in terms of overall physical condition, growth and development, and risk of cancer, and no significant differences have been found [53].

Conclusion

In summary, ART procedures, such as suboptimal culture conditions, could lead to epigenetic alterations [10], which is an important reason for the cardiovascular impairment and increased cardiovascular risk of ART offspring. The prevalence of perinatal conditions known to increase cardiovascular morbidity and mortality is relatively high in ART group, which is the other reason. Currently, the research results regarding the impact of ART on the cardiovascular system of offspring are inconsistent. However, it can be concluded that when ART is combined with other adverse factors, including preeclampsia [9], preterm birth [54], and low birth weight [55], the risk of cardiovascular system impairment in offspring increases. Although studies have identified subclinical structural changes and functional impairments in the cardiovascular system during the fetal period and postnatally, there are also studies that have not found significant cardiovascular metabolic risks [51, 56]. These research findings to some extent alleviate concerns about the use of ART.

Overall, offspring conceived through ART represent a relatively young population. With the continuous advancement of ultrasound technology, researchers are able to assess various aspects of the cardiovascular system, such as structure and function, in this population. The non-invasive, cost-effective, and convenient nature of ultrasound evaluation enables the dynamic monitoring of cardiovascular health in this large population at an early stage of life. Although there are currently no guidelines, fetal echocardiography is recommended for ART pregnancies. The American Heart Association states that performing a fetal echocardiogram is reasonable in pregnancies resulting from assisted reproductive technologies [39]. According to the American Institute of Ultrasound in Medicine, fetal echocardiography is indicated if there is in vitro fertilization, including intracytoplasmic sperm injection [34]. Additionally, the American College of Obstetrics and Gynecology suggests that some professional organizations recommend fetal echocardiography in all ART pregnancies [35]. However, the incremental yield of such studies after reassuring targeted ultrasonography is unclear and should be balanced against available resources. Patient-specific risks identified during a patient’s medical evaluation may warrant the need for specific studies or other fetal assessments during pregnancy [35]. Limited recommendations have been proposed for ART offspring after birth. Scherrer et al. [21]. recommended echocardiography for pulmonary hypertension monitoring in ART offspring living at high altitudes or suffering from diseases associated with chronic hypoxia. Sciuk et al. [32] recommended echocardiography for monitoring cardiac function impairments in ART offspring born preterm. However, recommendations of studies above are simple, without more details to follow. Collectively, we suggest fetal echocardiography for ART pregnancies when necessary and additional cardiovascular ultrasound examinations during routine check-ups for ART offspring with other risk of cardiovascular diseases.

One limitation is that the current research endpoints only focus on subclinical changes in the structural and functional aspects of the cardiovascular system. The occurrence rate of cardiovascular diseases in offspring conceived through ART has not been fully determined. For future research, there are still several aspects to focus on. Firstly, clarify the long-term cardiovascular health of ART offspring and refine the guidelines for cardiovascular examinations of ART offspring. Secondly, identify the specific stages of the ART process that may cause cardiovascular system impairments and investigate the underlying mechanisms involved. Thirdly, explore approaches to prevent or restore cardiovascular impairments in ART offspring during in vitro, pregnancy, and after birth.

Author contribution

All authors contributed equally to this review paper.

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No funds, grants, or other support was received.

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Competing interests

The authors declare no competing interests.