A Review of Cardiovascular Health and Factors Influencing Assisted Reproductive Technology (ART) Offspring
Background and Importance
Assisted Reproductive Technology (ART) has provided fertility hope to infertile families worldwide, but there is growing concern about the long-term health of its offspring. Available evidence suggests that there is some variation in cardiovascular developmental markers in ART offspring, which may be associated with epigenetic mechanisms, technology manipulation, and environmental factors. This article systematically reviews the current status of cardiovascular health of ART offspring, the influencing factors and potential mechanisms, aiming to provide a scientific basis for clinical optimization of ART technology and improvement of offspring health.
I. Markers of cardiovascular health in ART offspring
1. Blood pressure performance
Divergent findings: Most studies showed no significant difference in blood pressure between ART offspring in childhood and adolescence and offspring from natural pregnancy, but some found high blood pressure in infancy and early childhood, which may be related to ovarian stimulation or embryo culture techniques.
LONG-TERM TRENDS: Differences tend to disappear with age; data for adulthood remain to be added.
Clinical significance: no pathological associations such as carotid intima-media thickening in ART offspring have been observed.
2. Cardiac Structure and Function
Early differences: ART fetuses and children show subclinical changes such as enlargement of the right ventricle, increased left ventricular mass, and decreased ejection fraction, but do not reach the diagnostic threshold for disease.
ENVIRONMENTAL SENSITIVITY: High altitude exposure may amplify the risk of abnormal right heart function.
LONG-TERM SAFETY: Resting cardiac function in adolescence is comparable to that of naturally conceived offspring, and there is no significant elevation in the incidence of cardiovascular events.
3. Vascular Health
Endothelial function and stiffness: Some studies have shown reduced vascular endothelial function (FMD) and increased arterial stiffness (PWV) in children with ART, but the differences are not significant in adulthood.
II. Influencing factors and mechanisms
1. Influence of ART technical operation
Superovulation (COS):
Animal models show abnormal maternal gene imprinting and elevated blood pressure in offspring, but human studies suggest that low parental fertility may be the primary cause.
Ovarian hyperstimulation syndrome (OHSS) is associated with abnormal vascular function in the offspring.
Embryo culture conditions:
The in vitro culture environment may interfere with epigenetic reprogramming (e.g., eNOS gene methylation) through oxidative stress, leading to vascular dysfunction.
Medium composition (e.g., G5 vs. HTF) affects embryo metabolism and birth outcomes.
Frozen Embryo Transfer (FET):
Reduces the effects of ovarian stimulation, but hormone replacement cycles increase the risk of preeclampsia and greater-than-gestational-age (LGA) infants, indirectly affecting cardiovascular health.
Intracytoplasmic single sperm injection (ICSI):
Invasive procedure may increase risk of embryonic aneuploidy, transient elevation of blood pressure in childhood.
2. Parental and intrauterine environmental factors
Parental fertility and age: high blood pressure in offspring of low-fertility couples, increased risk of transmission of epigenetic abnormalities in parents of advanced age.
Pregnancy complications: preeclampsia, preterm labor, and abnormal birth weight (SGA/LGA) independently increase the risk of CVD in the offspring.
Nutrition and stress: low-protein diet or mental stress during pregnancy affects vascular development through epigenetic mechanisms.
3. Growth patterns and epigenetic inheritance
Catch-up growth: rapid postnatal growth in ART offspring may be associated with elevated blood pressure and decreased endothelial function in childhood.
Epigenetic timeliness: ART-associated DNA methylation differences disappear in adulthood, but transient abnormalities during the developmental window may leave long-term effects.
Future Research Directions
Long-term cohort study: Extended follow-up into adulthood is needed to clarify the clinical significance of blood pressure and vascular index variations.
Optimization of technology: Developing low oxygen pressure culture system, improving the composition of culture medium, and reducing the damage of embryo manipulation.
Mechanism exploration: Combining multi-omics techniques (e.g. epigenome, metabolome) to analyze ART-specific risk pathways.
Personalized intervention: Reversal of potential CVD risk through lifestyle modification (e.g., antioxidant supplementation).
Conclusion
Available evidence suggests subclinical variability in cardiovascular health markers in ART offspring that has not yet translated into significant disease burden. The interaction of technical manipulation, parental factors, and the intrauterine environment influences developmental trajectories through epigenetic mechanisms. Future interdisciplinary collaboration is needed to optimize the ART process and establish a global birth cohort to accurately assess long-term risk.