Abstract
Study question
Do 8–9-year-old singletons conceived after frozen (FET) or fresh embryo transfer (Fresh ET) have increased vascular stiffness compared to naturally conceived (NC) children?
Summary answer
FET and Fresh ET was not associated with increased vascular stiffness or altered cardiovascular autonomic reflexes as compared to NC children.
What is known already
Normally, vascular stiffness increases during childhood, and in adults with the metabolic syndrome increased vascular stiffness is associated with symptomatic cardiovascular disease. Children conceived after FET and Fresh ET are at risk of being large- and small-for-gestational-age, respectively. Epigenetic modulation during assisted reproductive technologies (ART) has been suggested to influence cardiovascular risk factors, and previous studies have shown that children conceived after ART are at increased risk of insulin resistance, endothelial dysfunction and increased arterial blood pressure. It is not known if ART procedures alter vascular stiffness of children.
Study design, size, duration
In a cohort study including 8–9 years old singletons conceived after FET, Fresh ET and NC (50 in each group), we used cardiac magnetic resonance imaging (CMR) and cardiovascular autonomic reflex testing (CART) to compare arterial stiffness. The study was powered to detect a difference between groups of aortic distensibility from 8.9 to 8.0, comparable to what is seen in a 5-year older cohort of children (beta 0.80, alpha 0.05). Inclusion period 18 months.
Participants/materials, setting, methods
Singletons were identified through the Danish IVF Registry and the Medical Birth Registry. NC children were matched by sex and birth year with FET children. Exclusion criteria were congenital heart disease, maternal preeclampsia, gestational diabetes or diabetes mellitus. Artery stiffness was assessed from blood pressure and aortic distensibility, pulse wave velocity (PWV), cardiac output and total peripheral resistance by CMR. CART was investigated non-invasively in 40 children. Measurements were performed blinded to the child group.
Main results and the role of chance
Maternal age at delivery was higher in the FET (42.5±5.5 years) and Fresh ET (40.5±6.1 years) compared to the NC group (38.2±5.7 years). In the ART groups, mothers were more likely to have a high educational level (FET 50% and Fresh ET 56.2%) compared to mothers in the NC group (30.6%) (both ANOVA-p<0.05). As expected, children conceived after FET had a higher birth weight standard-deviation-score (0.4±1.1+) compared to Fresh ET (–0.1±1.0) and NC (–0.2±1.1). Among study groups, no significant differences were observed in systolic and diastolic blood pressure (FET 109±6/64±6 mmHg; Fresh ET 109±7/65±5 mmHg; NC 108±8/65±5 mmHg; ANOVA-p>0.05). Heart rate was also similar in all study groups (FET 79±12 bpm; Fresh ET 79±9 bpm; NC 78±11 bpm; ANOVA-p>0.05). No significant differences were observed between groups in total aortic PWV (FET 3.69±0.75 m/s; Fresh ET 3.49±0.31 m/s; NC 3.59±0.61 m/s; ANOVA-p>0.05). Aorta ascendens distensibility was similar in study groups (FET 11.12±3.55 10–3mmHg–1; Fresh ET 11.77±2.97 10–3mmHg–1; NC 11.43±2.82 10–3mmHg–1, ANOVA-p> 0.05). Furthermore, distensibility of aorta descendens and aorta abdominalis, PWV of arcus aorta and PWV from aorta descendens to abdominalis, cardiac output, total peripheral resistance and CART were similar in study groups. Outcome variables remained non-significant after adjustment for potential confounders.
Limitations, reasons for caution
The participation rate was higher in the ART groups (FET 40% and Fresh ET 32%) compared to NC (17%) and hence a selection bias is possible. Data from CART should be interpreted cautiously due to lower number of participating children in these tests.
Wider implications of the findings: Our study did not find any associations between FET or Fresh ET compared to NC children and arterial stiffness. Nor, any associations to CART could be made. Further studies are needed in younger adults to better exclude important long-term effects of ART.
Trial registration number
NCT03719703
