STUDY QUESTION Do 8- to 9-year-old singletons conceived after frozen embryo transfer (FET) or fresh embryo transfer (Fresh-ET) have increased arterial stiffness compared to naturally conceived (NC) children? SUMMARY ANSWER The process of FET or Fresh-ET is not associated with altered cardiovascular function in 8- to 9-year-old singletons, including arterial stiffness, as compared to NC children. WHAT IS KNOWN ALREADY ART has been suggested to influence cardiovascular risk factors (i.e. endothelial dysfunction, increased arterial blood pressure and insulin resistance). It is not known if ART procedures alter arterial stiffness in singletons. STUDY DESIGN, SIZE, DURATION A cohort study was carried out, including 8- to 9-year-old singletons conceived after FET, Fresh-ET and NC children (50 children in each group). This study was conducted between November 2018 and August 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 150 singletons were identified through the Danish IVF Registry and the Medical Birth Registry. They underwent cardiac magnetic resonance imaging (CMR) and anthropometric measurements. Parental data were collected using questionnaires. NC children were matched by sex and birth year with FET/Fresh-ET children. Exclusion criteria were congenital heart disease, maternal gestational diabetes or maternal diabetes mellitus. Our primary outcome was arterial stiffness, which is assessed from noninvasive arterial blood pressure and aortic ascendens distensibility. The secondary outcome was the pulse wave velocity of total aorta and exploratory outcomes were left ventricular ejection fraction, mean arterial pressure, cardiac output and total peripheral resistance. Measurements and analyses were performed blinded to the child group. MAIN RESULTS AND THE ROLE OF CHANCE Aortic ascendens distensibility of children conceived after FET and Fresh-ET did not differ from NC children (mean (SD): FET 11.1 (3.6) 10−3 mmHg−1, Fresh-ET 11.8 (3.0) 10−3 mmHg−1, NC 11.4 (2.8) 10−3 mmHg−1, P > 0.05). Multivariate linear regression was performed to adjust for potential confounders (i.e. child sex and age, maternal BMI at early pregnancy and maternal educational level). Data showed no statistically significant differences between study groups and aortic ascendens distensibility. However, the fully adjusted model showed a non-significant tendency of lowered aortic ascendens distensibility in children born after FET compared to Fresh-ET (β estimate (95% CI): −0.99 10−3 mmHg−1 (−2.20; 0.21)) and NC children (β estimate (95% CI): −0.77 10−3 mmHg−1 (−1.98; 0.44)). Lastly, secondary and exploratory outcomes did not differ between the groups. Primary and secondary outcomes showed good intra-rater reliability. LIMITATIONS, REASONS FOR CAUTION This study is possibly limited by potential selection bias as the participation rate was higher in the ART compared to the NC group. Also, in some variables, the study groups differed slightly from the non-participant population. The non-participant population (n = 1770) included those who were excluded, not invited to CMR scan, or declined to participate in this study. WIDER IMPLICATIONS OF THE FINDINGS Our findings indicate that children born after FET or Fresh-ET do not have altered cardiovascular function, including arterial stiffness. This is reassuring for the future use of ART. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Novo Nordisk Foundation (grant reference number: NNF19OC0054340) and The Research Foundation of Rigshospitalet. All authors declared no conflict of interests. TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier: NCT03719703.
STUDY QUESTION Does BMI at 7–10 years of age differ in children conceived after frozen embryo transfer (FET) compared to children conceived after fresh embryo transfer (fresh-ET) or natural conception (NC)? SUMMARY ANSWER BMI in childhood does not differ between children conceived after FET compared to children conceived after fresh-ET or NC. WHAT IS KNOWN ALREADY High childhood BMI is strongly associated with obesity and cardiometabolic disease and mortality in adulthood. Children conceived after FET have a higher risk of being born large for gestational age (LGA) than children conceived after NC. It is well-documented that being born LGA is associated with an increased risk of obesity in childhood, and it has been hypothesized that ART induces epigenetic variations around fertilization, implantation, and early embryonic stages, which influence fetal size at birth as well as BMI and health later in life. STUDY DESIGN, SIZE, DURATION The study ‘Health in Childhood following Assisted Reproductive Technology’ (HiCART) is a large retrospective cohort study with 606 singletons aged 7–10 years divided into three groups according to mode of conception: FET (n = 200), fresh-ET (n = 203), and NC (n = 203). All children were born in Eastern Denmark from 2009 to 2013 and the study was conducted from January 2019 to September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS We anticipated that the participation rate would differ between the three study groups owing to variation in the motivation to engage. To reach the goal of 200 children in each group, we invited 478 in the FET-group, 661 in the fresh-ET-group, and 1175 in the NC-group. The children underwent clinical examinations including anthropometric measurements, whole-body dual-energy x-ray absorptiometry-scan, and pubertal staging. Standard deviation scores (SDS) were calculated for all anthropometric measurements using Danish reference values. Parents completed a questionnaire regarding the pregnancy and the current health of the child and themselves. Maternal, obstetric, and neonatal data were obtained from the Danish IVF Registry and Danish Medical Birth Registry. MAIN RESULTS AND THE ROLE OF CHANCE As expected, children conceived after FET had a significantly higher birthweight (SDS) compared to both children born after fresh-ET (mean difference 0.42, 95% CI (0.21; 0.62)) and NC (mean difference 0.35, 95% CI (0.14; 0.57)). At follow-up (7–10 years), no differences were found in BMI (SDS) comparing FET to fresh-ET, FET to NC, and fresh-ET to NC. Similar results were also found regarding the secondary outcomes weight (SDS), height (SDS), sitting height, waist circumference, hip circumference, fat, and fat percentage. In the multivariate linear regression analyses, the effect of mode of conception remained non-significant after adjusting for multiple confounders. When stratified on sex, weight (SDS), and height (SDS) were significantly higher for girls born after FET compared to girls born after NC. Further, FET-girls also had significantly higher waist, hip, and fat measurements compared to girls born after fresh-ET. However, for the boys the differences remained insignificant after confounder adjustment. LIMITATIONS, REASONS FOR CAUTION The sample size was decided in order to detect a difference of 0.3 SDS in childhood BMI (which corresponds to an adult cardiovascular mortality hazard ratio of 1.034). Thus, smaller differences in BMI SDS may be overlooked. As the overall participation rate was 26% (FET: 41%, fresh-ET: 31%, NC: 18%), selection bias cannot be excluded. Regarding the three study groups, many possible confounders have been included but there might be a small risk of selection bias as information regarding cause of infertility is not available in this study. WIDER IMPLICATIONS OF THE FINDINGS The increased birthweight in children conceived after FET did not translate into differences in BMI, however, for the girls born after FET, we observed increased height (SDS) and weight (SDS) compared to the girls born after NC, while for the boys the results remained insignificant after confounder adjustment. Since body composition in childhood is a strong biomarker of cardiometabolic disease later in life, longitudinal studies of girls and boys born after FET are needed. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Research Foundation. There were no competing interests. TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier: NCT03719703.
Windkessel function is governed by conductance artery compliance that is associated with cardiovascular disease in adults independently of other risk factors. Sex-related differences in conductance artery compliance partly explain the sex-related differences in risk of cardiovascular disease. Studies on sex-related differences in conductance artery function in prepubertal children are few and inconclusive. This study determined conductance artery compliance and cardiac function by magnetic resonance imaging in 150 healthy children (75 girls) aged 7-10 years. Any sex-related difference in conductance artery function was determined with correction for other potential predictors in multivariable linear regression models. Our data showed that ascending (crude mean difference 1.11 95% CI (0.22; 2.01)) and descending (crude mean difference 1.10 95% CI (0.09; 1.91)) aortic distensibility were higher in girls, but differences disappeared after adjustment for pubertal status and other identified potential predictors. Systolic and diastolic blood pressure, cardiac output, left ventricle (LV) systolic function, and total peripheral resistance did not differ between the sexes. In girls, heart rate was 7 bpm higher, whereas pulse pressure (by 2 mmHg), and LV end-diastolic volume index (by 7 mL) and stroke volume (by 5 mL) were lower. LV peak filling rate indexed to LV end-diastolic volume was 0.5 s-1 higher in girls. In conclusion, prepubertal girls and boys have equal conductance artery function. Thus, the well-known sex difference in adult conductance artery function seems to develop after the onset of puberty with girls initially increasing aortic distensibility.
Study question Is cardiometabolic health in children conceived after frozen embryo transfer (FET) different from children conceived after fresh embryo transfer (fresh-ET) and natural conception (NC)? Summary answer FET-children had similar anthropometrics, glucose- and lipid profile in childhood compared to fresh-ET and NC. Blood pressure was higher in FET-girls compared to fresh-ET-girls. What is known already Children conceived after assisted reproductive technology (ART) with FET are more often born large-for-gestational age (LGA) while children born after fresh-ET are at risk of being small-for-gestational age (SGA).In general, children born LGA or SGA are at increased risk of obesity, diabetes and cardiovascular disease later in life. Smaller studies on the whole ART-population have raised concerns about premature vascular aging, increased risk of insulin resistance and higher blood pressure. The long-term cardiometabolic health of children born after ART and especially FET is scarcely explored. Study design, size, duration This study was part of the large cohort study “Health in Childhood following Assisted Reproductive Technology” (HiCART) which included 606 singletons (292 boys) born between December 2009 and December 2013: 200 children were conceived after FET; 203 children were conceived after fresh-ET; and 203 children were conceived naturally and matched for birth year and sex. The study period lastet from January 2019 to September 2021. Participants/materials, setting, methods The children were 7-10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging and blood pressure measurement. Furthermore a whole-body dual-energy x-ray absorptiometry-scan (DXA) was performed and a fasting blood sample was drawn. Anthropometric measurements and blood pressure were converted to standard deviation scores (SDS) using a Danish reference. The three study groups were compared pairwise using univariate linear regression model. Main results and the role of chance Data is presented as mean (SD). Children conceived after FET had significantly higher birth weight (SDS) (0.20 SDS (1.09)) compared to children conceived after fresh-ET (-0.22 SDS (1.00), mean difference: 0.42 SDS (95% CI: 0.21; 0.62)) and NC-children (-0.16 SDS (1.09), mean difference: 0.35 SDS (95% CI: 0.14; 0.57)). At 7-10 years height (SDS), weight (SDS) and BMI (SDS) were similar between the groups. Fat percentage (DXA) and waist-to-height ratio were also comparable between the groups. Markers of glucose metabolism were similar in the groups including fasting glucose, C-peptide, HbA1c and insulin resistance (HOMA-IR). Lipid profiles including, cholesterol, LDL and HDL were also similar. Blood pressure was comparable between the three groups, but stratified on sex girls conceived after FET had significantly higher systolic blood pressure (SDS) (0.75 SDS (0.84)) compared to girls concieved after fresh-ET (0.49 SDS (0.61), mean difference: 0.25 SDS (95% CI: 0.05; 0.45)) and significantly higher diastolic blood pressure (SDS) (FET: 0.54 SDS (0.57), fresh-ET: 0.38 (0.58), mean difference: 0.16 SDS (0.00; 0.31)). Puberty had started in 17% of the girls, equally distributed in the three groups. Limitations, reasons for caution As the participation rate was between 18-42% in the three groups, selection bias cannot be excluded. We currently do not have information regarding endometrial preparation protocol in the FET-cycles which may bias the results. Due to multiple testing type I errors cannot be excluded. Wider implications of the findings Higher birth weight in children conceived after FET did not translate into differences in anthropometrics, glucose- or lipid profile in children ages 7-10 years. However, the higher systolic- and diastolic blood pressure (SDS) found in girls concieved after FET compared to fresh-ET is of concern and should be further explored. Trial registration number NNF18OC0034092, NFF19OC0054340
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
Study question Is BMI in children conceived after frozen embryo transfer different from children conceived after fresh embryo transfer and after natural conception? Summary answer BMI in children conceived after frozen embryo transfer was similar to BMI in children conceived after fresh embryo transfer or children born after natural conception. What is known already Children conceived after frozen embryo transfer (FET) have higher risk of being born large for gestational age (LGA) than children conceived after natural conception (NC). Generally, being born LGA increases the risk of obesity in childhood. Childhood BMI is strongly associated with obesity and cardiometabolic disease and mortality in adulthood. The long-term effects of ART on the metabolic health of the offspring and the underlying mechanisms are scarcely explored. However, it has been proposed that ART may induce epigenetic variations around fertilization, implantation, and early embryonic stages that may influence size at birth. Study design, size, duration The study “Health in Childhood following Assisted Reproductive Technology” (HiCART) includes 606 singletons (292 boys, 314 girls) – 200 conceived after FET; 203 after fresh-ET; and a random sample of 203 naturally conceived children matched for age and sex. All children were born in Eastern Denmark from 2009-2013 and had a clinical examination performed at the Copenhagen University Hospital - Rigshospitalet when they were 6-9 years of age. Participants/materials, setting, methods The children underwent a clinical examination with anthropometric measurements, whole-body dual-energy x-ray absorptiometry-scan (DXA), pubertal staging, and a blood sample. All anthropometric measurements were converted to standard deviation scores (SDS) using a Danish reference. Parents filled in a questionnaire regarding the pregnancy and the current health of the child and themselves. Maternal, obstetric and neonatal data from the national ART and birth registry were obtained. Main results and the role of chance Children conceived after FET had higher birthweight SDS (0.20SDS, 1.09SD) than children conceived after fresh-ET (-0.22SDS, 1.00SD), p < 0.001 and children conceived naturally (-0.16SDS, 1.09SD), p = 0.001. Mothers conceiving naturally were younger and had higher parity than mothers conceiving after ART. The three groups were similar regarding pregestational maternal BMI and gestational age. Puberty had started in 57 children (54 girls), evenly distributed among the groups. There were no differences in height SDS between FET (0.25SDS, 1.00SD) compared to fresh-ET (0.17SDS, 0.96SD), p = 0.50 and compared to NC (0.07 SDS, 1.06SD), p = 0.11 or in weight SDS between FET (0.22SDS, 1.07SD) compared to fresh-ET (0.10 SDS, 1.06SD), p = 0.22 and compared to NC (0.14SDS, 1.00SD), p = 0.43. Similarly, no differences were found in BMI SDS between FET (0.16SDS, 1.16SD) compared to fresh-ET (0.04SDS, 1.10SD), p = 0.25 and compared to NC (0.20SDS, 1.01SD), p = 0.80. Our primary endpoint BMI SDS remained non-significant after adjustment for child sex, age and birthweight SDS, parity, maternal BMI and smoking in pregnancy. Limitations, reasons for caution The sample size was decided to be able to detect a difference of 0.3 SDS in childhood BMI, corresponding to a 3.4% increased mortality hazard. Thus, smaller differences in BMI SDS may be overlooked. As the participation rate was between 18-42% in the three groups, selection bias cannot be excluded. Wider implications of the findings The increased birth weight in children conceived after FET did not translate into a difference in BMI in this large cohort. Since BMI in childhood is a strong biomarker of cardiometabolic disease later in life, the findings are reassuring and may reduce concerns associated with the long-term consequences of FET. Trial registration number NCT03719703
Study question Do children conceived after assisted reproductive technologies (ART) with frozen or fresh embryo transfer have altered cardiovascular autonomic nervous function compared to naturally conceived children? Summary answer Cardiovascular autonomic nervous function was comparable in singletons conceived after ART with frozen or fresh embryo transfer, and naturally conceived children. What is known already Cardiovascular autonomic nervous function (CANF) exert important homeostatic mechanisms to prevent major arterial blood pressure fluctuations by adjusting heart rate, cardiac contractility, and peripheral vascular tone. CANF is impaired in children with obesity and diabetes mellitus, and conductance artery stiffness is documented to influence CANF. Previous studies have reported that children conceived after ART are at risk of increased carotid intima-media thickness; insulin resistance; arterial stiffness; and hypertension. This is the first study to investigate CANF in children conceived after ART. Study design, size, duration CANF was studied in 110 singletons aged 7-12 years conceived after frozen embryo transfer (FET, N = 35), fresh embryo transfer (fresh-ET, N = 39) or natural conception (NC, N = 36). Children were born between 2009 and 2013. This study was conducted between June 2019 and October 2021. Participants/materials, setting, methods Participants were identified through the Danish IVF and Medical Birth Registries. CANF was evaluated by heart rate (HR) changes (ratio to rest) during deep breathing; Valsalva; and active stand test with continuous non-invasive hemodynamic measurements. Anthropometric measures, fasting blood samples, and maternal questionnaires were collected. Neonatal and maternal pregnancy data were collected from the Medical Birth Registry. Children with a history of congenital heart disease or mothers with gestational diabetes or diabetes mellitus were excluded. Main results and the role of chance A total of 110 singletons with a median age of 9.0 years were included in this study. We found no significant associations between conception method and our measures of CANF. For FET, fresh-ET, and NC, respectively, the HR-ratio for deep breathing was 1.62 (0.2 SD), 1.62 (0.16) and 1.63 (0.17) (ANOVA-P = 0.97). For Valsalva, the HR-ratio was 1.97 (0.4), 1.88 (0.41) and 1.63 (0.17), respectively (ANOVA-P = 0.24). For the active stand test, the HR-ratio was 1.43 (0.17), 1.41 (0.2) and 1.43 (0.19), respectively (ANOVA-P = 0.91). Associations remained non-significant after adjustment for age, sex, body surface area, body mass index, and mean arterial pressure. In the multivariate analysis, several other factors were significantly associated with HR-ratio for deep breathing: age (β = -0.06, P = 0.03), body surface area (β = 0.79, P = 0.01), body mass index (β = -0.03, P = 0.04), and mean arterial pressure (β =-0.01, P = 0.03), but not with other measures of CANF. All data for CANF were within reference limits. Also, mothers in the ART groups were older at childbirth than NC group as expected. No significant differences were observed in clinical characteristics, including neonatal and other maternal data. Limitations, reasons for caution This study is limited by its observational design to draw any firm conclusion on causality. Also, it is a limitation that the pubertal status was not systematically assessed as pubertal hormones may play a role in CANF. Wider implications of the findings This study contributes to the current knowledge about cardiovascular health risks in ART children. Reassuringly, this study found that children conceived after ART (frozen or fresh-ET) did not exhibit impaired cardiovascular autonomic nervous function compared to naturally conceived children. Trial registration number NCT03719703
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