Blood pressure and lipid profiles in children born after ART with frozen embryo transfer
Authors: Asserhøj Louise Laub , Mizrak Ikram , Lebech Kjaer Anna Sophie , Clausen Tine Dalsgaard , Hoffmann Eva R , Greisen Gorm , Main Katharina M , Madsen Per Lav , Pinborg Anja , Jensen Rikke Beck 
Published: March 2024

Abstract

STUDY QUESTION
Are blood pressure (BP) and lipid profiles different between children conceived after ART with frozen embryo transfer (FET), fresh embryo transfer (fresh-ET), and natural conception (NC)?

SUMMARY ANSWER
Girls conceived after FET had significantly higher systolic BP and heart rate compared with girls born after fresh-ET; boys conceived after FET had a slightly more favourable lipid profile compared with boys born after fresh-ET and NC.

WHAT IS KNOWN ALREADY
Children conceived after ART with FET are more often born large for gestational age (LGA). LGA in general increases the risk of obesity, diabetes, and cardiovascular disease later in life. Studies on mice and humans on the whole ART population have raised concerns about premature vascular ageing and higher BP. The cardiovascular health of children born after FET is scarcely explored and the results are diverging.

STUDY DESIGN, SIZE, DURATION
This study was part of the 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 lasted from January 2019 to September 2021.

PARTICIPANTS/MATERIALS, SETTING, METHODS
The included children were 7–10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging, and BP measurement. Additionally, a fasting blood sample was collected and analysed for cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides. Systolic and diastolic BP were converted to standard deviation scores (SDS) using an appropriate reference and accounting for height (SDS) of the child. The three study groups were compared pairwise using a univariate linear regression model. Mean differences were adjusted for confounders using multiple linear regression analyses.

MAIN RESULTS AND THE ROLE OF CHANCE
Girls and boys conceived after FET had significantly higher birthweight (SDS) compared with naturally conceived peers (mean difference: girls: 0.35, 95% CI (0.06–0.64), boys: 0.35, 95% CI (0.03–0.68)). Girls conceived after FET had significantly higher systolic BP (SDS) and heart rate compared with girls conceived after fresh-ET (adjusted mean difference: systolic BP (SDS): 0.25 SDS, 95% CI (0.03–0.47), heart rate: 4.53, 95% CI (0.94–8.13)). Regarding lipid profile, no significant differences were found between the three groups of girls. For the boys, no significant differences were found for BP and heart rate. Lipid profiles were more favourable in boys born after FET compared with both boys conceived after fresh-ET and NC. All outcomes were adjusted for parity, maternal BMI at early pregnancy, smoking during pregnancy, educational level, birthweight, breastfeeding, child age at examination, and onset of puberty.

LIMITATIONS, REASONS FOR CAUTION
The participation rate varied from 18 to 42% in the three groups, and therefore selection bias cannot be excluded. However, extensive non-participant analyses were performed that showed almost no differences in background characteristics between participants and non-participants in the three groups, making selection bias less likely.

WIDER IMPLICATIONS OF THE FINDINGS
The higher birthweight in children conceived after FET was associated with increased systolic BP (SDS) and heart rate in girls conceived after FET compared with fresh-ET. This may be an early indicator of compromised long-term cardiovascular health in this group. The study was not powered to investigate these outcomes and further studies are therefore warranted to confirm the findings.

STUDY FUNDING/COMPETING INTEREST(S)
The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Forskningsfond. The authors have no conflicts of interest to declare.

TRIAL REGISTRATION NUMBER
ClinicalTrials.gov identifier: NCT03719703.