P-780 Bone health in Danish children aged 7-10 years born after assisted reproductive technology with frozen and fresh embryo transfer
Authors: Kjaer A  S L , Grønlund E  W , Asserhøj L  L , Mizrak I , Clausen T  D , Madsen P  L , Pinborg A , Jensen R  B 
Published: July 2024

Study question

Is bone 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 higher bone mineral density (BMD) and bone mineral content (BMC) compared to fresh-ET-children. Insulin-like-growth-factor-I (IGF-I) levels and lean bodymass were similar between groups.

What is known already

Children conceived after assisted reproductive technology (ART) with FET have a higher average birthweight (BW) and increased risk of being born large-for-gestational-age (LGA) while children born after fresh-ET are more often born small-for-gestational-age (SGA).

In general, BW is a determinant of BMD and BMC in childhood with LGA being associated with higher BMD and BMC compared to children born appropriate-for-gestational-age. The relationship between BW and BMD and BMC may be mediated by IGF-I levels and lean bodymass as IGF-I is an important regulator of muscle and bone development.

Bone health in children born after ART is scarcely explored.

Study design, size, duration

This study was part of the large Danish cohort study “Health in Childhood following Assisted Reproductive Technology” (HiCART) which included 606 singletons (292 boys) born in Denmark between 2009 and 2013. The children were conceived after FET (n = 200), fresh-ET (n = 203) and NC (n = 203) and matched for birth year and sex. The study examinations were performed from January 2019 to September 2021.

Participants/materials, setting, methods

The children underwent a clinical examination at 7-10 years of age with anthropometric measurements, pubertal staging, a fasting blood sample and a whole-body dual-energy x-ray absorptiometry-scan (DXA). Anthropometric measurements and circulating growth factors were converted to standard deviation scores (SDS) using Danish reference material. The study groups were compared pairwise using univariate linear regression and multiple linear regression adjusting for relevant confounders including sex, age, puberty, maternal pregestational BMI, breastfeeding and BW (SDS).

Main results and the role of chance

Children conceived after FET had significantly higher BW (SDS) (mean, SD: 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 (-0.16 SDS, 1.09), mean difference: 0.35 SDS (95% CI: 0.14; 0.57).

In the adjusted model, children born after FET had significantly higher total BMD (g/cm2) (mean difference 0.01, 95% CI: 0.00; 0.03) and size-adjusted BMC (BMC/height, g/m) (mean difference 0.21, 95% CI: 0.01; 0.40) compared to children born after fresh-ET. There was no significant difference in total BMD or BMC/height when comparing FET and fresh-ET to NC children, respectively.

There was a trend towards higher lean bodymass (g) in children born after FET and lower lean bodymass in children born after fresh-ET compared to NC children, however this did not reach the level of significance. IGF-I (SDS), IGF-binding-protein-3 (SDS) and serum calcium (mmol/L) levels were comparable between the groups.

In the entire cohort, there was a significantly positive correlation between BW (SDS) and size-adjusted BMC (BMC/height, g/m) (b: 0.21, 95% CI: 0.14; 0.27) and total lean bodymass (g) (b: 755, 95% CI: 531; 978), while a significantly negative correlation with IGF-I (SDS) (b: -0.07, 95% CI: -0.13; -0.01).

Limitations, reasons for caution

The study was powered to detect a clinically relevant difference in BMI (SDS), the primary outcome. Hence, secondary analyses are exploratory by nature. We have no information regarding endometrial preparation protocol in the FET-cycles which may bias the results. Multiple testing may increase our risk of type I errors.

Wider implications of the findings

Reassuringly, BMD and size-adjusted BMC in children born after ART with FET and fresh-ET were comparable to NC children. Potential determinants of BMD and BMC (IGF-I and lean bodymass) were also similar. Increased BMD and size-adjusted BMC in FET compared to fresh-ET suggests that the different BW-profiles play a role.

Trial registration number

NCT03719703