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Bone mineralization in children aged 7-10 years born after ART with frozen and fresh embryo transfer
Elisabeth Waldemar Grønlund1, Anna Sophie Lebech Kjaer1,2, Louise Laub Asserhøj1
1The Fertility Clinic, Department of Gynaecology, Fertility and Obstetrics, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
Insights
Children conceived via frozen embryo transfer (FET) had higher height-adjusted bone mineral content (BMC) due to increased birthweight. This difference disappeared when birthweight was accounted for, suggesting birthweight is a key mediator.
Area of Science:
- Pediatric Endocrinology and Bone Health
- Reproductive Medicine and Assisted Reproductive Technology (ART)
- Human Growth and Development
Background:
- Children conceived via ART using frozen embryo transfer (FET) exhibit higher birthweight (BW) compared to naturally conceived (NC) children.
- The association between BW and bone mineral content (BMC) is established in NC children, but bone health in ART-conceived children remains under-explored with inconsistent findings.
- Previous research indicates fresh embryo transfer (fresh-ET) is associated with lower BW compared to NC children.
Purpose of the Study:
- To investigate whether height-adjusted bone mineral content (BMC) differs at 7-10 years of age among children conceived via ART using FET, fresh-ET, or naturally conceived (NC).
- To explore the mediating role of birthweight (BW) in any observed differences in BMC between these groups.
Main Methods:
- Retrospective cohort study (HiCART cohort) of 606 singletons (200 FET, 203 fresh-ET, 203 NC) aged 7-10 years.
- Data collected via Danish Medical Birth Registry, Danish IVF Registry, clinical examinations (anthropometry, DXA scan), and parental questionnaires.
- Statistical analysis involved univariate and multiple linear regression to compare BMC, adjusting for confounders and mediators like BW.
Main Results:
- Initially, no crude differences in height-adjusted BMC were observed between FET, fresh-ET, and NC groups.
- After adjusting for confounders, children conceived via FET showed significantly higher height-adjusted BMC compared to fresh-ET and NC groups.
- Subsequent adjustment for birthweight standard deviation score (BW SDS) eliminated these differences, indicating BW mediates the association between FET and BMC.
Conclusions:
- Increased birthweight in children conceived via FET is associated with higher height-adjusted BMC at 7-10 years compared to fresh-ET and NC children.
- The observed differences in BMC are primarily mediated by higher birthweight in the FET group.
- Longitudinal studies are recommended to investigate the causes of increased BW after FET and its long-term bone health implications.
Study Question:
Does height-adjusted bone mineral content (BMC) at 7-10 years of age differ between children conceived after ART with frozen embryo transfer (FET) compared to children conceived after ART with fresh embryo transfer (fresh-ET) or naturally conceived (NC) children?
Summary Answer:
Children conceived after FET had an increased BMC corrected for height compared with fresh-ET and NC when adjusted for confounders, a difference primarily mediated by the higher birthweight (BW) found in children conceived after FET compared with fresh-ET and NC.
What Is Known Already:
Children conceived after ART with FET have a higher BW compared to NC children, while the opposite association is known for fresh-ET. In NC children, BW is positively associated with BMC and bone mineral density (BMD), but bone health in children born after ART is scarcely explored with inconsistent results.
Study Design Size Duration:
This study was a retrospective cohort study as part of the 'Health in Childhood following Assisted Reproductive Technology' (HiCART) cohort, consisting of 606 singletons (292 boys), conceived after FET (n = 200), fresh-ET (n = 203), and NC (n = 203) born from November 2009 to December 2013. The children were 7-10 years old when clinically examined, and the study was conducted from January 2019 to September 2021.
Participants/Materials Setting Methods:
Children were identified through the Danish Medical Birth Registry and Danish IVF Registry. These registries were also used to collect information regarding ART treatment, pregnancy, and delivery. The clinical examination involved anthropometric measurements, pubertal staging, fasting blood samples, and a whole-body dual-energy x-ray absorptiometry (DXA) scan. Both parents completed a questionnaire on background information regarding themselves and their child. The three groups were compared pairwise using univariate linear regression, and possible confounders and mediators were adjusted for using multiple linear regression analysis.
Main Results And The Role Of Chance:
Crude values of BMC corrected for height did not differ between children born after FET, fresh-ET, or NC. When adjusted for relevant confounders, children born after FET had a statistically significant higher BMC corrected for height compared with both fresh-ET and NC. After further adjustment for BW SD score, the differences in BMC corrected for height disappeared, and no statistically significant differences in BMC corrected for height between any of the three groups were found. Factors potentially affecting bone mineralization, such as calcium, parathyroid hormone (PTH), insulin-like growth factor-1 (IGF-1), lean mass, and physical activity in childhood, did not differ between the three groups.
Limitations Reasons For Caution:
All relevant confounders were adjusted for, although the cause of infertility was not available, hence a risk of residual confounding. The use of a parental questionnaire on the child's physical activity level sets a risk of information bias.
Wider Implications Of The Findings:
Increased BW in children conceived after FET was associated with increased BMC corrected for height at age 7-10 years when compared to children conceived after fresh-ET and NC. Longitudinal studies of pregnancies and newborns after FET are needed to explore the causes of the increase in BW and the possible effects on long-term bone health.
Study Funding/Competing Interests:
The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalet Research Foundation. A.P. has received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck, and Cryos; consulting fees from Gedeon Richter, Ferring Pharmaceuticals, Merck, Cryos, and IBSA; speaker fees from Gedeon Richter, Ferring Pharmaceuticals, Merck, and Organon; and travel grants from Gedeon Richter. The remaining authors declare no conflicts of interest.
Trial Registration Number:
ClinicalTrials.gov identifier: NCT03719703.
