Objective: To investigate the effect of maternal estradiol (E₂) elevation on long-term metabolic manifestations in the offspring.
Study Design and Setting: This was a retrospective cohort study. Overall, 3690 children conceived by in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) between July 2014 and December 2017 were recruited and divided into four groups categorized by maternal E₂ quartiles (Q1, < 2420; Q2, 2420– 3839; Q3, 3839– 5599; and Q4, ≥ 5599 pg/mL). The metabolic profiles were measured during childhood. Linear mixed models were used to evaluate the association between maternal E₂ elevation and metabolic phenotypes of the offspring.
Results: Lipoprotein cholesterol (LDL-C) was significantly higher in the highest quartile group than in the lowest quartile group during infancy (adjusted mean difference [95% confidence interval, CI]): 0.11 [0.02, 0.20], P = 0.005), but the difference disappeared in the later childhood phase. In children born after fresh embryo transfer, LDL-C showed an increasing trend with the increase in maternal E₂ level (adjusted mean difference [95% CI]: Q2 vs Q1, − 0.01 [− 0.11, 0.08], Q3 vs Q1, 0.06 [− 0.04, 0.15], Q4 vs Q1, 0.10 [0, 0.20]). Other metabolic variables were comparable across increasing quartiles of maternal E₂ levels.
Conclusion: This study demonstrates a temporary increase in LDL-C levels in infants with higher levels of maternal preconception E₂ levels. However, the long-term safety of hyperestrogens after ovarian stimulation in the next generation is favorable. The mechanism underlying the transiently increased metabolic dysfunction risk in infants conceived by IVF/ICSI requires investigation in future studies.
Keywords: offspring, supraphysiologic estradiol, controlled ovarian hyperstimulation, assisted reproductive technology