"Double Frozen Transfer" Could Influence the Perinatal and Children's Growth: A Nested Case-Control Study of 6705 Live Birth Cycles

Objective: This study aims to evaluate neonatal and children growth outcomes of cryotransfer of embryos developed from frozen gametes [double frozen transfer (DR)]. Methods: This nested case-control study included 6,705 women who had a singleton live birth after embryo transfer at the Center for Reproductive Medicine, Shandong University, from 2008 to 2020. Of these, 745 women underwent frozen embryo transfer (FET) using embryos developed from frozen gametes (DFT). Propensity score methodology was used to balance the two groups by maternal age and body mass index (BMI) before evaluating outcomes. After age and BMI were matched using the propensity score methodology in a ratio of 1:4, the control groups enrolled 2,980 women who underwent fresh embryo transfer (ET) and 2,980 women underwent FET from fresh gametes. The children born were followed to at least 5 years of age, and some were followed up to 10 years. Neonatal outcomes and childhood growth measurements were compared among the three groups. Results: The average birth weight of the DFT group (3,462 g) was significantly higher than the FET group (3,458 g) and ET group (3,412 g). The rate of large for gestational age (LGA) babies in the DFT and FET group was higher than that for the ET group (30.9% vs. 24.8%; 29.4% vs. 24.8%, respectively). After adjusting for different confounder combinations in the three models, the birth weight and risk of LGA in the DFT and FET groups were still higher than in the ET group, and the values group of P for trend in the models were significant. In multiple linear regression analysis of the children's development, the height Z-score of children born from the DFT and FET group was higher than that for children from the ET group (beta = 0.21, 95% CI 0.07-0.35; b = 0.17, 95% CI 0.05-0.28, respectively). However, childhood growth measurements including body weight Z-score and BMI Z-score were not significantly different among the three groups. In addition, the proportion of male children born from DET was higher than that from ET. Conclusions: There is an increased risk of LGA babies associated with pregnancies conceived from DFT. Children are inclined to be taller in the future in this group than after FET. The related etiology and pathophysiology mechanisms still need to be revealed. In the future, well-designed, observational studies with in-depth collection of patients' characteristics may shed more light on this issue.