The Gender-specific Difference In Singleton Birth Weight After Frozen Embryo Transfer Compared With Fresh Embryo Transfer

BackgroundAssisted reproductive technology(ART),as a way to treat infertility,has rapidly developed over the past four decades and has become a commonly used clinical treatment.According to surveys,more than 8 million newborns worldwide have been born through ART,and about 300,000 newborns following ART are born in China each year.Since Devroey and colleagues proposed the concept of "freezing of all embryos"in 2011,the clinical application of the "freezing-only strategy" has increased year by year along with the continuous improvement of thawed cryopreserved embryo technology.Research data has shown that the number of frozen embryo transfer(FET)cycles and live birth rates in multiple countries and regions have exceeded those of fresh embryo transfer cycles.The results of two prospective randomized controlled trials(RCT)conducted by our team in women with polycystic ovary syndrome(PCOS)and in ovulatory women with single blastocyst transfer showed that the FET group had a higher live birth rate compared to the fresh embryo transfer group.Although there is still controversy about the widespread adoption of the "freezing-only strategy",its application worldwide is still on the rise.The birth weight of newborns is considered an important predictor of childhood and adult health,and research has shown that both low and high birth weights increase the risk of cardiovascular and metabolic diseases throughout life.Low birth weight increases the risk of developing type 2 diabetes,cardiovascular disease,hypertension,kidney disease,and other conditions in adulthood,while high birth weight is closely associated with an increased risk of chronic kidney disease and obesity in adulthood.Previous studies have shown that compared to fresh embryo transfer,singleton live birth born after FET have a higher risk of being born with a higher birth weight and a higher risk of being born larger than gestational age(LGA),and a lower risk of being born smaller than gestational age(SGA).However,the mechanisms of the difference in birth weight between FET and fresh embryo transfer newborns are still unclear.Studies have shown that the lower birth weight of newborns in fresh embryo transfer cycles may be related to supra-physiological levels of estradiol(E2)produced during controlled ovarian hyperstimulation(COH),while the higher birth weight of newborns in FET cycles may be related to embryo cryopreservation techniques.The factors that affect the difference in birth weight between FET and fresh embryo transfer have not been fully clarified,and further research is needed to determine whether the infant gender affects the difference in birth weight between singleton born after FET and fresh embryo transfer.ObjectiveTo assess whether the between-group differences in singleton birth weight following frozen versus fresh embryo transfer varied with infant sex.MethodsThe data from three multicenter randomized controlled trials(RCT)led by the Center for Reproductive Medicine affiliated with Shandong University were reanalyzed.The purpose of these three RCT studies was to evaluate the difference in live birth rates between the FET group and the fresh embryo transfer group.This study only selected patients who achieved single live birth after FET and fresh embryo transfer.Interaction analysis was added to the multivariate regression analysis to evaluate whether the difference in birth weight between FET and fresh embryos is affected by the sex of the newborn.At the same time,we conducted multiple stratified analyses of clinical factors that affect birth weight reported in previous studies,such as human chorionic gonadotropin(HCG)-triggered estradiol(E2)levels,HCG-triggered progesterone(P)levels,whether the mother was diagnosed with PCOS,and the stage of embryo transfer(cleavage stage or blastocyst stage),which is to further clarify the impact of gender factors on the difference in birth weight between frozen and fresh embryos.In women who were randomized to the FET group,we conducted sub-group analyses with different endometrial preparation regimes.The primary outcomes of the study were the average birth weight of newborns,LGA,and SGA.Result(s)A total of 1886 study subjects were included,including 1043 in the FET group and 843 in the fresh embryo transfer group.In the regression analysis model,interaction analysis showed that different types of embryo transfer(FET or fresh embryo transfer)and newborn gender had a significant interaction effect on the primary pregnancy outcome indicators,including the average birth weight of newborns(P<0.001),LGA(P=0.012),and SGA(P=0.030).Among male newborns,compared with the fresh embryo transfer group,newborns in the FET group had a higher average birth weight[3520.6 ± 526.1 g vs.3345.1 ± 524.9g,adjusted absolute difference:168.2g,95%confidence interval(CI):104.5g-232.0g],a higher risk of LGA[25.2%vs.15.7%,adjusted odds ratio(OR):1.70,95%CI:1.22-2.37]and a lower risk of SGA[3.3%vs.6.1%,adjusted OR:0.48,95%CI:0.51-1.64].Among female newborns,there was no significant difference in the average birth weight(3336.5 ± 514.8g vs.3299.5±485.0g,adjusted absolute difference:40.0g,95%CI:-27.3g-107.2g),LGA(18.8%vs.15.7%,adjusted OR:1.30,95%CI:0.90-1.88),and SGA(5.2%vs.6.0%,adjusted OR:0.92,95%CI:0.51-1.64)between FET group and fresh embryo transfer group.Subgroups analyses showed that in male single live birth infants born after FET,the average birth weight was significantly higher than that of the fresh embryo transfer group in the three subgroups of the E2 level on the day of hCG trigger,the subgroups of the P level≥0.78ng/ml on the day of hCG trigger,the cleavage embryo transfer subgroup,the blastocyst embryo transfer subgroup,the PCOS subgroup,the normal ovulation subgroup,and the subgroups of gestational weeks≥37 weeks.The birth weight of female singletons was only significantly higher in the FET group than in the fresh embryo transfer group in the subgroup with the highest E2 and P level on the day of the hCG trigger and in the subgroup of mothers with PCOS.In addition,this study did not find significant gender-specific differences in birth weight,LGA,and SGA in different endometrial preparation regimes in the FET population.Conclusion(s)The between-group difference in the birth weight of singleton live births after FET and fresh embryo transfer varied with infant sex.Compared with fresh embryo transfer,male fetuses were more likely to have a higher birth weight after FET,while there is no significant between-group difference in the birth weight of female fetuses between FET and fresh embryo transfer.