| BackgroundThe fertility preservation methods currently mainly include:egg cryopreservation,sperm cryopreservation,embryo cryopreservation,testicular tissue cryopreservation,and ovarian tissue cryopreservation,among which gamete cryopreservation(egg,sperm)and embryo cryopreservation are one of the most commonly used techniques in assistant reproductive technology(ART).The world’s first frozen-thawed sperm,embryo and egg pregnancy babies were born in 1983,1984 and 1986,respectively.Since then,the technology has been widely used in the clinical field of reproductive medicine.The Chinese Reproductive Medicine Survey in 2020 showed that the proportion of frozen embryo transfer cycles in 2013 was 34.8%[1],and by 2016,the proportion of frozen embryo transfer cycles had increased to 40.5%[2].It can be seen that the frozen embryo transfer cycles have tendency to surpass the fresh embryo transfer cycles to become the dominant trend of ART.However,both gamete and embryo frozen-thaw are non-physiological exposures in early life.Studies have shown that maternal outcomes differ from frozen-thaw cycles in pregnant women compared to fresh cycles,and according to the Developmental Origins of Health and Disease theory,the effects of these exposures may also map to distant offspring period health.This study will evaluate the effects of repeated freezing about gamete and embryo stages on perinatal and child growth outcomes by comparing frozen-thawed gamete-derived frozen embryo transfers with only embryo frozen and fresh embryo transfers in a nested case-control study.The aim is to further discover the short-term and long-term safety of cryogenic freezing technology for offspring,and to provide theoretical basis for clinical application and related management policies.ObjectiveTo evaluate the perinatal outcomes and long-term growth and development of frozen embryo transfer derived from frozen-thawed gametes.MethodsThis study is a nested case-control study.The study included female patients who underwent assisted reproductive technology and delivered singleton live births at the Reproductive Hospital Affiliated to Shandong University from April 2008 to May 2020.We included a total of 745 female patients in the exposure group according to strict inclusion criteria,all of whom received a double frozen transfer(DFT)developed from frozen gametes.In order to balance the baseline characteristics,we used the method of Propensity Score Matching(PSM)to match patients during the same period conceived by ART,the mother’s age and body mass index(BMI)were matched in a ratio of 1:4,and 2980 female patients were separately enrolled in the two control groups(FET group,ET group).All transferred embryos achieved pregnancy and were singleton live births.Families were followed up from birth,and perinatal outcome analysis was performed on all offspring.Among them,3943 children were included in the long-term outcome analysis and were followed up to 5-10 years old.Measures of perinatal,neonatal outcomes,and child growth were compared between the three groups.Perinatal outcome indicators include:gestational age,fetal sex,birth weight,birth length,mode of delivery,Gestational diabetes mellitus(GDM),pregnancy-induced hypertension(PIH),breastfeeding,small for gestational age(SGA),large for gestational age(LGA),preterm birth(including indicated preterm birth<32 week,spontaneous preterm birth<32 week,indicated preterm birth during 32-37 week,spontaneous preterm birth during 32-37 week,unknown cause preterm birth),neonatal intensive care unit(NICU)hospitalization rate and length of hospital stay,perinatal mortality,neonatal mortality,polyhydramnios,oligohydramnios,placental malformation,placenta accrete,placenta previa,placental abruption,umbilical cord abnormality,birth injury,neonatal disease,birth defect[disease code classification according to the International Classification of Diseases(ICD)].Observational indicators of children’s growth and development:height,weight and BMI.ResultsThe average birth weight of DFT group(3462g)was significantly higher compared to FET group(3458g)and ET group(3412g).The rates of large for gestational age(LGA)babies in DFT and FET groups were higher than ETs group(30.9%vs.24.8%;29.4%vs.24.8%,respectively).After adjusted for different confounders combination in three models,the birth weight,risk of LGA in DFTs and FET groups were still higher than ET groups,and the values 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 DFT and FET groups were higher than children from ET(β=0.24,95%CI 0.1-0.39;β=0.18,95%CI 0.07-0.30,respectively).However,childhood growth measurements including body weight Z-score and BMI Z-score were not significantly different among three groups.In addition,the proportion of male children born from the DFT was more than that from ET.ConclusionsPregnancies with frozen embryo transfers developed from frozen-thaw gametes have an increased risk of large for gestational age.Compared with frozen embryo transfers,children in this group tended to be taller in the future.Its associated etiology and pathophysiological mechanisms remain to be revealed.In the future,well-designed observational studies with larger samples from multiple centers and in-depth collection of patient characteristics are needed to clarify this issue more clearly. |
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