| BackgroundAssisted reproductive technology(ART),including artificial insemination(AI),in vitro fertilization-embryo transfer(IVF-ET)and its derivative technologies,is an effective therapy to help infertile patients get conceived.IVF-ET technology can also be divided into in vitro fertilization(IVF),intracytoplasmic sperm injection(ICSI),and preimplantation genetic diagnosis(PGD).In the process above,both sperms and oocytes need to be separated from human body and fertilized in vitro.After fertilization and culture in vitro,embryos are transferred into uterine cavity to continue developing.Previously,doctors mainly chose cleavage stage embryos to transfer.However,recently the success rate of blastocyst culture is increasing due to advances in technology,and single blastocyst transfer is more commonly used.Blastocyst culture can weed out embryos without developmental potential in a natural way,leading to increased implantation rate,reduced transfer number,fewer multiple and ectopic pregnancy.Nevertheless,prolonged embryo culture increases unnatural exposure in vitro.Although the culture system emphasizes the simulation of environment in vivo,there are still many conditions that cannot be simulated,because of the complexity of internal environment.Periconceptional period,from germ cell genesis to embryo implantation,is an extremely important stage for early development.Among this period,every single cell with pluripotency or totipotency can be fully exposed to environmental conditions.Even minute variation can cause a cascade effect in the subsequent development and finally change the programming.These changes may either make embryo survive or lead to detrimental long-term effect.According to the developmental origins of health and disease theory(DOHaD),chronic disease in later life may originate from the poor developmental experience.Changes in the early stage could have long-term effect on individuals which may express at any stage of life.Most of the previous studies focused on neonatal outcomes of blastocyst transfer after frozen-thaw procedure which may introduce the confounding effect of cryopreservation.Research investigating the role of embryo transfer timing in long-term growth and endocrinal development of offspring is limited.ObjectivesTo compare growth and endocrinal development of offspring after fresh embryo transfer on blastocyst versus cleavage-stage following in vitro fertilization.Materials and methodsThis study was designed within the longitudinal prospective birth cohort in Reproductive Hospital Affiliated to Shandong University.We collected and analyzed the data of patients and their singleton offspring born after in vitro fertilization and embryo transfer from August 2014 to April 2018.Inclusion criteria:?fresh embryo transfer cycles;?singletons;?Maternal age was restricted to no more than 43 years old.Exclusion criteria:?freeze-thawed oocyte cycles;? donor oocyte cycles;? offspring with congenital abnormities or chromosomal disorders.Offspring born after embryo transfer on day 3(cleavage stage)or day 5(blastocyst stage)were divided into two groups respectively.Parents'information were collected as baseline data,including age,type of ART treatment,height,weight of the couples;maternal antral follicle count(AFC),blood indicators of reproductive hormones(FSH,LH,E2,P),Anti-Mullerian hormone(AMH)and thyroid function(FT3,FT4,TSH).The selected offspring were followed up longitudinally.A total of 1850 follow-up visits were involved,including 389 visits in blastocyst transfer group(D5-ET group)and 1461 visits in cleavage-stage transfer group(D3-ET group).We collected and calculated the length,weight,head circumference,weight/length ratio(WLR),body mass index(BMI)and tri-ponderal mass index(TMI)of the offspring,then we compared them between D5-ET and D3-ET group.We used the following methods to adjust the confounding effects:1.Calculate length-for-age(offspring over 2 years old use height to calculate height-for-age z score,height=length-0.7cm),weight-for-age,BMI-for-age and head circumference-for-age z scores according to WHO standard;2.Use generalized estimating equation(GEE)to eliminate the effect of repeated measurement;3.Perform subgroup analysis according to type of ART treatment and gestational age of offspring.WLR,BMI,TMI were also compared within 5 age subgroups respectively to evaluate metabolic status.Besides,reproductive hormones(FSH?LH?E2?PRL?T)and thyroid function indicators(FT3?FT4?TSH)in peripheral blood samples of offspring aged 24-36 months were detected.Due to the small sample size in the above age group,we expanded the recruitment to 60 cases.Serum AMH was measured by enzyme-linked immunosorbent assays(ELISA).Reproductive hormones and thyroid function indicators were measured by electrochemiluminescence.Analyses were performed using IBM SPSS Statistics 25.0.Inspection level:a =0.05.ResultsNo significant difference was found in length(or height),weight,head circumference and BMI between offspring aged 0-36 months in D5-ET and D3-ET group.IVF and ICSI subgroup analysis also indicated a negative outcome.There was no significant difference in full-term birth subgroup analysis,but weight-for-age z score(1.28±1.04 vs.0.45±1.11,P<0.05)and BMI-for-age z score(1.42±1.22 vs.0.60± 1.29,P<0.01)in preterm birth subgroup were significantly different between D5-ET and D3-ET group.Age-stratified analysis revealed a transiently increase in D5-ET group of TMI in 7-12 months(26.57 vs 26.08 kg/m3,P<0.05)and 13-18 months(23.48 vs 22.77 kg/m3,P<0.05)respectively.But WLR and BMI were comparable.The comparison of endocrine indicators of offspring aged 24-36 months indicated that there was no significant difference in FSH,LH,E2,PRL,T,TSH,FT3 and FT4 between D5-ET and D3-ET group.And no difference was found after expanding the sample size.ConclusionEmbryo transfer at blastocyst or cleavage stage made no difference on growth and endocrinal development of offspring aged 0-36 months.Further study of larger sample size and longer follow-up is still needed. |
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