Comparative Of Fresh Embryo Transfer And Frozen Embryo Transfer On The Offspring Birthweight

Over the last decade,the use of frozen embryo transfer(FET)cycles has dramatically risen[1].According to a report conducted by the Society for Assisted Reproductive Technology(SART),the number of FET cycles has increased by 82.5% between 2006 and 2012,outpacing the increasing rate of fresh embryo transfer(ET)cycles[2].The main reasons underlying the increasing trend for FET cycles are threefold.First,a newer vitrification technology has become the dominant method used for embryo cryopreservation,significantly increasing the embryo cryosurvival rate compared with slow-freezing[3].Second,a rapid rise in single ET,combined with the development of pre-implantation genetic screening(PGS)and pre-implantation genetic diagnosis(PGD),has increased the number of embryos available for freezing[11].Third,a large number of studies have demonstrated that FET may lead to more favourable perinatal outcomes[4-10],but whether poor neonatal outcomes,including low birth weight(LBW),small for gestational age(SGA),large for gestational age(LGA),macrosomia and congenital malformations are due to differences in the type of embryo transfer method used is unknown.Objective The initial aim was to investigate whether FET was preferable to a fresh ET in terms of neonatal outcomes,including birthweight,LBW,SGA,macrosomia,LGA and congenital malformations,for infertile women with singleton full-term births,excluding cycles with pregnancy-related complications.The second aim was to investigate whether a supraphysiological estrogen(E2)level on the HCG trigger day is associated with LBW and SGA for singletons born of fresh ET cycles.Materials and Methods 1 Fresh versus frozen embryo transfer for full-term singleton birthThis was a retrospective cohort study of patients with no pregnancy-related complications who had undergone fresh ETs(n=2,059)or FET cycles(n=2,053)resulting in full-term(37 weeks ≤ delivery weeks < 42 weeks)singleton births between July 2008 and September 2016 at the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University.Singleton full-term births after IVF/ICSI cycles were included.We excluded cycles with pregnancy-related complications,including pregnancy-induced hypertension,gestational diabetes mellitus,placenta previa,placental abruption and premature rupture of membranes.Furthermore,cycles with donor oocytes,donor embryos,PGD/PGS,vanishing twins or incomplete records were excluded.For our study,we compared neonatal outcomes,including birthweight,term LBW,SGA,LGA,macrosomia and congenital malformations,of fresh ETs and FETs.All statistical management and analyses were performed using SPSS software,version 22.0.The Wilcoxon rank sum test was used to assess between-group differences in continuous variables with abnormal distributions,and these variables were expressed as the mean ± SD.Categorical variables were represented as the number of cases(n)and the percentage(%).The means from chi-square analyses were used to assess the differences between groups.For neonatal outcomes,logistic regression was used to adjust for the baseline characteristics(age,BMI,No.of embryos transferred and embryo stage)between the two groups.Unadjusted odds ratios and adjusted odds ratios(AORs)with 95% confidence intervals(CIs)were calculated for the above variables.Statistical significance was set at P<0.05.2 The relationship between supraphysiological E2 level on the h CG trigger day and LBW as well as SGA for singletons born of fresh ET cyclesPatients with singleton pregnancies with delivered after transfer of fresh embryos,including Day-3 and Day-5 embryos,during the period of July 2008 to July 2017 at the Reproductive Center were included.Only patients aged 35 years or younger,cycle days-2/3 FSH<10 m IU/ml,anti-mullerian hormone(AMH)>1 ng/ml were included.The cycles with multiple births,vanishing twins,donor oocytes and incomplete records were excluded.A total of 2784 cycles met the criteria.According to the serum E2 level on the day of HCG trigger,we divided all patients into 6 groups.A: E2≤2000 ng/l(referent group),B: E2 2001-3000 ng/l,C: E2 3001-4000 ng/l,D: E2 4001-5000 ng/l,E: E2 5001-6000 ng/l,F: E2>6000 ng/l.The outcome measures were SGA,LBW,very low birth weight(VLBW: neonatal birthweight≤1500 g),preterm birth(gestational age <37 weeks)and full-term LBW.We compared the odds ratio(OR)of SGA,LBW,VLBW,preterm birth and full-term LBW between the groups(P=0.70;P=0.85).Than we use multivariable logistics regression to analysis whether these outcome measures could be explained by the E2 level on the trigger day.Results 1 Fresh versus frozen embryo transfer for full-term singleton birth(1)Baseline data: Maternal age was higher in the FET group than in the fresh ET group(29.8±4.2 vs.29.4±4.3;P=0.00).Body mass index(BMI)was lower in the fresh ET group than in the FET group(22.4±3.0 vs.23.3±3.9;P=0.00).More cleavage-stage ETs were included in the fresh ET group than in the fresh ET group,while more blastocyst transfers were included in the FET group than in the fresh ET group(P=0.00).Meanwhile,the rate of caesarean delivery was higher in the FET group(73.5% vs.85.2%;P=0.00).(2)Neonatal birthweight: The mean neonatal birthweight of singletons born after FET was higher than that of singletons born after fresh ET(3,386.7±448.1 vs.3,468.7±475.3;P=0.00).The frequencies of full-term singleton LBW and SGA after FET were significantly lower than those after fresh ET(1.7% vs.3.0% and 4.4% vs.6.7%,respectively),with adjusted rate ratios of 0.59(95% CI: 0.37 to 0.98;P=0.03)and 0.73(95% CI: 0.55 to 0.99;P=0.04).However,the frequency of macrosomia was higher after FET than after fresh ET(15.1% vs.10.2%),with a rate ratio of 1.43(95% CI: 1.16 to 1.75;P=0.00).The incidence of LGA was significantly higher in the FET group than in the fresh ET group(22.8% vs.17.5%),with a rate ratio of 1.26(95% CI: 1.07 to 1.49;P=0.01).(3)There was no significant difference between the rates of congenital malformations(1.20% vs.0.90%;P=0.29),including Trisomy 13/18/21(0.4% vs.0.3%;P=0.60),congenital heart disease(0.3% vs.0.15%;P=0.21),polydactyly/syndactyly(0.2% vs.0.15%;P=0.48)and others(0.2% vs.0.3%;P=0.76),between the two groups.2 The relationship between supraphysiological E2 level on the HCG trigger day and LBW as well as SGA for singletons born of fresh ET cycles(1)Baseline data: the age of women,AMH,antral follicles,number of oocytes retrieval,and embryo transfer stage were significantly different between groups(P=0.00;P=0.00;P=0.00;P=0.00;P=0.00),group E and group F.The amount of gonadotropins(Gn)was significantly smaller than that of groups A,B,and C(P = 0.00).There was no significant difference in the remaining basic data(P>0.05).(2)Comparison between groups: SGA: Compared with group A,the incidence of SGA in group D,group E and group F increased significantly(group D: OR=1.87,95% CI:1.15-3.02,P=0.01;Group E: OR =2.18,95% CI :1.27-3.73,P = 0.01;Group F: OR = 2.55,95% CI : 1.54-4.22,P = 0.00).LBW: Compared with group A,the incidence of LBW in group D,group E and group F increased significantly(group D: OR=1.98,95% CI: 1.13-3.48,P=0.02;group E: OR=2.54,95 %CI:1.38-4.69,P=0.00;Group F: OR=3.36,95% CI:1.91-5.92,P=0.00).Full-term LBW: Compared with group A,the incidence of full-term LBW in group D,group E,and group F increased significantly(group D: OR=5.57,95% CI:2.09-14.83,P=0.00;group E: OR = 7.43,95% CI: 2.69-20.51,P = 0.00;Group F: OR = 12.18,95% CI: 4.66-31.83,P = 0.00).However,the incidence of VLBW and PTB did not change significantly with the increase of E2(P=0.70;P=0.85).(3)Binary logistics analysis:After eliminating confounding factors via binary logistic regression analysis(including age,BMI,parity,infertility diagnosis,IVF/ICSI,D3/D5,endometrial thickness on the trigger day,newborn sex,number of embryos transferred),we found that high E2(≥4001 ng/ml)was associated with the significantly increase of SGA(group D:AOR=1.69,95%CI: 1.03-2.75,P=0.04;group E:AOR=1.94,95%CI:1.12-3.36,P=0.02;group F :AOR=2.31,95%CI:1.38-3.87,P=0.00),LBW(group D:AOR=1.95,95%CI: 1.11-3.44,P=0.02;group E: AOR=2.57,95%CI:1.38-4.78,P=0.00;group F:AOR=3.36,95%CI:1.89-5.98,P=0.00),and full-term LBW(group D :AOR=5.36,95%CI:2.00-14.37,P=0.00;group E:AOR=7.35,95%CI:2.64-20.49,P=0.00;group F:AOR=12.02,95%CI:4.55-31.78,P=0.00).Conclusions(1)FET was associated with lower rates of LBW and SGA than fresh ET cycles,even after adjusting for confounders.However,FET protocols are associated with a higher neonatal birthweight and higher risks of macrosomia and LGA than fresh ET.(2)Additionally,our study demonstrates that FET protocols do not adversely affect the rate of neonatal malformations,including Trisomy 13/18/21,congenital heart disease,polydactyly/syndactyly and others.(3)Our results indicated that for fresh ET cycles,supraphysiological E2(≥4001 pg/ml)on the day of h CG trigger increases the risks of singleton SGA,LBW and full-term LBW,further confirming the adverse effects of a supraphysiological hormonal environment on offspring safety.When serum E2 is overly high,the elimination of fresh ET in favor of whole embryo cryopreservation is recommended.