| BackgroundIn vitro fertilization embryo transfer(IVF-ET)technology has developed rapidly in the past 40 years,and the embryo implantation rate and clinical pregnancy rate have also been increasing.It should be noted that one of the complications of IVF is multiple pregnancy.According to the systematic statistics of reproductive medicine branch of Chinese Medical Association in 2016,the multiple pregnancy rate of reproductive medicine in China exceeded 30%,and even was as high as 40%in some reproductive centers.Multiple pregnancy caused by human assisted reproductive technology are often closely related to obstetric complications such as pre pregnancy hypertension,preeclampsia,placenta previa,elective cesarean section,postpartum hemorrhage,premature delivery,extremely preterm delivery,low birth weight and other obstetric complications.The purpose of assisted reproductive technology is to give birth to single,full-term and healthy infants.Single embryo transfer is the most effective way to reduce the risk of multiple pregnancy.With the development of blastocyst culture technology and vitrification technology,the clinical pregnancy rate of single embryo transfer can be increased to 50-70%by culturing blastocyst and frozen thawed embryo transfer,and the incidence of multiple pregnancy can be significantly reduced.Previous clinical trials have shown that for women with good prognosis,frozen single blastocyst transfer cycle is better than fresh cycle to achieve single live birth.However,frozen single blastocyst transfer is associated with a high risk of preeclampsia.Endometrial preparation is an important aspect of frozen embryo transfer(FET)cycle.At present,the most commonly used endometrial preparation methods for FET include hormone replacement therapy cycle and natural cycle regimen.It is unclear whether perinatal complications are due to different endometrial preparation protocols used during the freezing cycle.Some studies have shown that there is no significant difference in the cumulative live rate between single embryo transfer and double embryo transfer,but the implantation rate of double embryo transfer is lower than that of single embryo transfer.If double embryo transfer,not only increases the multiple embryo rate,but also reduces the implantation rate of single embryo,resulting in the loss of embryo utilization and the cumulative pregnancy rate.However,there is no strong evidence-based evidence to prove that single embryo transfer can improve the implantation rate and the utilization of single embryo.When a patient has remaining blastocysts to be frozen,is it cryopreservation alone or two blastocysts frozen together?These problems need further research to confirm,in order to guide clinical decision-making and embryo laboratory freezing strategy.At present,two strategies for embryo transfer are in cleavage stage or in blastocyst stage.Cleavage transfer usually refers to the transfer of embryos on the second or third day after fertilization,which is suitable for all population.The pregnancy success rate of single embryo transfer is about 30%-35%.Blastocyst transfer is an extension of embryo culture in vitro for 2-3 days.Only high-quality embryos with implantation potential can get to the blastocyst stage.Compared with embryo transfer in cleavage stage transfer,the pregnancy rate and delivery rate of blastocyst transfer are significantly improved.However,two cleavage embryos are usually transferred to improve pregnancy rate,but the risk of multiple pregnancy is also increased to 20-30%.At present,there is a lack of high-quality research data on cumulative live rate,pregnancy complications and neonatal outcomes of single embryo transfer,Based on the above thinking,this paper will focus on the clinical hot issue of assisted reproductive technology-single embryo transfer,and carry out a series of studies,to evaluate whether endometrial preparation program is related to the outcome of obstetrics and neonatal complications in the single blastocyst frozen transfer cycle,and then compare single blastocyst transfer and double blastocyst transfer from the perspective of embryo implantation rate,and finally through the clinical trial to analyze the difference of cumulative live rate between single blastocyst transfer and single cleavage embryo transfer,so as to provide the basis for further promoting the strategy of single embryo transfer.Part ? Maternal and neonatal complications after natural versus hormone replacement therapy cycle regimen for frozen single blastocyst transferObjective:To evaluate the maternal and neonatal complications after frozen-thawed blastocyst transfer cycles utilizing different endometrial preparation regimens.Methods:This is a retrospective cohort study and a secondary analysis of a multicenter,randomized,controlled trial comparing live birth rate after fresh versus frozen single blastocyst transfer(Frefro-blastocyst).A total of 800 women with regular menstrual cycles undergoing their first cycle of in-vitro fertilization after frozen-thawed single blastocyst transfer.Endometrium preparation was performed with a natural cycle regimen or hormone replacement therapy(HRT)cycle regimen,at the discretion of local investigators.All pregnancies were followed up until delivery.Result(s):513 infertile patients who underwent natural cycles regimen and 287 who underwent HRT cycles regimen were analyzed.The incidences of maternal and neonatal complications were comparable between the natural cycle and HRT cycle regimen.Regarding the risk of gestational diabetes,gestational hypertension,pre-eclampsia,preterm delivery,small for gestational age and large for gestational age,the HRT cycle was still not a significant risk factor after adjusting for potential confounders.The natural cycle regimen yielded an insignificant higher total live birth rate[59.45%versus 50.17%,P=0.001,adjusted odds ratio(AOR)1.366,95%confidence interval(CI)0.975-1.913,adjusted P=0.07],clinical pregnancy rate(68.23%versus 58.89%,P=0.008,AOR 1.406,95%CI 0.992-1.991,adjusted P=0.055)and ongoing pregnancy rate(62.18%versus 52.61%,P=0.008,AOR 1.387,95%CI 0.988-1.948,adjusted P=0.059)than did the HRT cycle regimen.However,compared to natural cycles,HRT cycles were associated with a significantly higher risk of biochemical miscarriage(6.86%versus 18.18%,P<0.001,AOR 0.328,95%CI,0.176-0.611,adjusted P<0.001).Conclusion(s):The incidence of maternal and neonatal complications in natural cycle and HRT cycle regimens after frozen single blastocyst transfer were comparable.Frozen-thawed single blastocyst transfer in a natural cycle was associated with lower biomedical miscarriage than the use of the HRT cycle.Part ? Can single blastocyst transfer improve implantation rate compared with double blastocyst transfer?Objective:To determine the effect of single blastocyst transfer and double blastocyst transfer on embryo implantation rate,so as to make full use of embryos,improve clinical pregnancy rate and reduce the risk of assisted pregnancy.To provide clinical data support for promoting elective single embryo transfer(eSET)strategy.Methods:Patients who underwent vitrified-thawed blastocyst transfer in Reproductive Medicine Center of the First Affiliated Hospital of Wenzhou Medical University,from January 2013 to December 2019,were retrospectively analyzed.Inclusion criteria:the first or second cycle of embryo transfer,vitrified-thawed blastocyst transfer cycle after in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI)treatment.Exclusion criteria:uterine malformations(such as mediastinal uterus,uniangular uterus,bicornate uterus),severe intrauterine adhesions,hydrosalpinx,repeated implantation failure,recurrent abortion;simultaneous transfer of cleavage embryos and blastocysts in the same cycle;failure of blastocyst resuscitation and cancellation of the cycle.A total of 5730 cases were analyzed,including 2262 cases of single blastocyst transfer and 3468 cases of double blastocyst transfer.By comparing the implantation rate,biochemical pregnancy rate,clinical pregnancy rate,ongoing pregnancy rate,live birth rate,abortion rate,multiple pregnancy rate and preterm delivery rate of single and double blastocyst transfer,the related factors affecting embryo implantation were analyzed.Then the commonly used transfer strategies were divided into five groups:single good-quality embryo group,single lower-quality embryo group,double good-quality embryo group,good-quality plus lower-quality embryo group and double lower-quality embryo group.According to the results of the preliminary analysis,stratified analysis was carried out on the age<38 years old,?38 years old,and Day5,Day6 freezing days.Main outcome measures:implantation rate.Secondary outcome measures:live birth rate,multiple pregnancy rate.Results:After adjusting the confounding factors by multivariate logistic regression analysis,double blastocyst transfer was associated with the increase of biochemical pregnancy rate,clinical pregnancy rate,ongoing pregnancy rate,live birth rate,multiple pregnancy rate,late abortion rate and preterm delivery rate,and was related to the decrease of biochemical miscarriage rate and early abortion rate.Day6 cryopreservation days and advanced age were negatively correlated with biochemical pregnancy rate,clinical pregnancy rate,ongoing pregnancy rate and live birth rate,but positively correlated with high-quality embryo transfer.Therefore,it is speculated that the factors affecting embryo implantation include the number of transferred embryos,the quality of transferred embryos,age and embryo freezing days.When Day5 blastocyst was available for transfer,for women under 38-year old,the implantation rate of single good-quality embryo group was 53.45%which was significantly higher than that of single low-quality embryo group(40.03%),good-quality plus lower-quality embryo group(46.71%)and double lower-quality embryos group(42.22%)(P<0.01),and the trend was higher than that of double good-quality embryo group(50.46%)(P>0.01).There was no significant difference in implantation rate between DBT and SBT when low-quantity embryo transferred.The results showed that the live birth rate in each group was as follow:two good-quality embryo group(56.64%),good-quality plus lower-quality embryo group(55.33%),double lower-quality embryo group(51.05%)>single good-quality embryo group(42.76%)>single lower-quality embryo(30.74%).The multiple pregnancy rate in each transfer strategy group showed:double good-quality embryo group(50.19%)>good-quality plus lower-quality embryo group(42.31%),double lower-quality embryo group(37.04%)>single good-quality embryo group(1.48%)and single lower-quality embryo group(1.72%).For women aged 38 years or older,the implantation rate of single good-quality embryo group and single lower-quality embryo group was 39.77%,25.58%,which were significantly higher than that of good-quality plus lower-quality embryo group(21.25%)(P<0.01).There was no significant difference in live birth rate among groups.The highest multiple embryo rate was 57.69%in the double good-quality embryo group,and 21.43%in good-quality plus lower-quality embryo group and 29.17%in the double lower-quality embryo group,while no multiple embryo was found in the single embryo group.When Day6 blastocysts were available for transfer,for women aged<38 years,there was no significant difference in the implantation rate between single good-quality embryo group and other groups(P>0.01),while the implantation rate of single lower-quality embryo group was significantly lower than that of double good-quality embryo group and good-quality plus lower-quality embryo group(P<0.01),and there was no difference between single low-quality embryo group and double lower-quality embryo group(P>0.01).The results showed that the live birth rate in each group was as follows:double good-quality embryo group(52.28%)>double lower-quality embryo group(34.33%)>single lower-quality embryo group(21.09%),The good-quality plus lower-quality embryo group(43.03%)>single good-quality embryo group(28.04%)and single lower-quality embryo group.The multiple pregnancy rate in each group showed:double good-quality embryos group(37.29%),good-quality plus lower-quality embryo group(33.33%),double lower-quality embryo group(28.57%)>single good-quality embryo group(1.01%),single lower-quality embryo group.For women aged 38 years or older,there were no significant difference in embryo implantation rate,live birth rate and multiple pregnancy rate among the groups.Conclusions:In order to improve the live birth rate,Day5 blastocyst is preferentially transferred when there are Day5 and Day6 blastocysts at the same time,and high-quality embryos are preferentially transferred when there are both good-quality embryos and low-quality embryos.In order to improve embryo utilization and reduce the multiple pregnancy rate,single embryo transfer is recommended,especially when Day5 blastocyst is formed,so as to improve embryo implantation rate and avoid embryo waste.Double blastocyst transfer is not recommended for women aged 38 years or older who do not have a higher live birth rate than single embryo transfer,but increase the risk of multiple pregnancy.Part ? Coumulative live bitrh rate after single blastocyst versus single cleavage-stage embryo transferObjective:Using high quality evidence-based medicine data to investigate the effect of blastocyst transfer and cleavage-stage embryo transfer on cumulative live rate in single embryo transfer.To guide the clinical use of embryos more reasonably,reduce adverse pregnancy events,achieve the ideal purpose of healthy live birth,and make the best treatment decision for patients.Methods:It was conducted in Center for Reproductive Medicine,Shandong University from November 2018 to June 2019.The infertile women were randomly divided into cleavage-stage single embryo transfer group and blastocyst-stage single embryo transfer group.Inclusion criteria:age?20 years old and?40 years old;planned to undergo IVF or ICSI in the first or second cycle;and more than 3 embryos in cleavage stage.Exclusion criteria:abnormal uterine cavity,submucosal uterine fibroids or intrauterine adhesions;planned in vitro maturation(IVM),preimplantation genetic diagnosis/screening(PGD/PGS);hydrosalpinx visible under ultrasound;recurrent abortion;planned to undergo whole embryo frozen transfer;contraindications of assisted reproductive technology and pregnancy,or diseases with definite impact on pregnancy.The first live birth was the end of the study,and the first frozen embryo transfer was carried out if the fresh embryo cycle did not get live bitrh.If the live birth was not achieve,the second frozen embryo transfer was continued;if not,the third frozen embryo transfer was continued until the last embryo transfer.To compare the cumulative live rate of at least three consecutive single embryo transfers in one year between the two groups.Results:A total of 122 patients were enrolled in this study,including 61 in cleavage-satage group and 61 in blastocys-stage group.There were no significant differences in age,duration of infertility,menstrual regularity,secondary infertility,infertility reason,body mass index(BMI),antral follicle number,basic endocrine and anti-mullerian hormone(AMH)between the two groups(P>0.05).In the cleavage-stage group and blastocyst stage-group,the ovulation induction program,gonadotropin(Gn)dosage,luteinizing hormone(LH),estradiol(E2)and progesterone(P)levels on the day of human chorionic gonadotropin(hCG)injection,the fertilization mode,the number of oocytes retrieved,two pronuclear(2PN),cleavage of 2PN,transplantable embryos and high-quality embryos in Day3(D3),and the incidence rate of moderate to severe ovarian hyperstimulation(OHSS)were comparable.The number of frozen embryos in cleavage-stage group was(5.77±2.47),significantly higher than that in blastocyst-stage group(3.66±2.37)(P<0.05).There were 49 cases of fresh embryo transfer in the cleavage-stage group,and the fresh cycle transfer rate was 80.33%in the cleavage-stage group and 72.13%in the blastocyst-stage group.There was no significant difference in endometrium thickness between the two groups on the day of fresh embryo transfer.The live birth rate of cleavage-stage group was 42.86%,which was slightly higher than that of blastocyst-stage group(34.08%)(15/44),but there was no significant difference between the two groups(P>0.05).There was no significant difference in biochemical pregnancy rate,clinical pregnancy rate,abortion rate and ectopic pregnancy rate between the two groups.Except for one patient no blastocyst,the other patients who did not get live birth and those who did not transfer in fresh cycle underwent the first frozen embryo transfer.There were 40 cases in cleavage-stage group and 41 cases in blastocyst-stage group.There was no difference in endometrial preparation and endometrial thickness between the two groups.There was no significant difference in biochemical pregnancy rate and clinical pregnancy rate.The live birth rate of blastocyst group was 53.54%(22/41),which was higher than 37.50%(15/40)of cleavage group,but the difference was not statistically significant(P>0.05).In the second frozen embryo transfer cycle,the live rate of cleavage-stage group and blastocyst-stage group were 21.05%(5/11)and 33.33%(1/3),respectively,with no significant difference(P>0.05).In the third frozen embryo transfer cycle,there were 11 cases in cleavage-stage group and 3 cases in blastocyst-stage group.The live birth rate were 27.27%and 33.33%respectively.In the fourth frozen embryo transfer group,one case in cleavage-stage group had ongoing pregnancy,and two cases in blastocyst stage group got live birth.According to the intention-to-treat(ITT)analysis,the cumulative live birth rate of the two groups was 70.49%(43/61).According to the per-protocol(PP)analysis,the cumulative live birth rates of the two groups were 76.47%(39/51)and 70.49%(43/61),respectively.The incidence of premature birth,birth weight,cesarean section rate and sex ratio were not significantly different between the two groups.Conclusions:There was no significant difference in the cumulative live rate of single embryo transfer in cleavage stage and blastocyst stage after one-year follow-up. |
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