| Multiple pregnancy refers to a pregnancy in which there are two or more fetuses in the uterus at the same time.And a multiple birth was defined as the birth of two or more infants,at least one of whom was live-born.Infertility has shown rapid growth and younger trend in recent years,and assisted reproductive treatment is the main effective measure.At present,the assisted reproductive technology(ART)mainly includes artificial insemination(AI)and in vitro fertilization-embryo transfer(IVF-ET)and its derivative technology.The derivative technology of IVF-ET mainly includes intra cytoplasmic sperm injection(ICSI),frozen-thawed embryo transfer(FET),and preimplantation genetic disgnosis(PGD).Currently,approximately 1.5 million cycles of IVF are performed annually,resulting in the birth of 350,000 babies in worldwide since first ART-conceived infant was born in 1978.In order to improve clinical pregnancy rates,IVF-ET treatment usually transplants two or more embryos,and as such,assisted reproductive treatment greatly increases the chances of multiple pregnancies.Multiple pregnancies are the most common complication of ART,and the rise in multiple pregnancies is synchronous with the widespread use of ART.At present,multiple live births account for about 3% of the total number of live births,and the rate of multiple pregnancies with ART is about 30%.The incidence of multiple pregnancies in human natural pregnancy is related to genetic background,maternal reproductive age,and parity.In addition to the biological effects of these factors,ovarian stimulation therapy is an important cause of multiple births.The number of transplanted embryos,the number of eggs obtained,the quality of transplanted embryos,assisted hatching(AH),intracytoplasmic sperm injection(ICSI)and other embryo manipulations,prolonged embryo culture time,blastocyst transplantation etc.may affect the occurrence of multiple pregnancies during ART treatment.In the process of multiple pregnancies,there may be a phenomenon that the early embryo fails to continue to develop,and the number of the final delivered fetus is less than the number of early pregnancy embryo,which is called spontaneous reduction.The incidence of spontaneous reduction with ART ranged from 5% to 52.6%,about 30%.It has been found in previous studies that endometrial thickness and the number of transferred embryos were independent predictors of spontaneous reduction in IVF conceived multiple pregnancies.However,due to the small sample size,the results had some limitations.Further studies were conducted to further understand the influencing factors of spontaneous reduction following assisted reproductive technology.In summary,the assisted reproductive process increases the incidence of multiple pregnancies.Individual factors and clinical treatment factors may affect multiple pregnancies and spontaneous reduction.However,which factors have an impact and how it affected remains unclear.In view of the potential adverse effects of multiple pregnancies and spontaneous reduction on maternal and child health during assisted reproduction,our study was based on multi-center assisted reproductive diagnosis data,using a large sample case-control study design,in the first part to explore patients’ personal factors and assisted reproductive treatment factors on multiple pregnancies,in the second part to explore the influencing factors of spontaneous reduction.Through the above two parts of research,explore the factors affecting the multiple births of assisted reproductive.Part Ⅰ: Study on the influencing factors of multiple pregnancies after assisted reproduction technologyBackground: With the widespread use of human assisted reproductive technology,the consequent iatrogenic multiple pregnancy problems have become increasingly serious.In 2016,the rate of multiple pregnancies in China’s reproductive medicine center still exceeded 30%.Previous studies have explored factors affecting multiple pregnancies following ART treatment.Groeneveld et al.showed that the higher number of oocytes obtained from ovulation induction therapy was associated with an increased risk of dizygotic twins after double embryo transfer based on data from 6 598 Dutch women with IVF/ICSI treatment.Kim and Abdollahi also reported the association between age and embryo quality and multiple pregnancies.With regard to monozygotic twins in single embryo transfer,ICSI and AH may increase the risk,while Liu et al.only found that prolonging embryo culture time was associated with increased risk of monozygotic twins.Therefore,the current influencing factors for assisted reproductive multiple pregnancies are still unclear.Methods: The study included 19 434 embryo transferred cycles(14 765 singleton pregnancy cycles,4 669 multiple pregnancy cycles)resulted in clinical pregnancy from four reproductive centers in China(the First Affiliated Hospital of Nanjing Medical University,the Obstetrics and gynecology Hospital Affiliated to Nanjing Medical University,the Third Affiliated Hospital of Zhengzhou University,and the Shengjing Hospital of China Medical University),during January 2013 and December 2016.The odds ratio(OR)of the logistic regression model and its 95% confidence interval(CI)were used to assess the association of individual and clinical factors with multiple pregnancies.Statistical analysis was performed using R software(version 3.3.3).All statistical tests are two-sided test,test level α=0.05Result: In this study,the overall incidence of multiple pregnancies was 24.0% of all clinical pregnancies.Compared with singleton pregnancies,the age of women with multiple pregnancies is significantly younger,the duration of infertility is shorter,the dose of gonadotropin and the endometrial thickness on h CG trigger day are larger,and the progesterone level on h CG trigger day,the number of oocycts obtained and the cumulative embryo score are higher.In the multiple pregnancies cycles,fresh embryo transfer is preferred,and the infertility type is primary infertility,and two embryos and cleavage stage embryos are transplanted.In the univariate analysis,except for duration of infertility,estradiol level on h CG trigger day,and fertilization methods,the other factors were related to the probability of multiple pregnancies.In multivariable logistic regression analysis,transplanting two embryos was the major factor in multiple pregnancies,and the OR compared with single embryo transfer was 36.54,95% CI: 27.89-47.86.Age,cycle type,progesterone level on h CG trigger day,number of oocytes retrieved,stage of embryo transferred and cumulative embryo score were associated with multiple pregnancies from double embryo transfer(OR(95% CI)were: 0.62(0.55-0.70),0.84(0.77-0.92),0.86(0.80-0.92),1.21(1.12-1.31),1.28(1.13-1.46),1.19(1.15-1.23),respectively).High cumulative embryo score was the only factor associated with decreased risk of multiple pregnancies from single embryo transfer(OR: 0.68;95% CI: 0.47-0.99).Conclusion: Number of embryos transferred,age,cycle type,progesterone level on h CG trigger day,number of oocytes retrieved,stage of embryo transferred and cumulative embryo score were identified as related factors of multiple pregnancies following assisted reproductive technology.Part Ⅱ: Analysis on factors related to spontaneous reduction in twin pregnancy following assisted reproductive technologyBackground: The rapid spread of assisted reproductive technology has led to widespread attention in the anomalous event that occurred in this treatment.Multiple pregnancies are the most common complication of assisted reproduction.Reducing the number of fetuses in multiple pregnancies can reduce the incidence of maternal complications during pregnancy and improve perinatal outcomes.Therefore,multifetal pregnancy reduction(MFPR)has become the primary means to treat failure of primary prevention of multiple pregnancies.However,even if there are multiple pregnancies without MFPR,spontaneous fetal reduction may occur.Spontaneous reduction may increase the risk of neonatal cerebral palsy,premature birth and very low birth weight.Although the relative frequency of spontaneous reduction must be correctly considered when considering the MFPR,the factors causing the risk are relatively poorly understood,and the research sample size is small with certain limitations.Methods: 2 851 twin pregnant women after treatment of IVF-ET or ICSI cycles were enrolled at Assisted Reproductive Centre of the First Affiliated Hospital of Nanjing edical University,Nanjing Maternity Hospital and Shengjing Hospital of China Medical University from January 2013 to December 2016 respectively.According to the pregnancy outcome,the patients with spontaneous reduction were classified as case group(n=686),and those with normal twin birth after age frequency matching were classified as control group(n=2 165).Logistic regression model was used to analyze the related factors of the occurrence of spontaneous reduction.Result: The overall incidence of spontaneous reduction in this study was 18.8%(686/3648).The age of case group and control group were(30.55 ± 4.31)and(30.25 ± 4.02)years old respectively.In the univariate analysis,these statistically significant variables between the two groups: male infertility factor,gonadotropin dose,estradiol and luteinizing hormone level on h CG trigger day,number of embryo transferred,stage of embryo transferred,and endometrial type on h CG trigger day are associated with spontaneous reduction.After adjustment of male infertility factor,gonadotropin dose,estradiol level on h CG trigger day,number of embryo transferred,stage of embryo transferred,and endometrial type on h CG trigger day,multivariate logistic regression showed that compared with women with luteinizing hormone level less than 2.76 IU/L,the risk of spontaneous reduction increased by 33% of those with luteinizing hormone level higher than 2.76 IU/L(OR=1.33,95% CI=1.01-1.75,P=0.043).When transplanting 3 embryos,the OR(95% CI)of spontaneous reduction in pregnant women was 0.24(0.08-0.74).Embryo transfer at the blastocyst stage was 57% lower risk than that at the cleavage stage(OR=0.43,95% CI=0.28-0.68,P<0.001).Conclusion: Luteinizing hormone level on h CG trigger day,number and stage of embryo transfer were related factors to spontaneous reduction in twin pregnancy following assisted reproductive technology. |
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