新鮮周期或凍融周期移植課件

1、新鮮周期或凍融周期移植 這是個問題？新鮮與凍融周期移植歷史發(fā)展與目前趨勢the first pregnancy of a thawed cryopreserved human embryo was reported in 1983 in Australia , and the first live birth in 1984 in The Netherlands1988年AFS(ASRM)的IVFspecial interest group(SART) 首次報告1985至1986年ART數(shù)據(jù)：822個總?cè)焉镏?個FET妊娠，F(xiàn)ET小于1%In 1995,SART collaborated wi

2、th CDC to publish data:1282 FET births among12000 deliveries ,FET10%In 2012, 15408 FET births, accounting 1/3 ART births新鮮與凍融周期移植歷史發(fā)展與目前趨勢新鮮與凍融周期移植歷史發(fā)展與目前趨勢Initially, owing to low success rate, all available embryos were transferred in IVF treatments, that is to say, fresh ET almost always coincided

3、 with stimulation improvements of clinical and laboratory aspects of IVF(multiple follicular stimulations, egg retrieval, culture conditions) increased pregnancy rates increased risk of multiple pregnancies fewer embryos transferred supernumerary (second best) embryos need to be cryopreserved dramat

4、ic improvement in cryopreservation of eggs and embryosSegmentation of IVF process such that embryo replacement is avoided during the cycle of ovarian stimulation and egg retrievalCohort cryopreservation in case of OHSS etc.Embryonic/endometrial asynchrony might also be handled by cryopreservation an

5、d delayed ETPGS with trophectoderm biopsy requiring freezing embryos to allow time for genetic analysis .Cohort banking is routine after the use of a GnRH agonist trigger Accumulation of eggs/embryos over multiple cycles as a strategy for managing low responder patients 新鮮與凍融周期移植歷史發(fā)展與目前趨勢segmentatio

6、n of IVF process such that embryo replacement is avoided during the cycle of ovarian stimulation and egg retrievalEmbryo donation programs Embryo banking Fertility preservation for whom gonadotoxic chemotherapy is planned or are wishing to delay pregnancy for more than 1 years新鮮與凍融周期移植歷史發(fā)展與目前趨勢超排導致的

7、非（超）生理圍植入期環(huán)境的影響Superovulation is an integral part of IVF and results in supraphysiologic levels of multiple hormones and other factors, including E2, P, and VEGF etc. Forming a non(supra)physiologic(peri-implantation) environment during oocyte development and after embryo transfer, having multiple e

8、ffects to oocyte, endometrium, and implanting embryoEffect on oocyte超排導致的非（超）生理圍植入期環(huán)境的影響Effect on endometrium植入窗期內(nèi)膜腺體顯示核下空泡腺上皮表面出現(xiàn)胞飲突內(nèi)膜核仁通道系統(tǒng)出現(xiàn)動物實驗顯示超排卵影響表面上皮深度微絨毛的數(shù)目和深度表面上皮與基質(zhì)細胞有絲分裂活性IVF取卵日子宮內(nèi)膜活檢研究顯示多數(shù)樣本內(nèi)膜提前，年輕及獲卵數(shù)多提前更明顯超排導致的非（超）生理圍植入期環(huán)境的影響Effect on endometrium超排導致的非（超）生理圍植入期環(huán)境的影響Effect on endometr

9、ium超排導致的非（超）生理圍植入期環(huán)境的影響Groups I and II showed a secretory activity of the endometrium on the day of oocyte retrieval, the high P group showing a mean maturation advance of 0.7 day (P 3 days.Effect on endometriumthe timing of P exposure differs in a fresh cycle, the premature elevations in P often se

10、en during stimulation in a fresh cycle do not occur in a frozen cycleelevations of P during superovulation(before hCG administration), shifting the time period that the endometrium is receptive to the implanting embryoEffect on endometrium內(nèi)膜容受窗的移動（shift）影響妊娠，提前超過3天與植入失敗相關超排導致的非（超）生理圍植入期環(huán)境的影響（一定水平的雌激

11、素有利于妊娠，但雌激素水平過高會降低妊娠率）Effect on endometrium超排導致的非（超）生理圍植入期環(huán)境的影響Effect on endometrium超排導致的非（超）生理圍植入期環(huán)境的影響Effect on endometrium超排導致的非（超）生理圍植入期環(huán)境的影響women with a PE of 0.81.1 ng/mL had a lower chance of pregnancy compared with women with progesterone levels 0.8 ng/mL (odds ratio OR 0.79, 95% confidence

12、interval CI 0.670.95)no effect of PE on pregnancy chances was observed when embryos resulting from women exhibiting PE on the day of hCG were cryopreserved and transferred in a subsequent cycle (OR 1.03, 95% CI 0.791.34) The same results hold for embryo transfers in donor-recipient cycles (OR 1.18,

13、95% CI 0.761.84)Effect on endometrium超排導致的非（超）生理圍植入期環(huán)境的影響Pregnancy rates were not decreased when these embryos were transferred in subsequent frozen-thaw or in donor-recipient cycles, demonstrating the detrimental effect of the elevated P is on the endometrium, not the embryoEffect on endometrium超排導

14、致的非（超）生理圍植入期環(huán)境的影響D5囊with COS VS D6囊 with COS 高 VS D6囊 w/o COS 無差異D5囊w/o COS VS D6囊 with COS 高 VS D6囊 w/o COS 無差異D6囊Fresh ET VS D6囊 FET 低Shared oocytes供卵者自身鮮周期妊娠率 VS 受卵者妊娠率 低 （with COS） (w/o COS) Effect on endometrium超排導致的非（超）生理圍植入期環(huán)境的影響內(nèi)膜組織學提前（年輕、卵多）PE胚胎發(fā)育慢Effect on endometrium超排導致的非（超）生理圍植入期環(huán)境的影響超排

15、導致的非（超）生理圍植入期環(huán)境的影響Effect on endormetrial immue 子宮內(nèi)膜免疫在種植中發(fā)揮重要作用，現(xiàn)已證實NK細胞、血管內(nèi)皮生長因子（VEGF）和內(nèi)膜容受性相關種植發(fā)生時，NK 細胞分泌白介素-15將NK細胞轉(zhuǎn)化為蛻膜NK細胞，其分泌多種因子包括血管生成因子如VEGF、活化因子、生長因子如LIF，對種植是重要的超排導致的非（超）生理圍植入期環(huán)境的影響Effect on endormetrial immue 小鼠實驗（NK細胞）：Percentage of total NK cells (CD56 + CD3) on all endometrial cells (a

16、) and percentage of CD56brightCD16-on total NK cells (b) as assessed by ow cytometry in endometrial biopsies from fertile oocyte donors in natural and ovarian stimulated cycles with and with-out local injury treatment. *P 150 genes, including genes regulating angiogenesis and early implantation.(人體研

17、究)對促排卵周期供卵者和自然周期進行內(nèi)膜活檢，結果顯示，二者間有150個基因表達存在差異，其中很多基因在血管生成和早期種植方面有重要作用。對子宮內(nèi)膜相關基因表達的影響對宮外孕發(fā)生的影響有認為IVF鮮周期妊娠的EP風險高于自然妊娠，部分原因是雌激素對子宮收縮的作用及PE對cilia的影響超排導致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryoextension of the Barker hypothesis1995年，巴克提出“成人疾病的胎兒起源”假說（Fetal origins of adult disease，F(xiàn)OAD），即著名的“巴克假說”（Bark

18、er hypothesis），后發(fā)展成“健康和疾病的發(fā)育起源（DOHaD）”的理論。in utero stress may affect childhood development and propensity to adult disease Said another way, health at the time of or even before conception(periconceptional events) may affect in utero and childhood development, predisposition for adult disease.Natura

19、lly conceived blastocysts were flushed and transferred to pseudopregnant females after either natural mating (control) or gonadotropin administration and mating (experimental), Pregnant mice were then sacrificed near term (embryonic day 19) and the resultant placentas and fetuses isolated超排導致的非（超）生理

20、圍植入期環(huán)境的影響Effect on implanting embryoeffect of superovulation on Embryonic Development and Fetal Growth體外研究：將小鼠胚胎置于育齡期婦女內(nèi)膜中，并使胚胎暴露于高劑量雌激素環(huán)境中，最終導致胚胎發(fā)育受損及粘附力下降超排導致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryo人體研究：高雌激素水平增加與異常胎盤形成有關的妊娠并發(fā)癥的風險-除OHSS外還要關注的一個問題超排導致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryo超排導

21、致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryo超排導致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryo與COS exposure后的鮮周期移植有關的風險包括pre-eclampsia, low birth weight(LBW), small for gestational age (SGA), prematurity, preterm LBW, antepartum hemorrhage, placental abruption, and perinatal deathmeta-analysis reported

22、 that, when compared with fresh-transfer pregnancies, FET pregnancies were associated with significantly reduced risks of preterm birth (RR 0.84), SGA (RR 0.45), LBW (RR 0.69), perinatal mortality(RR 0.68), placental abruption (RR 0.44), and placenta previa (RR 0.71). Risks of very preterm birth, ve

23、ry LBW, congenital anomalies, and neonatal intensive care did not differ significantly. Increased risk of cesarean section delivery was observed with FET (RR 1.10) .FET was associated with reduced risk of preterm birthAn Australian registry study compared birth defects after fresh transfers and FET

24、with fertile controls, and found fresh transfer had increased risk for birth defects when compared with fertile controls, but found no significantly elevated risks with FET vs. fertile controls. Another Australian study of 6,946 birth outcomes found that the risk of blastogenesis birth defects was s

25、ignificantly greater after fresh transfer when compared with spontaneous pregnancies, but that births after FET did not exhibit this increased risk超排導致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryoA relatively small clinical study comparing fresh transfer and elective cohort cryopreservation followed b

26、y FET in high responders found reduced risk of pre-eclampsia with FET .An American registry study compared singleton births resulting from fresh autologous cycles, autologous FET, fresh oocyte donation cycles, and donor FET and found increased risk of LBW in fresh cycles when compared with FET. Howe

27、ver, when fresh donor cycles were compared with donor FET, no such differences were observedOne retrospective clinical study compared singleton births resulting from 2,531 fresh transfers and 4,092 FETs. This study used minimal stimulation (CC in combination with low-dose Gn) and single embryo trans

28、fer. No significant differences in prematurity, total birth defects, or perinatal mortality were found, but greater birth weight and reduced incidences of LBW and SGA with FET were reported.超排導致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryo超排導致的非（超）生理圍植入期環(huán)境的影響Effect on implanting embryoEpigenetic Chang

29、es to the EmbryoStudies of mouse oocytes have shown that superovulation has an effect not only on the methylation of the developing oocyte, but also on the developing embryo, with loss of methylation in select imprinted genes seen after superovulationLoss of methylation owing to a nonphysiologic ute

30、rine environment may have effects on placentation and fetal growthdisadvantages of cryopreservationpossibly altered embryo competence and subsequent implantationincreased spindle abnormalities have been demonstrated in(day 5) vitrified blastocysts compared with fresh blastocystsGenes involving the a

31、poptosis/stress pathway (BAX), pluripotency pathway(NANOG, SOX2, CDX2), maternal effect genes (ZAR1,EIF1AX, TSC2) were significantly altered in frozen-thawed embryos compared with freshly cultured embryos from the same developmental stagebe cryopreserved at all stages of preimplantation developmentM

32、ethod of cryopreservationif clinic uses very strict criteria, i.e., only top-quality embryos are cryopreserved, their success rates after FET will be higher compared with a clinic with lower cut-off criteria. however, they will conduct fewer FET cycles per initiated fresh cycle and thus in aggregate

33、 the contribution of cryopreservation to their cumulative success rates, i.e., the chance of live birth per initiated cycle is likely to be lowerCriteria for judgement to frozen-thaw survival and transferExtended culture after thawingdisadvantages of cryopreservationCost from freezing procedure and

34、the medications and monitoring required in some FET protocolsTimestressin the near absence of OHSS risk, esp after agonist trigger, it may be tempting to increase Gn dose to maximize oocyte yielddisadvantages of cryopreservationIt is nave to say that supraphysiologic environment is all simply relate

35、d to estrogen levels, even if estrogen levels are an appropriate surrogate marker for other molecular changeswe do not know at what threshold a cycle becomes supraphysiologic.; whether supraphysiologic conditions result from the use of Gn(at any dose) ;whether alterations occur only when stimulation thresh