4 What we DO agree on….Frozen embryo transfers are an important part of successful IVF clinicsVitrification has improved freezing success with both embryos and oocytesEndometrial-Embryo synchrony is very important for successful implantationAbsolute risks of both approaches are overall quite small
5 FRESH OR FROZEN EMBRYO TRANSFER??? Where we differ…What is the best first line approach…FRESH OR FROZEN EMBRYO TRANSFER???
6 What is the best FET cycle approach? Timing of embryo cryopreservation?2PN, CD2/3, CD5/6Slow-freezing vs vitrification?Transfer in a medicated or natural cycle?Use of leuprolide?Recommended number of embryos to transferCulture media?Frequency of SET?Timing of progesterone start?
7 Slow-freezing vs Vitrification: Perinatal risk No perinatal risks D3 embryosLiu SY, Hum Reprod 2013Shi W, Fertil Steril 2012No perinatal risks D5/6 embryosTakahashi K, Fertil Steril 2005 (no diff congenital defects)Wikland M, Hum Reprod 2010 (vit blastocyst vs D3 slow)The majority of perinatal risk data is from slow freezing and cleavage stage embryosAbout 4000 babies first couple studies
8 Is extended embryo culture ideal? Yes, for improving implantation and pregnancy rates, and minimizing higher order multiplesBUT D5/6 transfer as compared to D3 increases the risk of Preterm Delivery by 30-40%US: Kalra S et al. Obstet Gynecol 2012; SART data, 69,039 LB, fresh ETCanada: Dar S et al. Hum Reprod 2013; 12,712 LBSweden: Kallen B et al. Fertil Steril 2010; 13,873 LBD5/6 vs D3 also with increased absolute birthweight and incidence of LGAChina: Zhu J et al. Hum Reprod 2014; 2,929 singletons, fresh,Makinen S, Hum Reprod 20132/3 CD3; SARTFresh, no diff in LBW %China study-difference pt bias, initial tx d3 tfr; day 5/6 if past implantation failure
9 Fresh vs Frozen: Perinatal risks Numerous cohort and meta analyses suggest outcomes better with FET as compared to fresh (SGA, LBW, PTD) but still worst than spontaneousPelkonen 2010, Pinborg 2010, Sazonova 2013, Wennerholm 2009, Maheshwari 2012, Pinborg 2012No difference in birth defects in fresh vs FETMeta-analysis: Maheshwari A, Fertil Steril 2012; OR 1.1 ( )Hansen M Obstet Gynecol 2012, Davies NEJM 2012, Jalliday JL Hum Reprod 2010-most data with slow-freezingSGA, LBW and PTD often better with FET
10 Fresh vs Frozen: Perinatal risks BUT, Numerous studies suggest increased risk of LGA and macrosomia with FET vs fresh or spontaneousPelkonen 2010, Pinborg 2010, Sazonova 2012Wennerholm 2013: Nordic cohort, CoNARTaS group: 6647 FET, fresh, spontaneous singletons-increased risk LGA, macrosomia, and perinatal mortality (49% increase)Wennerholm 2013, most slow freeze, day 2, txfr natural cyclePerinatal risk: stillbirth> or equal 28 wks to neonatal deathAdj for mat age, parity, year of birth, gender, country
11 Perinatal risks: LGAIs the epigenetic regulation of the placenta altered?Nelissen 2011, Vergouw 2012Denmark study FET vs fresh, sibling subgroup 2-4 fold higher incidence of LGA in FET siblings; Pinborg 2014Is it in vitro culture media/methods?Young 1998 (cattle/sheep), Dumoulin 2010, Nelissen 2012In mice imprinting changes with in vitro culture more pronounced with freezing; Market-Velker 2010Is it the extended culture issue?Makinen 2013An endometrial synchrony issue?Wilmut I 1981; D3 sheep embryos transferred to advanced lining caused 40% increased fetal sizePinborg 2014, >99% FET slow frozen CD2
12 Perinatal risks: LGA More recent vitrification data Kato et al, 2012; Japan ( cycles)4092 vitrified SET vs 2531 fresh SETTransfers D2 and D5LGA crude OR 1.51 ( ), aOR 1.23 ( ) after adjustments including blastocyst cultureD3 fresh vs D3 vitrified-no difference perinatal outcomes in generalLiu SY et al 2013, Shi W et al 2012
13 And for SGA…?Fresh may have increased risk of SGA as compared to frozenHelmerhorst 2004, Jackson 2004, McDonald 2009Though underlying infertility etiology and supraphysiologic levels of hormone may be more to blame…Cooper A 2011 Fertil Steril1200 vs 460 F vs I; infertile had smaller neonates and more LBW than fertile at birth and in the first trimester; Within infertiliy subgroups no differences
14 Wash U fresh vs frozen sibling study CRL did not differ between the groups (difference 1.3 mm, 95% CI -1.1 to 3.7)No difference in birthweight between fresh & FET singleton siblings (difference 129 grams, 95% CI -155 to 412)FET singletons had a significantly shorter gestation than their fresh IVF siblings, delivering on average 14 days earlier (95% CI 3-25 days; p=0.01)Fresh (n=23)Frozen (n=23)p valueCrown Rump Length(millimeters)8.3 ± .87.3 ± 1.0p =.86Birthweight(grams)3280 ± 1003248 ± 158p = .87Gestational Age at Birth(days)252 ± 3241 ± 4p = .01O’Neill KE and Cooper AR. Fertil Steril 2010; 94(4); S19Primary outcome were size (measured in the 1st trimester with CRL in mm and at birth with weight in grams) and gestational length measured in days.
15 Perinatal risks: Neurodevelopment? Swedish study, births (2.5 million infants, 1.2% by IVF)IVF vs spont, ICSI vs no ISCI, fresh vs frozenNo increased risk of autism in fresh vs frozen, ICSI vs no, only with surgically extracted spermaRR MR if fresh + ICSI 1.47 ( ), ICSI + frozen + preterm birth 3.47 ( )When adjusting for singletons only ICSI + frozen remained significant for MR; 2.36 ( )Sandin S et al, JAMA 2013Rate per 100,000 person years. AR smallEvolving theories of epigenetics in brain developmentIncidence of autism and MR 1-1.5%Risk of MR in IVF vs spont disappeared w singletons onlyBlastocyst data available for 2002+, subanalysis no difference though smaller numbers
16 The forest through the trees… Subtle differences at birth mayhave health consequences thatmanifest as adultsBarker hypothesisGrace and Sinclair 2009 (animal review)Ceelen M, 2008; higher BP/FBG8-18 y/o ART kidsHart and Norman 2013; higher BP/FBG in ART adultsWe need to sort out the underlying etiologies
17 An additive (or masking) effect? Ovarian Stimulation…In subtle epigenetic effects…?In vitro maturationExtended Culture…Is cryo just one more piece…?Cryo-Preservation
18 Other issues with FET Additional cost Disposition of excess embryos Optimal length of storage for vitrification?