Published 23 July 2019
A new cohort study suggests a higher risk of pre-eclampsia from frozen embryos transferred in cycles programmed with hormone therapy than in natural cycles.
Preliminary data presented in Vienna by ESHRE's EIM Consortium for ART activity in 2016 show that, while IVF and ICSI use and success appear to have peaked, frozen embryo transfers continue their exponential rise. Pregnancy rate per FET in 2016 was 30.5%, an increase over 2015 of 1.3%, while around one half of all European cycles analysed by ESHRE were transfers from frozen embryos, also an increase over 2015. Christian de Geyter, outgoing chair of the Consortium, said the number of FETs was likely to increase as more and more clinics adopt a single embryo transfer policy or take up 'freeze-all' strategies.
In the USA the picture is even more dramatic. In its latest national report the Centers for Disease Control and Prevention (CDC) described the escalation in elective FET as 'dramatic', plotting a rise from almost zero cycles in 2007 to 65,840 in 2016.(1) According to CDC, these cycles - variously identified as 'banking', 'freeze-all', or 'segmentation cycles' - 'were started with the intent of cryopreserving and storing all resulting eggs or embryos for potential future use', and remarkably accounted for 25% of all IVF/ICSI cycles in the USA in 2016.
Similarly, the latest data reported from the Japan Society of Obstetrics and Gynecology for 2016 show that 41% of all IVF/ICSI treatments (from a total of 251,399 egg retrieval cycles) were freeze-all.(2) This Japanese report notes 'a significant transition to the freeze‐all policy' in 2016.
As we have noted in earlier reports, the evidence supporting a freeze-all strategy is patchy at best. Several trials (and a major meta-analysis) have found outcome benefit only in high responders - and only one in normally ovulating subjects.(3,4) Commenting on the latter study in The Lancet - and recently in conversation with Focus on Reproduction in Vienna - former ASRM President Christos Coutifaris drew attention to this study's three-times higher risk of pre-eclampsia in the FET patients, which, he speculated, might be attributed to hormonal programming (or not) prior to transfer.(5) In support of his suggestion, Coutifaris noted a recent study showing that pregnancies after natural (non-programmed) frozen transfer cycles and in the presence of a corpus luteum had a lower risk of pre-eclampsia than pregnancies in hormonally programmed cycles without a corpus luteum.(6) 'This observation needs to be investigated further,' wrote Coutifaris, 'because it could significantly alter the optimal protocol for frozen embryo transfer cycles in ovulatory patients, further modifying these patients’ risk of pre-eclampsia.'
And there is indeed now further evidence of this pre-eclampsia risk associated with preparation methods for FET in ART.(7) A huge retrospective analysis from Japan (>100,000 cycles) has found that, while pregnancy and live birth rates from FET in a hormonally programmed cycle were slightly lower than in non-programmed cycles, pregnancies after hormonal preparation had significantly higher risk of pregnancy hypertension (OR 1.43) and placenta accreta than those following natural cycle transfers. As Coutifaris had proposed in The Lancet, the Japanese investigators also conclude that 'the association between the endometrium preparation method and obstetrical complication merits further attention'. And as background to their study they note that 'the best method of preparing the endometrium for embryo transfer remains unknown', with the choice apparently between hormone replacement with estrogen and progesterone or 'normal ovulation'. The same group had already analysed the Japanese ART registry to find a higher rate of Cesarean sections and late deliveries in hormonally primed frozen transfers than in natural.(8)
The Chinese trial recently published in The Lancet showed that deferred frozen single blastocyst transfer in these normally ovulatory women did result in significantly higher rates of singleton live birth than from fresh transfers (50.4% vs 39.9%; RR 1·26).(4) It was this outcome benefit - shown in this study for the first time in normo-responders - which prompted Coutifaris to ask if this gain in live birth rate now 'justifies the observed increase in perinatal complications and supports the recommendation of elective frozen embryo transfer for all blastocyst-stage embryos'. As he told Focus on Reproduction in Vienna, and as suggested in his Lancet editorial, the likely answer is 'no' - or at least not yet. The other complication in the equation, of course, is OHSS, whose risk appears reduced in many freeze-all studies (though not the Chinese trial).
Meanwhile, results from the latest freeze-all trial, presented as preliminary data during an open session in Vienna, have again shown no outcome benefit for freeze-all over fresh transfers. 'Our findings give no support to a general freeze-all strategy in normally menstruating women,' said investigator Dr Sacha Stormlund from Copenhagen University Hospital. 'The results of this trial were as we expected, namely, to see similar pregnancy rates between the fresh and freeze-all treatment groups.' However, there was a safety benefit apparent from a freeze-all segmentation policy when 25 of the 220 patients in the fresh transfer group were judged at risk of OHSS towards the end of their treatment cycle and, to remove the risk, were switched to the freeze-all group.
1. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2016 Assisted Reproductive Technology National Summary Report.
2. Ishihara O, Jwa SC, Kuwahara A, et al. Assisted reproductive technology in Japan: A summary report for 2016 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology. Reprod Med Biol 2019; 18: 7-16.
3. Roque M, Haahr T, Geber S. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2-14.
4. Wei D, Liu J-Y, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet 2019; 393: 1310-1318.
5. Coutifaris C. Elective frozen embryo transfer for all? Lancet 2019; 393: 1264-1265.
6. von Versen-Höynck F, Schaub AM, Chi YY, et al. Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum. Hypertension 2019; 73: 640-649.
7. Saito K, Kuwashara A, Ishikawa T, et al. Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus. Hum Reprod 2019; doi:10.1093/humrep/dez079.8. Saito K, Miyado K, Yamatoya K, et al. Increased incidence of post-term delivery and cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle. J Assist Reprod Genet 2017; 34: 465–470.