Advertisement

Vitrification and the demise of fresh treatment cycles in ART

Published:April 29, 2020DOI:https://doi.org/10.1016/j.rbmo.2020.03.017

      Abstract

      The advent of vitrification has transformed the therapeutic landscape in assisted reproductive technology. Clear evidence for this is provided by the dramatic rise in the number of frozen embryo transfer (FET) cycles being carried out annually. In this review, we examine the reasons that underlie this trend and the current evidence that points to the place FET cycles will come to inhabit in the future. Safety issues have been central to the narrative around the clinical application of vitrification and, as the evidence base grows, the risk benefit balance will become clearer for different patient groups. These will include recipients of donor eggs, as in some centres the use of cryopreserved donor eggs now exceeds that of fresh oocytes. Efficient cryopreservation techniques have also affected international transport of gametes and embryos, increasing international access. The profound changes that vitrification has created promises to fulfil a prediction made by this journal's founding Editor, Bob Edwards, that embryo and cryopreservation would solve many of the challenges presented by assisted reproductive technology.

      KEYWORDS

      Introduction

      There is good evidence that embryos and blastocysts, as well as oocytes, survive in greater numbers after vitrification than after slow freezing (
      • Rienzi L.
      • Gracia C.
      • Maggiulli R.
      • LaBarbera A.R.
      • Kaser D.J.
      • Ubaldi F.M.
      • Vanderpoel S.
      • Racowsky C.
      Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance.
      ). Evidence in support of this remarkable observation has been strong enough to cause a decade-long increase in treatments with cryopreserved embryos in autologous cycles and cryopreserved eggs and embryos in autologous and heterologous cycles. This visible shift in approach is now reflected in three publications of recent (2016) registry data, from the USA, Japan and UK, in which the uptake of vitrification is evident in IVF and intracytoplasmic sperm injection (ICSI), and in the continuing widespread use of preimplantation genetic testing for aneuploidies (PGT-A).

      Increasing everyday use of vitrification in autologous cycles

      In its latest national report, the Centers for Disease Control and Prevention (CDC) described the escalation in elective frozen embryo tranfser (eFET) in the USA as 'dramatic', plotting a rise from almost zero eFET cycles in 2007 to 65,840 in 2016 (

      Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2016 Assisted Reproductive Technology National Summary Report.

      ). 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 (Figure 1).
      Figure 1
      Figure 1Number of assisted reproductive technology cycles carried out for banking all fresh non-donor eggs or embryos between 2007 and 2016. Centers for Disease Control and Prevention, American Society for Reproductive Technology, 2016; Assisted Reproductive Technology National Summary Report.
      Unfortunately, such figures are not yet available for global or European comparison. The latest published results from the European Society of Human Reproduction and Embryology's (ESHRE) European IVF Monitoring Consortium were for 2014, when FET cycles represented 24.7% of all activity, although this clearly included additional transfers after an initial fresh transfer (
      • De Geyter C.
      • Calhaz-Jorge C.
      • Kupka M.S.
      • Wyns C.
      • Mocanu E.
      • Motrenko T.
      • Scaravelli G.
      • Smeenk J.
      • Vidakovic S.
      • Goossens V.
      ART in Europe
      2014: results generated from European registries by ESHRE: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE).
      ). A press release issued by ESHRE last year and referring to preliminary European data for 2015 reported that, in 15% of all cycles monitored, all embryos were cryopreserved before later transfer, with uptake of this 'freeze-all' approach increasing by 7% on the previous year. Similarly, the latest global data published from the International Committee for Monitoring ART relate only to activity in 2011, although a preliminary report presented at ESHRE's Annual Meeting in 2018 (for 2015) estimated a global total of more than 130,000 freeze-all cycles, with more than half of them in Japan.
      Indeed, as the International Committee for Monitoring ART here suggests, the greatest indication of the rising appeal of a freeze-all programme comes from Japan. 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 (
      • Ishihara O.
      • Jwa S.C.
      • Kuwahara A.
      • Ishihara O.
      • Jwa S.C.
      • Kuwahara A.
      • Ishikawa T.
      • Kugu K.
      • Sawa R.
      • Banno K.
      • Irahara M.
      • Saito H.
      Assisted Reproductive technology in Japan: A summary report for 2016 by the Ethics committee of the Japan Society of Obstetirics and Gnecology.
      ). Moreover, 82.7% of the subsequent embryo transfers were single, which is among the highest in the world. This Japanese report notes 'a significant transition to the freeze-all policy' in 2016, recognized by the authors as 'an effective treatment option for patients at high risk for ovarian hyperstimulation syndrome (OHSS)'.
      The third registry report from the UK similarly states that the number of FET cycles 'has increased year on year and, in 2015, for the first time, birth rates from frozen embryo cycles surpassed those from fresh cycles' (HFEA, 2019). The Human Fertilisation and Embryology Authority (HFEA) report notes that, in 2016, 31% of all IVF cycles were 'frozen', which presumably includes freeze-all and additional transfers after an initial fresh cycle. This was an increase of 39% from 2014. With a 22% pregnancy rate (per transfer), these frozen cycles were marginally more successful than the fresh (21%).

      Evidence to explain the trend

      Why this seismic shift from fresh to frozen embryo transfers? First, benefits in frozen transfer cycles were emerging. Cryopreservation clearly allowed the storage of supernumerary embryos, thus enabling subsequent transfers without the immediate need for further stimulation. Moreover, as early as 1990 it became evident that the deferred transfer of frozen–thawed embryos provided important safety benefits against the risks of OHSS (
      • Amso N.
      • Ahuja K.K.
      • Morris N.
      • Shaw R.W.
      The management of predicted ovarian hyperstimulation involving gonadotropin-releasing hormone analog with elective cryopreservation of all pre-embryos.
      ).
      • Devroey P.
      • Polyzos N.P.
      • Blockeel C.
      An OHSS-Free Clinic by segmentation of IVF treatment.
      , in their concept of an OHSS-free clinic, had emphatically explained how the freeze-all component of a segmentation protocol for IVF could eliminate the risk of OHSS. An increasing understanding of the effect of ovarian stimulation on endometrial maturation and receptivity also emerged (
      • Macklon N.S.
      • Stouffer R.L.
      • Giudice L.C.
      • Fauser B.C.
      The science behind 25 years of ovarian stimulation for in vitro fertilization.
      ). Ameliorating this by segmenting treatment between the embryo generation and embryo implantation phase became feasible with the increased efficiencies offered by vitrification over slow freezing that became apparent within the first decade of this century (
      • Kolibianakis E.M.
      • Venetis C.A.
      • Tarlatzis B.C.
      Cryopreservation of human embryos by vitrification or slow freezing: which one is better?.
      ;
      • Rezazadeh Valojerdi M.
      • Eftekhari-Yazdi P.
      • Karimian L.
      • Hassani F.
      • Movaghar B.
      Vitrification versus slow freezing gives excellent survival, post warming embryo morphology and pregnancy outcomes for human cleaved embryos.
      ). Improved survival rates, of day-3 and day-5 embryos were reported in numerous later studies, including a systematic review that found vitrification superior to slow-freezing in clinical outcomes and cryosurvival for oocytes, cleavage-stage embryos and blastocysts (
      • Crawford S.
      • Boulet S.L.
      • Kawwass J.F.
      • Jamieson D.J.
      • Kissin D.M.
      Cryopreserved oocyte versus fresh oocyte assisted reproductive technology cycles, United States, 2013.
      ;
      • Rienzi L.
      • Gracia C.
      • Maggiulli R.
      • LaBarbera A.R.
      • Kaser D.J.
      • Ubaldi F.M.
      • Vanderpoel S.
      • Racowsky C.
      Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance.
      ). Indeed, the HFEA attributed its overall increase to 'improvements in freezing processes and the increased uptake in single embryo transfer'. The eFET results in both the 2016 Japanese and CDC updates, however, also suggest an improvement in eFET outcome, with the latter's real-life snapshot of higher pregnancy, live birth and singleton live birth rates than found with fresh transfers (56.3% versus 44.7%; 45.9% versus 36.3%; and 39.5% versus 29.3%, respectively).
      An analysis of freeze-all cycles from the Society of Assisted Reproductive Technology, based on the same US registry data but from 2014–2015, found better results (clinical pregnancy and live birth) only in high responders (61.5% versus 57.4%, 52.0% versus 48.9%, respectively), but not in the general ART population (
      • Acharya K.S.
      • Acharya C.R.
      • Bishop K.
      • Harris B.
      • Raburn D.
      • Muasher S.J.
      Freezing of all embryos in in vitro fertilization is beneficial in high responders, but not intermediate and low responders: an analysis of 82,935 cycles from the Society for Assisted Reproductive Technology registry.
      ). This same favourable bias towards high responders was also found in two important trials published in the New England Journal of Medicine in 2016 and 2018. The first randomly assigned 1508 anovulatory women with polycystic ovary syndrome to either fresh embryo transfer or embryo freezing followed by FET, with results showing a higher live birth rate in the freeze-all group (49.3% versus 42.0%) (
      • Chen Z.-J.
      • Shi Y.
      • Sun Y.
      • Zhang B.
      • Liang X.
      • Cao Y.
      • Yang J.
      • Liu J.
      • Wei D.
      • Weng N.
      • Tian L.
      • Hao C.
      • Yang D.
      • Zhou F.
      • Shi J.
      • Xu Y.
      • Li J.
      • Yan J.
      • Qin Y.
      • Zhao H.
      • Zhang H.
      • Legro R.S.
      Fresh versus frozen embryos for infertility in the polycystic ovary syndrome.
      ). It was, therefore, surprising when the second trial failed to find any difference in live birth rate in women with normal ovulatory cycles (
      • Shi Y.
      • Sun Y.
      • Hao C.
      • Zhang H.
      • Wei D.
      • Zhang Y.
      • Zhu Y.
      • Deng X.
      • Qi X.
      • Li H.
      • Ma X.
      • Ren H.
      • Wang Y.
      • Zhang D.
      • Wang B.
      • Liu F.
      • Wu Q.
      • Wang Z.
      • Bai H.
      • Li Y.
      • Zhou Y.
      • Sun M.
      • Liu H.
      • Li J.
      • Zhang L.
      • Chen X.
      • Zhang S.
      • Sun X.
      • Legro R.S.
      • Chen Z.J.
      Transfer of fresh versus frozen embryos in ovulatory women.
      ). The results from these two trials are clearly reflected in the latest meta-analysis of fresh and frozen transfers, which also found eFET associated with a higher live birth rate only in hyper-responders (
      • 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.
      ). No outcome difference was found between fresh and frozen transfers in normal responders, nor in the cumulative birth rate of the two overall groups, leaving the authors to conclude that 'currently there are no clinical data supporting the indiscriminate use of eFET for all patients submitted to IVF/ICSI'.
      That view, however, may well now have changed with the publication of a large trial whose findings, the authors write, have 'practice changing implications' (
      • Wei D.
      • Liu J.-Y.
      • Sun Y.
      • Shi Y.
      • Zhang B.
      • Liu J.Q.
      • Tan J.
      • Liang X.
      • Cao Y.
      • Wang Z.
      • Qin Y.
      • Zhao H.
      • Zhou Y.
      • Ren H.
      • Hao G.
      • Ling X.
      • Zhao J.
      • Zhang Y.
      • Qi X.
      • Zhang L.
      • Deng X.
      • Chen X.
      • Zhu Y.
      • Wang X.
      • Tian L.F.
      • Lv Q.
      • Ma X.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.
      ). This was a randomized trial conducted at 21 centres in China in which 1650 good-prognosis patients were assigned to either fresh or frozen single blastocyst transfer. This time, unlike in previous trials, results showed that deferred frozen single blastocyst transfer in these normally ovulatory women resulted in significantly higher rates of singleton live birth than did fresh (50.4% versus 39.9%; RR 1.26, 95% CI 1.14 to 1.41; P < 0.0001). This was the first time a randomized trial had found improved live birth rates in normal responders, and not in high responders.
      The results also showed a higher rate of pre-eclampsia in the freeze-all patients and a similar rate of OHSS in both groups. This greater incidence of pre-eclampsia prompted an accompanying editorial in The Lancet to ask if the gain in live birth rate 'justifies the observed increase in perinatal complications and supports the recommendation of elective frozen embryo transfer for all blastocyst-stage embryos' (
      • Coutifaris C.
      Elective frozen embryo transfer for all?.
      ). Therefore, in asking if the live birth results alone would now support eFET 'for all', Christos Coutifaris, a former president of the American Society for Reproductive Medicine, seemed to think not. In addition to the higher risk of pre-eclampsia, he noted 'other unresolved issues' in the emotional and financial costs of deferred transfer and the efficacy of freeze-all in older and poor-prognosis patients.
      Among these other 'issues' is a question of long-term safety, which was raised in 2019 in a national registry study from Denmark (
      • Hargreave M.
      • Jensen A.
      • Hansen M.K.
      • Dehlendorff C.
      • Winther J.F.
      • Schmiegelow K.
      • Kjær S.K.
      Association between fertility treatment and cancer risk in children.
      ). This reported a statistically higher relative risk of cancer in children born after FET than in children who were naturally conceived (14 cancer cases; HR 2.43, 95% CI 1.44 to 4.11). Many components of freezing technology and embryo culture, however, had changed since the study period (1995–2015), and the authors themselves described their findings as 'exploratory’.
      In a recent cohort study from the Nordic countries, however, any shorter-term safety concerns for pre-term birth were more 'related to the extended embryo culture rather than vitrification' (
      • Ginstrom Ernstad E.
      • Spangmose A.L.
      • Opdahl S.
      • Aaris Henningsen A.K.
      • Bente Romundstad L.
      • Tiitinen A.
      • Gissler M.
      • Wennerholm U.
      • Pinborg A.
      • Bergh C.
      • Malchau S.S.
      Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group.
      ) The study compared singletons born after embryo slow freezing and blastocyst vitrification and fresh transfer. The authors described their results as 'reassuring, indicating that the freezing technique per se has no major influence on the perinatal and maternal outcomes'.
      Vitrification has also been listed, alongside improved testing technologies, blastocyst culture and freeze-all approaches, as one reason for the continuing attraction of PGT-A. Although up-to-date figures, even from the main registries, are not available, recent data show the numbers of PGT-A cycles increasing slowly but steadily, despite the inconsistency of outcome results in studies (
      • Gorodeckaja J.
      • Neumann S.
      • McCollin A.
      • Ottolini C.S.
      • Wang J.
      • Ahuja K.
      • Handyside A.
      • Summers M.
      High implantation and clinical pregnancy rates with single vitrified-warmed blastocyst transfer and optional aneuploidy testing for all patients.
      ;
      • Hreinsson J.
      • Iwarsson E.
      • Hanson C.
      • Grøndahl M.L.
      • Løssl K.
      • Hydén-Granskog C.
      • Ingerslev H.J.
      Preimplantation genetic testing practices in the Nordic countries.
      ).

      The sustained effect of vitrification

      The national figures from the USA and Japan show quite clearly how the widespread introduction of vitrification has had such a revolutionary effect on ART, both in the cryopreservation of embryos and blastocysts and of oocytes. In our view, however, vitrification has had an even greater 'disruptive' effect on the entire landscape of reproductive medicine.
      First, oocyte vitrification was given wider clinical direction in studies from Spain and Italy (where embryo freezing remained outlawed), with results showing clearly that delivery rates from vitrified oocytes were reliable and consistent with those derived from fresh cycles (
      • Rienzi L.
      • Cobo A.
      • Paffoni A.
      • Scarduelli C.
      • Capalbo A.
      • Vajta G.
      • Remohí J.
      • Ragni G.
      • Ubaldi F.M.
      Consistent and predictable delivery rates after oocyte vitrification: an observational longitudinal cohort multicentric study.
      ). The authors' recommendation, that oocyte vitrification 'should be applied routinely for various indications', has now been applied with vigour, and in our view will quickly become the default standard practice in egg donation. For egg donation patients, the advantages are clear: no need for overseas travel in search of donor eggs; no need to wait for a suitable donor or for synchronized cycles; a greater choice of donor; and a more efficient programme at lower cost. Moreover, oocyte vitrification has become a standard means of offering fertility preservation to women undergoing gonadotoxic medical treatments, for addressing uncertainty about the likely duration of fertile years and in other situations, which argue for immediate recourse to IVF without immediate plans for pregnancy, such as the treatment of autoimmune conditions.
      Elective FET still lacks the strong evidence of randomized controlled trials and meta-analyses, despite the latest results from China (
      • Wei D.
      • Liu J.-Y.
      • Sun Y.
      • Shi Y.
      • Zhang B.
      • Liu J.Q.
      • Tan J.
      • Liang X.
      • Cao Y.
      • Wang Z.
      • Qin Y.
      • Zhao H.
      • Zhou Y.
      • Ren H.
      • Hao G.
      • Ling X.
      • Zhao J.
      • Zhang Y.
      • Qi X.
      • Zhang L.
      • Deng X.
      • Chen X.
      • Zhu Y.
      • Wang X.
      • Tian L.F.
      • Lv Q.
      • Ma X.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.
      ). In its latest traffic-light system to rate adjuvant treatments in ART, the HFEA gives elective freeze-all cycles an amber light, indicating in their view that the evidence is 'conflicting', that doctors don't yet know 'with enough confidence whether freeze all cycles are safer and more effective than conventional IVF or ICSI' (
      • Macklon N.S.
      • Ahuja K.K.
      • Fauser B.
      Building an evidence base for IVF 'add-ons'.
      ). The observational data from the registries of the USA (Centres for Disease Control and Prevention, ASRM, SART 2016, ART National Summary report) and Japan (
      • Ishihara O.
      • Jwa S.C.
      • Kuwahara A.
      • Tomonori I.
      • Koji K.
      • Rintaro S.
      • Kouji B.
      • Minoru I.
      • Hidekazu S.
      Assisted reproductive technology in Japan: A summary report for 2016 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology.
      ), however, show that freeze-all is not only on the march as a preferred option in ART, but that results too are gaining ground over fresh transfers in terms of outcome and of safety. There must also be many clinics like our own that cannot wait for the trials to catch up with their own domestic results, such is the rapid uptake of embryo freezing. Indeed, our own results from 2018 (2 years after the registry results from the USA, Japan and UK) show that 68% of all our transfers involved frozen embryos or embryos generated from vitrified oocytes (unpublished data).

      Safety and policy issues surrounding vitrification

      Although the growth of eFET cycle numbers globally and in cross-border treatments is undeniable, the emerging data have also raised some questions about the safety and long-term efficacy of the underlying crytotechnology. In a recent paper,
      • Gleicher N.
      • Kushnir V.A.
      • Barad G.H.
      Worldwide decline of IVF birth rates and its probable causes.
      consider the implications of a worldwide decline in published IVF birth rates from fresh embryo transfers, which also coincided with the introduction of newer laboratory technologies. Following a peak in 2001–2002, IVF birth rates declined in most world regions, including the nadir in 2016 when the prevailing low birth rates disappointingly compared with the lowest published rates from 1992.
      Could the steady lowering of birth rates from fresh embryos and the introduction of newer technologies, such as the cumulative storage of embryos for delayed single blastocyst transfer, be a mere coincidence? What could be the role of super-mild stimulation regimens as practised in Japan? The authors speculate that lowering of the birth rates might be a direct consequence of the ‘industrialization’ of IVF practices worldwide. The investor-driven market would always prioritise return on investment, even if it is at the expense of achieving the best possible outcome. Although most policymakers and practitioners welcome the reduction in multiple pregnancies, some argue that it is not always the most welcome outcome preferred by the paying customer hoping to optimize success in every treatment attempt. The authors argue that the growing appeal of more recent laboratory-based procedures, i.e. longer embryo culture, time-lapse imaging, egg vitrification and aneuploidy screening, combined with society's understandable desire for singleton pregnancies, could have collectively led to some clinical practices, i.e. eSET of cryopreserved blastocysts, for example, which arguably may not be in the best interest of patients.
      In a separate study based on a meta-analysis of published registries, the further evidence for continuous growth in frozen cycles is provided (
      • Groenewoud E.R.
      • Cohlen B.
      • Macklon N.S.
      Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles.
      ). The main reservations of the investigators about the development, however, focus on key safety issues rather than on low birth rates. ‘larger offspring syndrome’ associated with frozen embryos raises the incidence of perinatal complications in the newborn; conditions such as shoulder dystocia accompanying neonatal and maternal comorbidity worryingly result in some cases involving frozen embryos. The frequency of these incidents, although reassuringly low, does not seem to relent even when embryo transfers are switched from artificial to natural cycles. The authors conclude that, for the foreseeable future, patient choice and convenience, combined with the clinic's logistical support structures, would likely remain the principal determinants in the choice of FETs as a treatment modality.
      Difficulties in finding a common policy for many laboratory procedures, including egg freezing, are also recognized. In a Reproductive BioMedicine Online editorial, we argued that, at least in the short term, a policy consensus is likely to remain illusory (
      • Macklon N.S.
      • Ahuja K.K.
      • Fauser B.
      Building an evidence base for IVF 'add-ons'.
      ). We analysed the recent statement from the UK regulator, the HFEA, asking centres to act ‘ethically’ and offer patients protection from potential exploitation, particularly from paid add-on IVF treatments, which should be based on water-tight evidence from clinical trials. The HFEA's traffic light system for adjuvant treatments in ART gives embryo freezing and time-lapse microscopy an amber light, indicating that insufficient evidence currently exists to justify offering these procedures to patients. In 2019, the HFEA changed its traffic light warning for PGT-A on day-5 embryos from amber to red, whereas pprocedures such as physiological ICSI, assisted hatching and egg freezing received a red light or no light, indicating a complete lack of evidence for effectiveness and safety. No add-on laboratory procedure received a green light but, strangely, submission of the performance data on these procedures is a mandatory condition of continuing with the licence to practice in the UK. Consensus from the HFEA thus helped allay some media criticism of ‘private’ fertility clinics, yet unwittingly it also created a quagmire of questionable recommendations.

      Vitrified donor egg cycles overtake fresh donor egg cycles

      Notwithstanding the safety and policy considerations mentioned above, and without any strong evidence-base yet in its favour, a rapid shift has taken place towards eFET in routine IVF treatments. Moreover, the shift to frozen transfers in third-party egg donation has been even more striking. In the USA once again, the number of egg donation cycles from frozen embryos now far outstrips the numbers from fresh eggs (Figure 2), with delivery rates not far different from those achieved in synchronized fresh treatments.
      Figure 2
      Figure 2The number of donor cycles over time using fresh and frozen embryos between 2007 and 2016. Centers for Diseases Control and Prevention, American Society for Reproductive Technology, 2016; Assisted Reproductive Technology National Summary Report.
      Similarly, in Spain, where all clinics from 2016 were required by law to submit their data to a national registry run by the Spanish Fertility Society, 18% of all oocytes collected for egg donation treatments in 2016 were vitrified for egg banking, a total of more than 11,000 oocytes (www.registrosef.com/bulic/docs/sef2016). Significantly, egg donation (including fresh and frozen embryos) represented 53.3% of all Spain's cross-border activity in 2016 (which totalled almost 13,000 cycles, about 10% of overall activity in which 138,553 cycles were recorded).
      With the rapid uptake of vitrification and egg banking, Spain has already devised new cross-border arrangements in egg donation such that the gametes (and embryos) and not the patients do the travelling (
      • La Marca A.
      • Dal Canto M.
      • Buccheri M.
      • Valerio M.
      • Mignini Renzini M.
      • Rodriguez A.
      • Vassena R.
      A novel transnational fresh oocyte donation (TOD) program based on transport of frozen sperm and embryos.
      ). One strategy reported is based on shipping frozen spermatozoa from the country of the recipient (Italy) to the country of the egg donor (Spain). Here, the thawed spermatozoa are used to fertilize fresh oocytes collected from the donor and the resulting embryos are then frozen and shipped back to the referring IVF centre in Italy. A variation of this strategy, successfully introduced by another Spanish group involved the shipment to Italy of vitrified oocytes rather vitrified embryos (
      • Parmegiani L.
      • Quintero L.
      • Filicori M.
      Transnational oocyte donation program: fresh versus vitrified oocytes.
      ). Recent data from Italy, where the prohibition of gamete donation was removed in 2014 but where payment to gamete donors remains outlawed, show that gamete donation is still a minority activity of ART, and has not yet recovered from the Draconian restrictions of Italy's 2004 Law 40. Indeed, in 2016, almost all cycles of cryopreserved oocyte donation were carried out with oocytes from foreign banks (Figure 3).
      Figure 3
      Figure 3Distribution of all assisted reproductive technology cycles using donor gametes or cryopreserved embryos after donation and origin of the oocytes for the frozen donor oocyte cycles, 2016. Total cycles (n = 5533) (Registro Nazionale Procreazione Medicalmente Assistita - ISS, 2019).
      It was significant that the legal challenges to Italy's Law 40 came not from doctors but from patients, and significant too that Court rulings were made in the interests of patients and not of the Italian lawmakers. Such patient pressure was similarly evident in the UK when the regulatory authority sought to resolve anomalies in gamete donation first by public consultation (in 2011) and later by a change in regulation (
      • Ahuja K.
      Patient pressure: is the tide of cross-border reproductive care beginning to turn?.
      ). Until then, the UK had been critically unable to meet its own patient demands for donor spermatozoa or donor eggs, with the result that donor spermatozoa were almost exclusively imported and donor eggs only plentifully available in Spain, Cyprus, Ukraine and Czech Republic. After considering its consultation, the HFEA in April 2012 raised compensation to £35 ‘per visit’ for sperm donors, and to £750 per cycle for oocyte donors; the revised fees, said the HFEA, should be viewed ‘not in terms of crude sums but in terms of the value of donation’. In 2011, ESHRE had named 'fair access at home' as the most desirable circumstance of its cross-border good-practice manual (
      • Shenfield F.
      • de Mouzon J.
      • Pennings G.
      • Ferraretti A.P.
      • Goossens V.
      ESHRE's good practice guide for cross-border reproductive care.
      ).
      The effect of this publicly driven change was immediate and sustained and, coinciding with the growing confidence in egg vitrification, it caused a significant increase in the number of sperm and egg donors at many UK clinics. Accordingly, all gametes (male and female) for UK patients could now be supplied by donors recruited from within the UK. The need for overseas travel or imports is quickly becoming redundant.

      Experience from London Women's Clinic

      In the UK, all licensed activity must be reported to the HFEA in a distinct and specific format. The initiation of a treatment cycle is accompanied by the mandatory submission of an intention-to-treat form to the HFEA. Our own experience at the London Women's Clinic, a licensed centre in Central London, in treatment cycles documented between 2013 and 2018 points to a clear pattern of continuing relative decline in fresh transfer cycles (Figure 4), a pattern not dissimilar to those seen in national registries. In 2013, 79% of our treatment cycles were fresh transfers and 21% were frozen but, in 2018, 57% were fresh and 43% frozen embryo cycles.
      Figure 4
      Figure 4Initiated treatment cycles registered with The Human Fertilisation and Embryology Authority (n = 13,702 cycles), London Women's Clinic, Harley Street.
      Similarly, between 2014 and 2018, in a study of over 1086 consecutive treatment cycles, including donor eggs from 2015, the clinical pregnancy rates achieved from cycles using vitrified eggs equalled the rates achieved with fresh eggs (Figure 5) (
      • Linara E.
      • Wang J.
      • Shah T.
      • Gibson G.
      • Nair S.
      • Rahmati M.
      • Macklon N.
      • Ahuja K.
      ).
      Figure 5
      Figure 5Comparison of Clinical Pregnancy Rates per Embryo Transfer Utilising Embryos from Frozen or Fresh Eggs. London Women's Clinic, Harley Street (
      • Linara E.
      • Wang J.
      • Shah T.
      • Gibson G.
      • Nair S.
      • Rahmati M.
      • Macklon N.
      • Ahuja K.
      )
      This movement to greater patient autonomy in egg donation has now become even more pronounced with vitrification and frozen egg banking, which from 2014 gradually overtook overseas donation as the donor treatment of choice in our own clinic. Therefore, of the 1283 donor cycles completed between 2005 and 2013, 88% were carried out at as cross-border treatments at overseas clinics. Since then, however, recognizing the greater choice of frozen eggs available at home, 95% of patients have switched to ‘home sourcing’, compared with just 1% in 2013. The treatment is available without a waiting-list for donor matching and the tedious need for synchronized cycles, and at lower cost. Moreover, overall pregnancy rates per transfer in our frozen egg programme are above 50%, matching those with fresh cycles.

      Vitrification at the verge of fulfilling Robert Edward's dream

      This discussion highlights trends reflecting a recent and rapid shift in how we carry out ART today. Clearly, much work remains to satisfy the regulators and the media, but it is salutary to read that it at least fulfils the potential which Edwards and Steptoe reported in 1980, though describing developments in 1976–1977 (
      • Edwards Robert
      • Steptoe Patrick
      A Matter of Life: The story of a Medical Breakthrough.
      ). The following paragraph is an account of a conversation between Bob Edwards and Jean Purdy, extracted from their book ‘A Matter of Life’, published in 1980 almost 30 years before the concept of vitrification became introduced to the world of ART (
      • Kuwayama M.
      • Vajta G.
      • Kato O.
      • Leibo S.P.
      Highly efficient vitrification method for cryopreservation of human oocytes.
      ;
      • Kuwayama M.
      • Vajta G.
      • Shoko I.
      • Kato O.
      Comparison of open and closed methods for vitrification of human embryos and the elimination of potential contamination.
      ).'There is an alternative’, I said to Jean. ‘We could try freezing human embryos. We'd give the fertility drugs as usual to patients, collect the ripening eggs, fertilize them, and when the eggs have divided into sixteen or thirty-two cells, we'd freeze them and keep them in store until . . . the menstrual cycle was back to normal. Then we could thaw the embryos out and replace them in their mother.’.Professor Sir Robert Edwards (1980)
      Edwards's vision was the provision of a 'whole family' appropriately spaced from a single stimulation, but its realization - after 'many attempts at freezing' - proved elusive. But it was, said Edwards, 'a good idea in the future', and it is to the credit of vitrification that we can finally fulfil those ambitions. Almost every clinic with experience in embryo freezing can provide examples from their patients of families resulted from the multiple transfers of embryos derived from a single egg collection. This trend is likely to gain momentum as the concept of vitrification takes deeper root in the fabric of the day-to-day practice of ART. Even if the absolute evidence in favour of frozen-thawed embryo transfers in a non-stimulated cycle is still lacking, there is no doubt that technology has now evolved to the extent that a systematic examination of this prospect is feasible.
      In conclusion, vitrification has been the catalyst for a revolution in ART, allowing the efficient storage of oocytes, blastocysts and ovarian tissue. Procedures can be performed reliably and rapidly, and without the fear of damage from ice crystal formation. The recently published registry data are confirmation that the benefits of vitrification have been recognised, and it seems likely that the pace of uptake is so great that even the registry data of 2016 are a step behind what is actually happening right now.

      References

        • Acharya K.S.
        • Acharya C.R.
        • Bishop K.
        • Harris B.
        • Raburn D.
        • Muasher S.J.
        Freezing of all embryos in in vitro fertilization is beneficial in high responders, but not intermediate and low responders: an analysis of 82,935 cycles from the Society for Assisted Reproductive Technology registry.
        Fertil. Steril. 2018; 108: e390
        • Ahuja K.
        Patient pressure: is the tide of cross-border reproductive care beginning to turn?.
        Reprod. Biomed. Online. 2015; 30: 447-450
        • Amso N.
        • Ahuja K.K.
        • Morris N.
        • Shaw R.W.
        The management of predicted ovarian hyperstimulation involving gonadotropin-releasing hormone analog with elective cryopreservation of all pre-embryos.
        Fertil. Steril. 1990; 53: 1087-1090
      1. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2016 Assisted Reproductive Technology National Summary Report.

        • Coutifaris C.
        Elective frozen embryo transfer for all?.
        Lancet. 2019; (doi: org/)https://doi.org/10.1016/S0140-6736(19)30426-X
        • Crawford S.
        • Boulet S.L.
        • Kawwass J.F.
        • Jamieson D.J.
        • Kissin D.M.
        Cryopreserved oocyte versus fresh oocyte assisted reproductive technology cycles, United States, 2013.
        Fertil. Steril. 2017; 107: 110-118
        • De Geyter C.
        • Calhaz-Jorge C.
        • Kupka M.S.
        • Wyns C.
        • Mocanu E.
        • Motrenko T.
        • Scaravelli G.
        • Smeenk J.
        • Vidakovic S.
        • Goossens V.
        • ART in Europe
        2014: results generated from European registries by ESHRE: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE).
        Hum. Reprod. 2018; 33: 1586-1601
        • Devroey P.
        • Polyzos N.P.
        • Blockeel C.
        An OHSS-Free Clinic by segmentation of IVF treatment.
        Hum. Reprod. 2011; 26: 2593-2597
        • Ginstrom Ernstad E.
        • Spangmose A.L.
        • Opdahl S.
        • Aaris Henningsen A.K.
        • Bente Romundstad L.
        • Tiitinen A.
        • Gissler M.
        • Wennerholm U.
        • Pinborg A.
        • Bergh C.
        • Malchau S.S.
        Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group.
        Hum. Reprod. 2019; 34: 2282-2289
        • Gleicher N.
        • Kushnir V.A.
        • Barad G.H.
        Worldwide decline of IVF birth rates and its probable causes.
        Hum. Reprod. Open. 2019; 3 (hoz017)
        • Gorodeckaja J.
        • Neumann S.
        • McCollin A.
        • Ottolini C.S.
        • Wang J.
        • Ahuja K.
        • Handyside A.
        • Summers M.
        High implantation and clinical pregnancy rates with single vitrified-warmed blastocyst transfer and optional aneuploidy testing for all patients.
        Hum. Fertil. 2019; https://doi.org/10.1080/14647273.2018.1551628
        • Groenewoud E.R.
        • Cohlen B.
        • Macklon N.S.
        Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles.
        Fertil. Steril. 2018; 109: 768-774
        • Hargreave M.
        • Jensen A.
        • Hansen M.K.
        • Dehlendorff C.
        • Winther J.F.
        • Schmiegelow K.
        • Kjær S.K.
        Association between fertility treatment and cancer risk in children.
        JAMA. 2019; 322: 2203-2210
        • Hreinsson J.
        • Iwarsson E.
        • Hanson C.
        • Grøndahl M.L.
        • Løssl K.
        • Hydén-Granskog C.
        • Ingerslev H.J.
        Preimplantation genetic testing practices in the Nordic countries.
        Acta Obstet. Gynecol. Scand. 2020; https://doi.org/10.1111/aogs.13821
        • Ishihara O.
        • Jwa S.C.
        • Kuwahara A.
        • Ishihara O.
        • Jwa S.C.
        • Kuwahara A.
        • Ishikawa T.
        • Kugu K.
        • Sawa R.
        • Banno K.
        • Irahara M.
        • Saito H.
        Assisted Reproductive technology in Japan: A summary report for 2016 by the Ethics committee of the Japan Society of Obstetirics and Gnecology.
        Repro. Med. Biol. 2019; 18: 7-16
        • Ishihara O.
        • Jwa S.C.
        • Kuwahara A.
        • Tomonori I.
        • Koji K.
        • Rintaro S.
        • Kouji B.
        • Minoru I.
        • Hidekazu S.
        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
        • Kolibianakis E.M.
        • Venetis C.A.
        • Tarlatzis B.C.
        Cryopreservation of human embryos by vitrification or slow freezing: which one is better?.
        Curr. Opin. Obstet. Gynecol. 2009; 21: 270-274
        • Kuwayama M.
        • Vajta G.
        • Kato O.
        • Leibo S.P.
        Highly efficient vitrification method for cryopreservation of human oocytes.
        Reprod. Biomed. Online. 2005; 3: 300-308
        • Kuwayama M.
        • Vajta G.
        • Shoko I.
        • Kato O.
        Comparison of open and closed methods for vitrification of human embryos and the elimination of potential contamination.
        Reprod. Biomed. Online. 2005; 11: 608-614
        • La Marca A.
        • Dal Canto M.
        • Buccheri M.
        • Valerio M.
        • Mignini Renzini M.
        • Rodriguez A.
        • Vassena R.
        A novel transnational fresh oocyte donation (TOD) program based on transport of frozen sperm and embryos.
        Hum. Reprod. 2018; 34: 285-290
        • Linara E.
        • Wang J.
        • Shah T.
        • Gibson G.
        • Nair S.
        • Rahmati M.
        • Macklon N.
        • Ahuja K.
        Clinical outcomes of 1086 consecutive egg donation cycles from a single centre; a comparison of fresh and frozen eggs Abstract, BFS Annual Meeting, Edinburgh2020
        • Macklon N.S.
        • Stouffer R.L.
        • Giudice L.C.
        • Fauser B.C.
        The science behind 25 years of ovarian stimulation for in vitro fertilization.
        Endocr. Rev. 2006; 27: 170-207
        • Macklon N.S.
        • Ahuja K.K.
        • Fauser B.
        Building an evidence base for IVF 'add-ons'.
        Reprod. Biomed. Online. 2019; 38: 853-856
        • Parmegiani L.
        • Quintero L.
        • Filicori M.
        Transnational oocyte donation program: fresh versus vitrified oocytes.
        Hum. Reprod. 2019; 34: 2551
        • Rezazadeh Valojerdi M.
        • Eftekhari-Yazdi P.
        • Karimian L.
        • Hassani F.
        • Movaghar B.
        Vitrification versus slow freezing gives excellent survival, post warming embryo morphology and pregnancy outcomes for human cleaved embryos.
        J. Assist. Reprod. Genet. 2009; 26: 347-354
        • Rienzi L.
        • Cobo A.
        • Paffoni A.
        • Scarduelli C.
        • Capalbo A.
        • Vajta G.
        • Remohí J.
        • Ragni G.
        • Ubaldi F.M.
        Consistent and predictable delivery rates after oocyte vitrification: an observational longitudinal cohort multicentric study.
        Hum. Reprod. 2012; 27: 1606-1612
        • Rienzi L.
        • Gracia C.
        • Maggiulli R.
        • LaBarbera A.R.
        • Kaser D.J.
        • Ubaldi F.M.
        • Vanderpoel S.
        • Racowsky C.
        Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance.
        Hum. Reprod. Update. 2017; 23: 139-155
        • Edwards Robert
        • Steptoe Patrick
        A Matter of Life: The story of a Medical Breakthrough.
        William and Company, Inc, NY1980
        • 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 (See): 2-14
        • Shenfield F.
        • de Mouzon J.
        • Pennings G.
        • Ferraretti A.P.
        • Goossens V.
        ESHRE's good practice guide for cross-border reproductive care.
        Hum. Reprod. 2011; 26: 1625-1627
        • Shi Y.
        • Sun Y.
        • Hao C.
        • Zhang H.
        • Wei D.
        • Zhang Y.
        • Zhu Y.
        • Deng X.
        • Qi X.
        • Li H.
        • Ma X.
        • Ren H.
        • Wang Y.
        • Zhang D.
        • Wang B.
        • Liu F.
        • Wu Q.
        • Wang Z.
        • Bai H.
        • Li Y.
        • Zhou Y.
        • Sun M.
        • Liu H.
        • Li J.
        • Zhang L.
        • Chen X.
        • Zhang S.
        • Sun X.
        • Legro R.S.
        • Chen Z.J.
        Transfer of fresh versus frozen embryos in ovulatory women.
        N. Engl. J. Med. 2018; 378: 126-136
        • Wei D.
        • Liu J.-Y.
        • Sun Y.
        • Shi Y.
        • Zhang B.
        • Liu J.Q.
        • Tan J.
        • Liang X.
        • Cao Y.
        • Wang Z.
        • Qin Y.
        • Zhao H.
        • Zhou Y.
        • Ren H.
        • Hao G.
        • Ling X.
        • Zhao J.
        • Zhang Y.
        • Qi X.
        • Zhang L.
        • Deng X.
        • Chen X.
        • Zhu Y.
        • Wang X.
        • Tian L.F.
        • Lv Q.
        • Ma X.
        • Zhang H.
        • Legro R.S.
        • Chen Z.J.
        Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.
        Lancet. 2019; (doi: org/)https://doi.org/10.1016/S0140-6736(18)32843-5
        • Chen Z.-J.
        • Shi Y.
        • Sun Y.
        • Zhang B.
        • Liang X.
        • Cao Y.
        • Yang J.
        • Liu J.
        • Wei D.
        • Weng N.
        • Tian L.
        • Hao C.
        • Yang D.
        • Zhou F.
        • Shi J.
        • Xu Y.
        • Li J.
        • Yan J.
        • Qin Y.
        • Zhao H.
        • Zhang H.
        • Legro R.S.
        Fresh versus frozen embryos for infertility in the polycystic ovary syndrome.
        N. Engl. J. Med. 2018; 375: 523-533

      Biography

      After completing his PhD studies at the University of Cambridge with Professor Sir Robert Edwards, Kamal Ahuja moved to London to head the Cromwell Hospital IVF Programme as its founding Scientific Director, where he remained for over 20 years. In 2007, he founded the JD Healthcare Group that owns and runs all London Women's Clinics in the UK, as well as London Egg Bank and London Sperm Bank in central London. Kamal is a member of the Development Board of St John's College Cambridge and the current Chairman of Reproductive Healthcare Ltd UK.
      Key message
      Vitrification has catalysed a revolution in assisted reproductive technology that is disrupting models of care. Although questions about its optimal use and its implications for safety and health remain, the benefits it offers are compelling and explain the profound shifts in practice being observed.