Blastocystdyrkning vs dag 2-3, hva er best?

Steven Mansell

For noen dager siden publiserte en PhD-student ved Oslo Universitetssykehus en bloggpost hvor hun omtalte bevisene for blastocystdyrkning vs dag 2-3. Hennes konklusjon var at bevisene ikke er gode nok for å dyrke til blastocyst.

Vi i Medicus dyrker rutinemessig til blastocyst og har en annen forståelse av saken og har kommentert saken direkte på OUS sin blogg. Vi gjengir også saken her på vår blogg. Saken er skrevet av vår embryolog (PhD) Steven Mansell på engelsk da dette er hans morsmål.

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I am writing this response purely because I was perplexed to read the way this article was presented to couples reading it. The argument regarding cleavage stage (day 2 or day 3) versus blastocyst (day 5) embryo transfer is one that has been ongoing for many years. However, it is generally accepted in the scientific community that blastocyst transfer results in a higher pregnancy rate. In my opinion, this argument needs to be put to rest and the best interests of our couples need to be taken into account. We as embryologist have a duty to provide the best quality care and help our couples achieve their desired goal of having a family quickly and safely. In this response, I would like to address a number of issues that the author has highlighted in her blog post and I would strongly advise her to pay closer attention to the details within the papers she is referencing here. Particularly since attention to detail is the key requirement for good research and a good embryologist.

Issue 1: Norwegian private clinics charging for blastocyst

The author states that many private clinics charge more for blastocyst culture suggesting it will be more expensive for the couples. We at Medicus, and as far as I’m aware no private clinic in Norway charges extra for blastocyst culture. If they do, I would advise couples to seek another clinic, as this is unjustified. I also felt this comment was a poorly constructed attempt to vilify the private sector who sole interest is to provide the best of quality care for our patients.

Issue 2: Fewer embryos to freeze

The author states that there will be fewer embryos to freeze down. This is in fact accurate. Not every embryo has the capacity to reach blastocyst stage and therefore create a baby due to inherent abnormalities within the embryo itself. One of the main purposes of growing to blastocyst stage is to exclude embryos that cannot progress further. By freezing on day 2 or 3 you may inadvertently freeze down embryos that would inherently never become a viable pregnancy. This not only provides the lab with more work and resources but also give false hope to couples. Furthermore, I would be inclined to question the type of freezing method routinely used. If a clinic is currently doing slow freezing over vitrification, the survival rate after thawing is pretty poor, typically 60-70% compared to vitrification (~95%). Therefore, even though many embryos may have been frozen down, let’s say 10 embryos, only 6 or 7 will survive and that’s with a good slow freeze program. For any couples reading this response, I would recommend you to ask your clinic which method they are using. If their freezing program is not vitrification I would ask why as the survival rate after thawing with vitrification is ~95% or higher in a good clinic.

Issue 3: Cancellation rates are higher.

This is true, however, once again this is because we are removing embryos that cannot progress further than day 3. This is also obviously depended on the blastocyst culture conditions and the general quality of embryology within the clinic. But for the sake of argument let’s say these were completely optimized and the typical blastocyst formation rate was over 50%. Is it better to put back an average looking embryo on day 3 and allow that woman to wait two weeks to find out it hadn’t progressed, or is it better culture for 2 more days to see if it didn’t form a blastocyst and cancel the cycle, thereby preventing that anxious and emotional 2-week wait? Furthermore, freezing of embryos that would not reach blastocyst stage means additional lab resources and time. The time that could be better-spent training and implementing new techniques to improve success rates within the lab.

Issue 4: No difference in pregnancy rate.

I would suggest that the author reads the paper quoted in her blog in more detail. The paper actually says, and I quote; ”The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer”. It goes on to provide a statistic saying that if 36% of women fall pregnant after cleavage stage embryo transfer, around 39% to 46% of women would achieve a clinical pregnancy after a fresh blastocyst transfer. Furthermore the Human Fertilisation and Embryo Authority of the UK (HFEA), one of the strictest regulatory bodies in the field of reproductive medicine, states in their patient guide entitled “Decision to make about your embryos”, that blastocyst transfer will provide patients with a higher chance of falling pregnant over a day 2 or day 3 transfer. I strongly urge readers to click on this link to view their recommendations. This advice is based on the HFEA’s latest national statistics and can be found on page 32 of their ‘Fertility Treatments- trends and figures’ document. This document showed a ~16% increase in pregnancy rates per single embryo transfer for all ages after blastocyst transfer. Once again I would urge readers of this blog to look at this document.

The author does state that there is no difference in cumulative pregnancy rates between cleavage and blastocyst stage embryo transfer, and this is also stated in the paper she referenced. This is true, but why? So let’s think about it. In a cohort of 200 women, 100 will have day 3 transfer and 100 will have blastocyst transfer. Now let’s say these patients are between 18 and 35 years old and all have 1 egg collection. The blastocyst group had fewer embryos to freeze as not all embryos reach blastocyst stage while the cleavage stage embryos have more embryos frozen down. Statistically, ~ 50% of the women in each group have the potential to achieve a pregnancy per embryo transfer. In the blastocyst group, 40 patients achieved a pregnancy after the first transfer and 10 patients achieved a pregnancy in their second transfer with all embryos used up in the 2 transfers due to fewer embryos are frozen down. To calculate the cumulative pregnancy rate we take the number of patients achieving a pregnancy after the first transfer plus the number of patients achieving a pregnancy after subsequent transfers (frozen embryo transfers) and divide by the total number of women who had an egg collection. Therefore it would be (40+10)/100, and this is multiplied by 100 to give a cumulative pregnancy rate of 50%.

Now let’s compare cleavage stage. We know that cleavage stage transfer has roughly a 14% less rate of pregnancy per transfer in this age group (HFEA statistics). This means that in the first cycle 35 women will achieve a pregnancy in the first cycle, 9 in the second and for the sake of the argument, the rest fall pregnant (6 women) in the third. Therefore the cumulative pregnancy rate would be (35+9+6)/100*100 which equals 50%.

The cumulative pregnancy rate isn’t different but the time for all the women who could potentially achieve a pregnancy is longer. Consequently, these women would have to go through additional cycles in order to achieve a pregnancy compared to those receiving a blastocyst transfer. This means more days off work for the patient, increased medicine usage, more doctor appointments and increased emotional stress for the couple. The example given here is a gross simplification of the process and I admit that. However, what we also need to think of are the women in this cohort who had embryos that would never create a viable pregnancy. In the blastocyst group, many of those women would have had their first cycle canceled and would begin on their next treatment cycle. While those in the cleavage stage group would have had non-viable embryos frozen down for subsequent frozen embryo transfers. In this group, those patients may have to undergo many more frozen cycles without success before starting a fresh treatment. This not only wastes the couple’s time but could reduce the success rate of future cycles as the patient’s age increases.

Issue 5: The proposed study into the difference between cleavage and blastocyst stage pregnancy rates.

As a person from a scientific background with a Ph.D. and a post-doctoral fellowship in the field of reproductive medicine, I am completely for research in this field. However, I do have concerns over the study that is proposed here. For this study to be credible it is important that the institution in question should have a well-established blastocyst program with good blastocyst formation rates and a successful vitrification program. Although I do not wish to draw conclusions I cannot help but question the lack of blastocyst culture experience based on the content of this blog. Therefore I would have to evaluate the data published here with a more skeptical view over data published from a clinic with an optimized blastocyst program.

Summary

In summary, blastocyst transfer has been proven to result in higher pregnancy rates per transfer. Blastocyst culture programs can have fewer embryos to freeze down and higher cancellation rates but this is because the main purpose of this culture is to eliminate embryos that cannot develop past day 3 and therefore do not have the potential to create a viable pregnancy. Cumulative pregnancy rates are not different, however, the number of cycles required to achieve a pregnancy is fewer saving the couple time, money and emotional stress. As an additional note, the main argument I am often presented with is that ‘the uterus is a better incubator’. My response is typically that of a physiologist. The uterus is a better incubator for a blastocyst as the environment of the uterus is optimal for blastocyst development. However, the fallopian tubes are a better incubator for cleavage stage embryos as this is the sight of optimal embryo development for the first 4 days after fertilization. By replacing a cleavage stage embryo, especially a day 2 embryo, into the uterus we are artificially forcing that embryo to develop in suboptimal conditions. The culture media in the lab, although not perfect, is designed to support different stages of embryo development.

Lastly in a country that does not allow genetic testing of embryos prior to transfer to prevent multiple failed transfers or transmission of hereditary diseases, that does not allow egg donation, that does not allow routine vitrification of eggs and does not allow surrogacy, I feel scientific resources could be better allocated to investigate these areas in order to bring Norway up to the same standard as many other European countries. I feel it’s time to follow suit of countries such as the UK who have legalized many treatments such as 3 parents embryo cycles after rigorous research and public opinion, to provide world-class treatment to many couples desperate to fulfill their dream of becoming parents. So let’s put these dated arguments to rest and focus on the bigger picture.

Viser 4 kommentarer
  • Avatar
    Andreas
    Svar

    Hei. Min kone og jeg har nå fullført 2 fersk-forsøk og 2 tin-forsøk ved Riksen. Vi føler vi ikke blir hørt i det hele tatt når vi stiller spørsmål med hvorfor det settes 2-dagers embryo tilbake hver gang. Vi har begge lest oss opp på IVF og stiller oss undrende til måten vi blir mottatt på riksen. Det er absolutt ingen persontilpasset behandling vi har vært med på. Samlebåndfølelse er det vi sitter igjen med. Og når vi spør om muligheten for bruk av kort protokoll og dyrking til blastocyst blir vi avfeid uten noen god begrunnelse på hvorfor. Vi har begrunnet vårt ønske med det Steven Mansell har gått gjennom her tidligere. Ikke minst poenget hans om at livmor er beregnet for blastocyster, ikke 2-dagers embryo. Likevel får vi ikke gehør for noe av det vi legger frem. Totalt sett sitter vi igjen med inntrykket av at tallene Riksen presenterer er mest basert på flaks, og ikke vitenskap. Vi ønsker å bli hørt, det blir vi IKKE.

    • Magnus Finset Sørdal
      Magnus Finset Sørdal
      Svar

      Hei Andreas, beklager sent svar her på bloggen. Som du ser av diskusjonen vi har hatt med OUS så har vi forskjellig syn på dette. Dere kan gjerne ta kontakt med oss hvis dere ønsker en prat om eventuelle forsøk hos oss.

  • Avatar
    Steven Mansell
    Svar

    Hi Trine, I’ve written a response to your response in this new blogpost: https://medicus.no/debatt-del-2-blastocyst-vs-dag-2-3/

  • Avatar
    Trine Skuland
    Svar

    Vi takker Medicus og Steven Mansell for kommentarene på vårt blogginnlegg. Det er veldig hyggelig med respons, men det hadde vært fint om vi kunne holde oss til den faglige debatten og ikke sette spørsmålstegn ved hverandres kompetanse.

    Når det kommer til Mansells faglige kommentarer, ser det ut til å ha oppstått enkelte misforståelser. Mansell har rett i at graviditetsraten kan være høyere ved innsetting av blastocyst enn dag2-embryo når man ser på hver enkelt embryoinnsetting. Vi ønsker derimot å se nærmere på det som har størst betydning for pasientene våre, nemlig samlet «take home baby rate», dvs. sjansen for at et par får barn etter behandlingen i sin helhet. Parene ønsker seg babyer, ikke graviditeter, og vårt behandlingstilbud er 3 ferske sykluser, samt eventuelle tinforsøk – ikke én embryoinnsetting. For våre pasienter er det derfor viktigst hva den kumulative fødselsraten er for disse syklusene, og det er denne måleenheten som er gullstandarden når vi skal se på behandlingsresultater. Dette er også noe Cochrane-rapporten som bloggen refererte til har sett på. De peker på den lave kvaliteten på randomiserte, kontrollerte studier (RCTs), fordi mange av dem ikke rapporterer fødselsrate, kumulativ fødselsrate og spontanaborter. I vår studie ønsker vi derfor å se på disse faktorene slik at vi har et solid bevisgrunnlag for hvilke pasienter som vil dra nytte av blastocystdyrkning og hvilke som vil ha større fordel av innsetting på dag 2. Dette vil gi oss et optimalt utgangspunkt for å gi hvert enkelt par en persontilpasset behandling.

    Videre er det mange ubesvarte spørsmål når det kommer til blastocystdyrkning. Den viktigste problemstillingen er hvorvidt forlenget kultivering er en vinn-vinn-situasjon. I hvor stor grad forbedres embryoseleksjon ved blastocystdyrkning og i hvor stor grad svekker dette embryoets utvikling? Balansen mellom disse to står sentralt når man sammenligner dag 2/3- og blastocystkultivering, og det er foreløpig ingen som vet hvor denne balansen ligger. Det er ingen poeng i å vinne seleksjonen dersom flere levedyktige embryo faller fra før de når blastocyststadiet, og vice versa. Denne fundamentale problemstillingen er avgjørende for både antall embryoer som kan fryses og hvor mange innsettinger som må avbrytes. Igjen; det er den kumulative fødselsraten som er utfallet det gir mest mening å se på, og her finnes det ikke bevisgrunnlag for at blastocystdyrkning er bedre.

    Vi kommer til å invitere andre klinikker til å bli med i studien. På den måten kan vi skape et rammeverk for kliniske multisenterstudier slik at reproduktiv medisin igjen kan bli et fagfelt basert på bevis av høy kvalitet. Det finnes mange eksempler på tilleggsbehandlinger innen assistert befruktning som har blitt tatt i bruk i stor skala uten bevis for at dette er til pasientenes fordel, og det er mange klinikker i Europa som tar ekstra betalt for slike tilleggsbehandlinger. Ved Oslo Universitetssykehus har vi et internasjonalt syn og Mansell har sikkert fått med seg engelske mediers dekning av den refererte artikkelen i British Medical Journal, hvor de så på ekstrakostnader ved IVF-behandling. En av disse var £800 (ca. 8000 NOK) for blastocystdyrkning. I Norge er dette kanskje ikke en separat kostnad, men heller regnet inn i totalprisen på en standardbehandling. Hovedpoenget her er uansett at behandlinger som tilbys på enhver fertilitetsklinikk må ha overbevisende og godt dokumenterte effekter – noe som ofte ikke er tilfellet fordi metoder generelt innføres prematurt.

    Reproduksjonsmedisinsk avdeling ved Oslo Universitetssykehus har et svært godt utgangspunkt for å utføre randomiserte, kontrollerte kliniske studier. Vi er en av de største IVF-klinikkene i Europa med tanke på antall sykluser og vi har et faglig dyktig personale. Flere av våre ansatte har jobbet på fertilitetsklinikker i blant annet UK, Hellas, Sverige, Spania, USA og Japan, og har derfor bred erfaring med ulike kultiveringsmetoder og avanserte teknikker innen assistert befruktning. Med dette ønsker vi alle klinikker som deler den samme interessen velkommen til å samarbeide med oss mot målet om mer evidensbasert reproduksjonsmedisin!

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