Innen assistert befruktning har dyrbare teknikker blitt innført i stor skala uten godt nok grunnlag for om dette virkelig er til pasientenes fordel. Behandlingen bør baseres på solide forskningsbevis. Dette ønsker vi på Reproduksjonsmedisinsk avdeling å gjøre noe med.
Tekst: Trine Skuland, PhD-student ved Reproduksjonsmedisinsk avdeling, Oslo universitetssykehus.
Fruktbarhetsproblemer
Bli med på fortellingen om Mari og Mats, de er i slutten av 30-årene, de har kjøpt hus og stasjonsvogn, nå venter de bare på å få oppleve det som de begge har drømt om så lenge – å bli foreldre.
De har prøvd og prøvd i over 1 år nå. Det ser ut til at de er en del av de 10 prosentene som rammes av ufrivillig barnløshet.
Heldigvis finnes det hjelp å få. De utredes for fruktbarhetsproblemer, men legene finner ingen årsak til at det ikke skal kunne fungere.
Mari og Mats får beskjed om å fortsette å prøve, men de er utålmodige – spesielt nå som det føles som om Maris biologiske klokke stadig tikker raskere og raskere.
Dyre teknikker og avanserte ord
De oppsøker hjelp hos en privat fertilitetsklinikk. Legen prøver så godt hun kan å forklare behandlingsforløpet, men det er mye informasjon og mange fagord. Mari noterer ivrig og sier til Mats at de skal søke på internett og lese seg opp når de kommer hjem.
Etter samtalen med legen blir de tilbudt en pakkepris på kr 70 000,-. De dyre medisinene kommer i tillegg. Dette innebærer at Mari kan få ta ut egg og sette inn embryo opp til tre ganger.
Skal de gå for tre med en gang eller betale for ett forsøk av gangen?
Klinikken tilbyr også en rekke kostbare tilleggsbehandlinger som de sier at skal øke sjansen for å bli gravid – for eksempel noe som kalles for blastocystdyrkning.
Internett har svar på mye, men ikke alt
Vel hjemme setter Mari og Mats seg ned for å avgjøre hva slags behandlinger de skal gå for. De har selvfølgelig lyst til å gjøre alt for å maksimere muligheten for å bli gravid, men det må jo også stå i stil til lommeboken.
De forsøker å søke opp informasjon og lese om de ulike tingene de ble forklart på fertilitetsklinikken slik at de har litt mer å basere valget sitt på.
Paret finner ut at blastocystdyrkning innebærer at de befruktede eggene dyrkes 5 eller 6 dager på laboratoriet, i stedet for kun 2 eller 3 dager som har vært standarden.
Det hevdes at dette gjør det lettere å velge ut det embryoet som har størst sjans for graviditet og at det å sette et dag 5-embryo inn i livmoren er mer i tråd med slik det skjer fra naturens side.
Til Mats og Maris store skuffelse finner de lite forskning som ser på effekten av dette og andre tilleggsbehandlingene de ble tilbudt.
Mangel på bevis
Etter en del grubling på hva de skal velge å betale for, kommer Mats på at en gammel venn av ham jobber innen assistert befruktning. De bestemmer seg for å ta kontakt med denne vennen for å spørre han om råd.
Vennen forteller at en nyere analyseartikkel publisert i «British Medical Journal» (Heneghan et al., 2016) så på nettopp den store mangelen på gode forskningsbevis for tilleggsbehandlinger som tilbys ved fertilitetsklinikker.
Vennen forklarer også at selv om mange fertilitetsklinikker i Norge tilbyr blastocystdyrkning, er det bekymringsverdig at bevisene for den påståtte økte suksessen ikke er sterke nok.
Ta for eksempel en granskning gjort av Cochrane, en global gruppe forskere og helsepersonell, som bedømmer kvaliteten på alle studier innen et tema slik at de som er interessert kan bruke dette til å ta informerte valg.
Gruppen av internasjonale forskere konkluderte med at det er få bevis for at dyrkning til dag 5 er forbundet med en økning i antall gravide og vellykkede fødsler (Glujovsky et al., 2016). Det mange pasienter ikke får beskjed om er at forlenget dyrkning som regel fører til at færre embryo kan fryses ned til senere bruk.
Dette er også grunnen til at samme Cochrane-undersøkelse ikke fant noe forskjell på suksessrate når de så på graviditeter etter innsetting av både ferske og opptinte embryo (kumulativ graviditetsrate) på dag 2 versus dag 5.
Det er også større sjans for at ingen av embryoene utvikler seg som de skal til dag 5 slik at innsetting av embryo må avlyses. Dessuten kan forlenget dyrkning ha effekter på embryoet og fremtidig avkom som til nå er ukjente.
Forskning som grunnlag for informerte valg
Vi ønsker å hjelpe pasientene våre til å forstå dette med blastocystdyrkning og hvem som eventuelt kan ha nytte av det.
For å få dette til må vi først skaffe et godt bevisgrunnlag. Derfor planlegger vi å utføre en såkalt randomisert kontrollert studie hvor vi sammenligner innsetting av embryo på dag 2 og på dag 5.
For at studien skal styrkes skal vi ikke bare se på andelen som blir gravide, men vi skal også se på antall levende fødte barn og kumulativ fødselsrate.
Avdelingen er også en del av et større forskningsprosjekt som ser på etiske problemstillinger og biologiske mekanismer rundt epigenetikk og utvikling av embryoet de første dagene. Les mer om dette her.
Resultatene fra forskningen vår vil i fremtiden kunne være med på å påvirke pasienters og fertilitetsklinikkers valg i tusenvis av behandlinger hvert år. Vi har et håp om at vi med dette kan utvikle en klinisk forskningsplattform som kan brukes til å godkjenne eller avvise nye metoder som måtte komme innen assistert befruktning.
Referanser:
GLUJOVSKY, D., FARQUHAR, C., QUINTEIRO RETAMAR, A., ALVAREZ SEDO, C. & BLAKE, D. 2016. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database of Systematic Reviews, Art. No.: CD002118.
HENEGHAN, C., SPENCER, E. A., BOBROVITZ, N., COLLINS, D. R. J., NUNAN, D., PLÜDDEMANN, A., GBINIGIE, O., ONAKPOYA, I., O’SULLIVAN, J., ROLLINSON, A., TOMPSON, A., GOLDACRE, B. & MAHTANI, K. R. 2016. Lack of evidence for interventions offered in UK fertility centres. BMJ, 355.
Du kan lese mer om Reproduksjonsmedisinsk avdeling ved Oslo universitetssykehus her.
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Tilbaketråkk: Ufrivillig barnløs? Disse metodene finnes
Tilbaketråkk: Blastocystdyrkning vs dag 2-3, hva er best? - Medicus
Dear Trine,
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 embryologists 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 you have highlighted in your blogpost and I would strongly advise you to pay closer attention to the details within the papers you are 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
You state that many private clinics charge more for blastocyst culture suggesting it will be more expensive for the couples. We at Medicus (www.medicus.no), 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
You state 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 viable pregnancy 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 baby. 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 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 then day 3. This is also obviously dependent 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 to 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. 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 you read the paper quoted in your 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 embryo transfer. (https://www.hfea.gov.uk/treatments/explore-all-treatments/decisions-to-make-about-your-embryos). 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. (https://www.hfea.gov.uk/media/1783/fertility-treatment-2014-trends-and-figures.pdf). 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.
You further 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 you referenced. This is true, but why? So let’s think about it. In a cohort of 200 women, 100 will have a 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 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 achieve a pregnancy after the first transfer and 10 patients achieve a pregnancy in their second transfer with all embryos used up in the 2 transfers due to fewer embryos 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 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 patients, 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 cancelled 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 patient 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 PhD 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 sceptical view over data published from a clinic with an optimized blastocyst program.
Summary
In summary, blastocyst transfers have 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 transferring 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.
LikerLiker
Vi takker Medicus og Steven Mansell for kommentarene på vår blogg i deres innlegg «Blastocystdyrkning vs dag 2-3, hva er best?». 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!
LikerLiker
I firmly believe that our main objective as professionals in this field is to best serve the needs of our patients. In this, we must strive continuously to ensure the information we release into the public arena is rooted in fact. This, I believe, is the best means by which the public electing to use our services can make an informed decision as to what is best for them. I have spent the last couple of weeks contacting international experts in the field of embryology to try to respond to this article in a manner that will address the points highlighted by the authors in a factual manner.
Blastocyst culture as an ‘add-on’
The UK paper regarding ‘add-on treatments’ within the fertility industry discussed blastocyst culture in the context of a service that attracted an additional charge. However, this did not reflect the practices of all clinics in the UK. Furthermore, this is not relevant to the fertility industry in Norway, given that no clinics here charge extra for this service. Some public hospitals actually now provide blastocyst culture entirely as standard. Lastly, the paper by Heneghan et al ., 2016 (https://www.bmj.com/content/bmj/355/bmj.i6295.full.pdf) also included a number of other IVF techniques, including surgical sperm retrieval (SSR), which cannot be described as an add-on as it is a necessity for the treatment of men with severe male factor infertility, notably Azoospermia. The point highlighted in the original blog is not reflective of the Norwegian fertility industry as it currently stands. As such, my aim in responding to the blog stems wholly from the inherent duty of care we all have to patients to ensure accurate and unambiguous information is made available to them. It is my contention that the original blog post does not achieve that high standard of care owed to patients.
Take home baby rate
One of the most significant comments provided against my response that blastocyst transfer results in higher pregnancy rates were that couples want babies, not just a pregnancy. What the author neglected to mention is that in the meta-analysis referenced in the original blog, the very first conclusion indicated that blastocyst transfer resulted in a higher live birth rate compared to cleavage stage (day2/3) transfer. I provide the actual quote from the referenced paper for the author’s reference; “The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I2 = 45%, low-quality evidence) following fresh transfer. This suggests that if 29% of women achieve a live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer. “ The author is correct in stating the level of evidence is indeed low quality (only 13 randomized controlled studies, RCTs), however, the evidence to suggest cumulative pregnancy rates are no different (which was the author’s pivotal argument) is of even lower quality. In the paper by Glujovsky et al., (https://www.ncbi.nlm.nih.gov/pubmed/27357126 ) only 5 RCT regarding cumulative pregnancy rates were included. Therefore, the author’s assertion that there is no difference in cumulative pregnancy between blastocyst and cleavage stage embryo transfer is based on weaker evidence than that of live birth rate or clinical pregnancy rates following blastocyst transfer.
Cumulative pregnancy rates as a measure of success
The author is correct in concluding that cumulative pregnancy rates are the historical ‘gold standard’ for assessing IVF outcome. However, as professionals in this field, we know there are many ways to assess IVF outcomes e.g. live birth per cycle started, clinical pregnancy rate/ transfer etc. However, it is of vital importance that we focus on what it is we are trying to assess. Furthermore, the method used needs to be examined for its effectiveness by the context of the case in question. I believe a better way to assess success is by looking at implantation rate per embryo transferred. The implantation rate is an important indicator of the overall laboratory performance and is reflective of the culture conditions of the lab. However, it can also be influenced by uterine receptivity and the different policies for embryo transfer in different centers e.g. cleavage vs. blastocyst transfer, single vs. double embryo transfer (Vienna consensus https://www.rbmojournal.com/article/S1472-6483(17)30268-7/pdf). The implantation rate is calculated by the number of gestational sacs, with heart activity, observed by ultrasound divided by the number of embryos transferred, multiplied by 100
The Vienna consensus set up in 2017 by a team of international experts have set key performance indicators (KPI) for a number of stages of the IVF process. One such KPI is implantation rate. Interestingly the KPI values for cleavage stage vs blastocyst stage implantation rates are different, with a higher implantation rate expected for blastocyst transfer (competency value of ≥25% vs ≥35%, cleavage vs blastocyst transfer). If, as the author suggests, there were no difference in cleavage vs blastocyst transfer then these would be similar.
Viable embryos being lost due to extended culture
The author is correct in saying that no one knows for certain if viable embryos may be lost during extended culture. However, we do have a good idea of how many viable embryos should reach day 5 and lower rates are reflective of poor laboratory culture conditions and techniques. This once again has been set out by the Vienna consensus and states a competent laboratory should expect ≥40% of all fertilized eggs to reach blastocyst stage. At Medicus, I monitor our blastocyst development rates daily to ensure we are meeting these standards. At present we have a 52% blastocyst formation rate and a 44% blastocyst utilization rate. Based on an average patient age of 38 years this is very good and meets the criteria of the Vienna consensus. Therefore, I feel confident based on our data from our blastocyst culture program that a viable embryo should reach day 5.
Blastocyst culture as personalized treatment
This leads me on to the notion that blastocyst culture is personalized treatment. I would like to make clear that blastocyst culture is in no way personalized treatment; it is a routine procedure in the vast majority of clinics globally.
I contacted the Human Fertility and Embryology Authority to provide me with some information regarding blastocyst transfer in the UK. From their latest data in 2014, over 40% of transfers were blastocysts in 2013 compared to 12% in 2008 and there was a steady upward trend in blastocyst transfer over cleavage stage. This indicates that blastocyst culture is more or less a standard procedure and the notion that somehow growing to blastocyst is a personalized treatment is not substantiated. In my opinion, personalized treatment begins prior to the creation of the embryo. Once the embryo is created you are stuck with what you have. Blastocyst culture will not make a bad embryo more viable.
Fewer embryos to freeze.
In the original blog, there was great emphasis placed on blastocyst culture resulting in fewer embryos to freeze. As I mentioned in my previous response this is because we are eliminating embryos that do not have the potential to progress further. I subsequently decided to contact two experts in the field of embryology to get their opinion to help address this issue. Both of which provided some really useful points which I would like to share.
Point 1: Fewer embryos are a good thing!
Let’s say you start with 10 embryos and grow them to day 3. Roughly 95% will make it to this stage and you pick 1-2 from 9,5 embryos. At this stage, you have 1 in 10, maybe a 2 in 10 chance of picking the right embryo. However, if you grow to blastocyst you may “lose” 40-50% of the embryos because they will not continue past day 3. Now you have 4-5 embryos to pick from narrowing the chances of picking the correct embryo for transfer. Given that blastocyst grading is so much more informative and given that the embryonic genome will not become active past day 3, consider if an embryologist picks an embryo that looks great on day 3 but is, in fact, part of the 40-50% of embryos that couldn’t make it to day 5. This would result in twice as many embryo transfers to go through the cleavage frozen embryos to basically select the same productive blastocyst that would filter out naturally in culture. Furthermore, freezing cleavage stage embryos can also be detrimental because the survival rate of a day 2/3 embryo can be lower given that losing 1 or 2 cells can equal 10-50% of the entire embryo. If you lost 1-2 cells in a blastocyst you would lose less then 3% of the embryo. The main message is that fewer embryos are not a bad thing, as it helps embryologists ‘weed out’ non-viable embryos reducing the number of transfers prior to success.
Point 2: Fewer embryos mean fewer failed transfers.
As a result of having more embryos frozen on day 3, some of which are potentially ‘non-viable’, couples may require more embryo transfers before achieving a pregnancy. One of the experts I spoke to pointed me to data indicating the likelihood of success at fertility treatment actually reduces as the number of unsuccessful transfers increased. This was not due to the reduced likelihood of pregnancy over multiple transfers (cumulative pregnancy rate), but in most part, due to the emotional and financial burdens, infertility treatment places on couples. In a paper by Dodge et al 2017(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306407/pdf/10815_2016_Article_839.pdf), the authors observed that as the number of unsuccessful transfers increase the higher the likelihood of couples to discontinue their treatment. They showed that by the third transfer roughly 21% of all couples (6534 couples) did not continue with their treatment. This was, of course, age-dependent as younger couples were less likely to discontinue treatment compared to older couples due to a better prognosis.
At Medicus, we are very fortunate to have a fantastic therapist, Mari Heger, who helps our couple deal with some of these emotional struggles. I asked Mari to give her professional opinion regarding the struggles many couples go through when undertaking infertility treatment. This is her response:
«Par som kommer til IVF behandling har forsøkt å bli gravid i opptil flere år på egenhånd. De har allerede kjent på nederlag, sorg og utilstrekkelighet. I oppstarten av en IVF prosess opplever mange et nytt håp om å lykkes, bli gravid og få et barn. Vi vet at det er intenst å være i en IVF prosess, det er sterke, dype og høyst reelle følelser involvert. Målet om barn er utenfor egen kontroll og påvirkning, det kan forsterke fortvilelse og maktesløshet. Disse følelsene gjør noe med kroppen og kan påvirke livskvaliteten i negativ retning. Par i IVF forsøk er villige til å gjøre alt for å nå det store målet, men på et tidspunkt kan noen oppleve at det sier stopp. Psyken og kroppen orker ikke mer. Hvert forsøk med negativt svar blir en ekstra påkjenning. Håpet som holder dem oppe og som hjelper dem med å mobilisere, blir svekket. Det gjør det vanskeligere å reise seg for å gå i gang med et nytt forsøk. Det er vondt å se par som ikke orker å stå i det, selv om vi vet at de kan bli gravide om de fortsetter.
I mitt arbeid som fertilitetsterapeut ser jeg tydelige endringer i tankene knyttet til håp og mobilisering hos de som må gjennom flere mislykkede forsøk. For hvert forsøk som gir negativt svar krever det mer å fortsette. Jeg oppfordrer alle par til å være åpen om prosessen, vonde følelser blir verre hvis man samtidig er alene om dem. Støtte fra nettverk og tett oppfølging fra klinikken er særdeles viktig for at par skal klare å stå prosessen fullt ut. Tid er en av store utfordringer parene møter på, livet blir satt på vent. Det påvirker tankene og følelsen, og hvordan de har det.»
The main message I would like to emphasize is that as embryologists we need to think about the stress that fertility treatment places on our patients and to be sure that what we are transferring or freezing has a good chance of resulting in a live birth. This can be achieved in some part by ensuring the embryos are capable of progressing past day 3.
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Trine Skulands innlegg ble kommentert av Steven Mansell på en annen nettside.
Mansell må tåle at også unge, kvinnelige stipendiater tar ordet i norsk offentlig debatt, hvor det ikke er plass til nedlatende kommentarer. Mansell må følge med på tiden, legge til side hersketeknikk og finne frem til bedre poenger enn å belære forfatteren for at «hun [sic!] sterkt anbefales å lese artikler nøyere […] siden oppmerksomhet for detaljer er viktig for god forskning og for å bli en god embryolog.» Veiledning kan Mansell trygt overlate til veiledere.
Videre må Mansell skjønne at bioteknologiloven setter tydelige rammer for assistert befruktning i Norge. Om Mansell vil mene at faglig standard i Norge er lavere sammenlignet med andre europeiske land på grunn av bioteknologiloven, får dette stå for hans regning. Det har imidlertid ingenting med bevisgrunnlag for dyrking til blastocyst å gjøre.
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Tilbaketråkk: Når sædcellen ikke befrukter
Tilbaketråkk: Blastocystdyrkning vs dag 2-3, hva er best? – Test website