embryo transfer Archives - Fertility Fact Checker

What to do other people do with left over embryos?

Before starting IVF, having numerous embryos ‘left over’ was my biggest fear. I mean obviously I was going to do one cycle, have my 1.8 children (1.8 being the average fertility rate in Australia) and then have all these embryos left over that I had created and didn’t need anymore.

It was why I wasted over a year doing several IUI’s despite being told I was not really the best candidate for it and also why I asked the laboratory to limit the amount of eggs they tried to fertilise on my first IVF cycle.

But to be fair, it also had a ‘protective factor’ in that it was also why I was never disappointed when I didn’t get the massive numbers of eggs retrieved and fertilised that women often hope for. It came as a relief in a way to get those small numbers because I wouldn’t have to make that decision.

For those who have read Eat Think Grow and know my story you would know that dozen’s of left over embryo’s wasn’t something that I needed to worry about, but none the less for a growing number of women it is.

As IVF increases in ‘popularity’ and accessibility, the industry matures and success rates increase, the issue of what to do with left over embryo’s is also going to increase. It also seems like a growing practice to do full cycles and ‘bank’ embryos while you are younger before doing transfers.

What to do with left over embryos is also an issue that is being discussed more frequently in mainstream podcasts (ie not just those for subfertiles), and in the numerous blog and news articles already written on the topic.

There are all sorts of reasons why women have embryos they won’t use. Relationships end, illness happens and now with PGS testing more embryos are likely to be found as mosaic or ‘abnormal’ meaning that, understandably, these embryos too will not be used (though if you read my article on PGS I think there is still reason to have some caution).

Generally, families have five main choices to choose from when they have completed their families (or can no longer use their embryos) and need to think about what to do with excess embryos.

Keep freezing

The problem with this is that, not only can it be expensive, but it is time limited to around 5 – 10 years depending on where you live. Again, depending on your location and surrounding circumstances, you can sometimes apply to have it extended for another 5 years, but that is generally only if you are still receiving IVF treatment, still want to extend your family or some other medical condition has temporarily stopped you from using them before now.

Image by Julio Pablo Vázquez from Pixabay

It isn’t an indefinite option, but it does buy you some time to make a decision that you can find peace with or at least access some counseling so that you can make a decision that you can live with.

Thaw and Dispose

This is also referred to as letting the embryos succumb, disposing of them or stopping cryopreservation. In this process they are taken out of the freezer and left at room temperature for a period of 24 hours, a process which destroys the cells and therefore the embryo.

In one piece of research done in Australia in 2006 (1; so it is over 13 years now and attitudes to IVF have changed a lot in that time) 30% of persons chose to dispose of their embryos when they had completed their family. Other studies have had this number as being higher.

There are many factors that influence what decision a couple (or person) makes for their embryos. Religion, psychosocial factors, values and beliefs and how they regard or think of the embryos all plays a role. Interestingly, in a recent study (2) it was found that couples who chose to ‘stop cryopreserving’, seemed to have had the most attachment to the embryos and thought of them as their ‘children-embryos’. The authors report that it could be that people who choose this option have invested a lot in the potential of their embryos and are too emotionally attached to them to donate them and know that they will have a future that they will never witness (2). They also report the most distress in needing to make the decision with 46% of respondents in a survey of 243 people reporting that it was a difficulty decision to make.

After the thaw

After the embryos have been thawed and destroyed there are several options. The laboratory can dispose of them for you, some people take them home for a ceremony to plant them under a tree for example and there is even the option of turning them into jewellery. In this process the embryo’s are cremated and then mixed with other substances so that they can be made into a ring, for example. Some women find comfort in knowing where their embryos are and having them close to their heart. Making the jewellery can also a symbol of not only what they have been through but also that the door has now closed. It probably wouldn’t be my first option, but I get it.

This is a pic of Baby Bee Hummingbird (BBH) jewellery from the Kidspot.com.au website.

Donate to another person or couple

I think this decision in itself takes a huge amount of bravery, strength and is perhaps the most altruistic thing a person could ever do. There are so many factors into what influence this decision but it does appear that those who have received donor sperm or eggs to make their embryos are more likely to donate them to a couple in need. As one articles puts its like they are continuing a Chain of Hope (2). I like it.

Approximately 16% of couples with excess embryos after completing their family choose to donate them to them to another person or couple (1).

But even if a couple does make the decision to donate their embryos, depending where you are in the world, there may be other reasons why your embryos wouldn’t be eligible to be donated (2). These can include the embryo coming from a couple where the man or woman is known to have a genetic anomaly, where a woman is over the age of 40, the quality of the embryo (for example if there is only one embryo of poor quality) and the parental status of the couple wanting to donate (it is sometimes a stipulation that the biological ‘parents’ of the embryo needs to have a child between them).

Once you decide to donate to another couple there is also the decision of whether to have an ‘open adoption’ or an anonymous donation. Although again, this is a decision that is going to have things to consider I’ve been listening to a great podcast recently called Half of Me. It is by a sperm donor conceived adult and covers issues around donor conception from all angles. Although there isn’t necessarily a one size fits all approach, there does seem to be reoccurring themes about how donor conceived adults found out about their genetics and generally speaking it seems that the earlier and more open you can be about your son or daughters genetic history the better.

A chain of Hope. Image by congerdesign from Pixabay

The good news is, that for those who chose to donate to another couple, 85% of people say that it was an easy decision to make and didn’t involve all the torment of some of the other decisions. When you know, you know I guess.

Donate to Research

This is traditionally where you would donate your embryos to science. One article has said that people that choose to donate to research tend to focus on the embryos being a bunch of cells and the biologic aspect of this as opposed to those couples that choose to donate and generally speaking tend to mentally represent embryos as being a potential child (2). Around 42% of couples who have left over embryo’s after completing their families choose to donate it to science (1).

I’ve read a few comments where people have been told that their laboratory couldn’t accept the embryos for research (and hence they needed to be thawed and disposed of instead) as there can be strict rules around needing to have proper research projects and ethics approvals and others being told they embryos will be used by lab staff to practice their techniques.

Couples who choose this option have reported that they also feel like they are contributing to the future happiness of fellow subfertiles by helping to contribute to the science and improve success rates, but couldn’t live knowing that a genetic sibling to their children or a genetic child is out there walking around.

Compassionate Transfer

This option doesn’t really get mentioned that much…but I do remember it being suggested to me by my Fertility Specialist when I couldn’t quite get my head into needing to do IVF for the reason of having loads of left over embryos. During a compassionate transfer, embryos are transferred into you, much like a normal fresh or frozen embryo transfer but at a time or location when pregnancy is going to be highly unlikely, for example transferring in the first week of your cycle or transferring into the vagina (over 26% of Reproductive Endocrinolgoists responding to a survey stated that they transfer embryo’s into the vagina when doing compassionate transfers; 3) . It is believed that you are still giving your embryos ‘a chance’ and their fate is a little less predetermined than if you, for example, donate to research.

It appears that not all doctors are willing to do a compassionate transfer though. Criticisms of it state that it is huge waste of resources and doctors time could be much better spent doing activities that was at least aiming to result in a positive outcome. They have a point. But in an industry that thrives on privatization surely if women are going to pay for it, as well as help support their long term mental health, than surely that is ok? According to the same survey costs for compassionate transfers range from $0 to the full $4500 frozen embryo transfer fee (3).

But is a compassionate transfer just trying to fool yourself? And I ask this from the perspective of someone who genuinely would have considered it as an option and thought about it with respect to my own circumstances. I say this because for all we know about reproductive cycles and anatomy we kind of know that transferring an embryo during week one of your cycle into the vagina (as opposed to where it should go in the endometrium a few days after ovulation) is kind of going to guarantee that the embryo is not going to implant. But then again there is such a wide variety in the reported timings and locations for transfers and after all three doctors in the above survey did report pregnancies after doing compassionate transfers. So in that respect, if you are doing a compassionate transfer to feel as if you are giving your embryo a chance than it might be an option for you.

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To sum it up

What to do with your surplus of embryos can be a massive and anguished decision. Other times the path of what to do with your left over embryos can either be that not big of a deal or it is obvious what path you are going to take. And often you can swing between the two as your thoughts and feelings change.

Typically, the longer you have experienced infertility the more troubling of a decision it may be. One study even point a time on it suggesting that those who have experienced infertility for three or more years have more trouble than those that have experienced less than three years. I guess experiencing infertility over that time allows a lot of time, money and emotion to go into creating those embryos. Also layered into that is that the thoughts you have on it now might also change by the time you have a child.

Nothing about infertility is easy. Above are the general options that you have to choose from, but remember you don’t necessarily need to make the perfect decision – because sometimes it doesn’t exist. But taking the time to know the details of what your options are and find the one that you can rest with is what is important.

References

Hammarberg, K. & Tinney, L. (2006) Deciding the fate of supernumerary frozen embryos: a survey of couples’ decisions and the factors influencing their choice. Fertility and Sterility 86 (1) 86 – 91.
Bruno, C., Dudkiewicz-Sibony, Co., Berthaut, I., Weil, E. Brunet, L., Fortier, C., Pfeffer, J., Ravel, C., Fauque, P, Mathieu, E., Antoine, J.M., Kotti, S. & Mandelbaum, J. (2016) Survey of 243 ART patients having made a final disposition decision about their surplus cryopreserved embryos: the crucial role of symbolic embryo representation. Human Reproduction 31 (7) 1508-14
Hairston, J. & Feinberg, E (2018). Compassionate Transfer: Provider Practices and Perspectives. Fertility and Sterility 110 (4) Supplement, Page e374

Have you considered PGS?

Chances are you probably have. Then when you realised that testing can cost between $3000 – $9000 on top of your IVF cycle costs¹ put this idea on the back burner as quickly as you thought to Google it.

Finances aside, logically, it makes sense that preimplantation genetic screening (PGS) should increase live birth rates significantly –you are testing your embryos so that only those which are chromosomally normal are chosen for transfer and after all, how many times have you heard that chromosomal abnormalities are one of the major reasons that a lot of IVF transfers fail? A lot.

In reality, although some evidence does exist to support this logic, overall it is scarce and IVF live birth rates following PGS, can drastically differ depending on the stage of growth your embryo is at when tested, what laboratory technique is used and not to mention the issue of ‘mosaicism’ which just ads next level confusion to the situation.

Is it PGS or PGD?

Although the two terms are often used interchangeably and to be fair the actual procedure of PGS and PGD are very similar, there are some subtle differences between the two terms. PGS, or preimplantation genetic screening is, as the name suggests, a screen of embryos for couples who have known fertility problems to try and improve their IVF success rates. This is done by routinely checking the 23 chromosomal pairs in an attempt to ensure there are no abnormalities. PGD, or preimplantation genetic diagnosis is used typically for fertile couples who carry a chromosomal mutation for a particular disease or gene, such as muscular dystrophy or cystic fibrosis and want to ensure that these conditions are not passed on to their children. It is generally used to diagnose a particular condition that the parents are known to be carriers for.

Different approaches to PGS

PGS has been around for over 20 years now² and over this time there have been several approaches¹.

The first approach was to test cells obtained from the polar bodies of fertilised eggs. Unfortunately it was found that this method was not very accurate and often resulted in lower implantation rates and therefore was believed to not be a reliable predictor of pregnancy and birth rates³. Additionally, because it was less accurate, more samples ended up needing to be tested which again increased the cost.

The next approach was to remove one or two cells from the embryo when it was at cleavage stage (and therefore only had around eight cells to begin with). Embryos tested in this fashion showed no increase in live birth rates and at times reduced birth rates³. This was thought to occur due to the damage being down to such a young embryo⁴.

The third, and current approach that is most likely what your IVF clinic supports, is to take five to ten cells from the outer layer (or trophectoderm) of a day 5 or 6 blastocyst. By this stage the embryo has up to a couple of hundred cells and it is believed that taking these cells is unlikely to cause any damage.

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Once the cells are taken they are then analysed in a laboratory. There are several different techniques to do this which can differ from laboratory to laboratory. One of the newer ways by which testing is done is using Next Generation Sequencing which has shown promising clinical results³.

Evidence supporting the use of PGS

One recent meta-analysis³ examined the results from three random control trials looking at the cycles of 659 women and showed that PGS testing on blastocysts reported a higher implantation rate (implantation rate greater than 50%) and a higher ongoing pregnancy rate (over 45%). This means that for women testing their embryos at day 5 or 6 there is a 15 to 45% chance of increasing implantation rates and 21 to 60% chances of a higher ongoing pregnancy rate than by just choosing an embryo based on morphological information (or what it looks like when examining under the microscope).

This led the authors to recommend two things. Firstly, when transferring embryos chosen after PGS single transfers should be the standard of care (no more transferring multiple embryos) given the higher success rates.

The other conclusion authors came to was that for women with normal ovarian reserve it seems possible to achieve higher pregnancy rates by using PGS than just using standard IVF practices. It has been noted, however, that unfortunately it is generally not women of ‘normal ovarian reserve’ that most need this technology and more studies are required before it can be relied on to be a standard treatment for women of advanced age, those with low ovarian reserves, recurrent pregnancy losses or where the male partner as very low sperm count.

Per transfer versus cycle start success rates

Additionally, these results, although very promising, are only looking at success rates when there are day 5 and 6 embryos to transfer and test. Although the success rates are higher for women who PGS test and can do a day 5 or 6 transfer it does not take into account the women who may have started a cycle though did not have any embryos survive to day 5 or 6 to test and transfer. In this way the results are kind of skewed.

A 2016 article⁵ did address the potential confusion between ‘per transfer’ success rates and ‘per cycle starts’ success rates. Examining the 2011-2012 US data it was found that particularly for women under 37 years of age PGS was found to reduce the chances of a live birth in both transfer only reports (39% live birth rate for PGS tested embryos vs. 46% for non PGS tested) and per cycle start (25% for PGS vs. 29% without PGS). With miscarriage rates hovering around 14% for both PGS and non PGS embryos it was suggested by the authors that not only does PGS not improve IVF outcomes but actually negatively affects them in the clinical reality of the national US data. Interestingly, for women over 37 years of age PGS was found to have a significantly lower miscarriage rate (17% of PGS embryos miscarried vs 26% of non PGS tested embryos) and higher live birth rate per cycle start and embryo transfer. So this research suggests that PGS is a of benefit for those women aged 37 years and older.

Mosaicism

Regardless of this review of the data (after all, it is not a randomised control trial, there is plenty of room for misinterpretation of data with even an article that published contradictory opinions when examining the same available data (Chang et al as cited in 5)) and all the potential conflicts in the current literature, if you had the money and thought it would mean an implantation rate of over 50% you’d still be keen though, right?

The concern is though as to the accuracy of PGS testing. It would be logical to assume that if you are told that your embryo was ‘normal’ or ‘abnormal’ than that is a pretty black and white issue. Either it has the accurate number of chromosomes and chromosomal arrangements or it doesn’t.

It seems it doesn’t necessarily work this way and that is due to ‘mosaicism’. Mosaicism occurs when the embryo can contain both normal and abnormal chromosomal arrangements in the cells that are tested. There is a very small but thought provoking pool of research that suggests that just because an embryo contains these abnormal cells it does not necessarily mean that the embryo itself will be ‘abnormal’ or wont correct itself.

The extent of the issue of mosaicism is documented in a 2016 article⁶. Medical staff working in an IVF clinic noticed that some women were having statistically improbable high numbers of abnormal embryos being reported after testing. This was especially in younger women, who you would expect to have a higher number of normal embryos. To cut a long-ish story short, after joining forces with other IVF Clinics who also noticed this trend, it led to the establishment of the ‘International PGS Consortium’ which was dedicated to investigating the effectiveness of PGS in IVF.

The consortium completed the following research⁶. Five women whose embryos underwent PGS and all their embryos were found to be ‘abnormal’ were allowed to transfer these abnormal embryos back into their uterus. That is, in the absence of any ‘normal’ embryos these women were allowed to have ‘abnormal’ embryos transferred to see if they would implant and result in a live birth. These are embryos that traditionally would have been discarded; however, from these five transfers three normal births were recorded. This trend was supported when in Italy 18 mosaic embryos (that is embryos with both normal and abnormal cells which would have been considered ‘abnormal’) were transferred which resulted in 6 chromosomally normal live births (that’s a 33% success rate for embryos that were deemed ‘abnormal’). As of the 2016 article, only 26 women with fertility problems worldwide received allegedly PGS tested abnormal embryos. This resulted in 11 chromosomally normal live births/ ongoing pregnancies and no miscarriages.

Although this is obviously only a very, very small sample size and is not the gold standard of a randomised control trial (which, to be fair, would be very difficult if not impossible to do) it does highlight doubts as to the accuracy and relevance of PGS testing. Especially for women who otherwise would have no ‘normal’ embryos to transfer. Should these women be allowed to take a chance on questionable embryos? And does taking a few cells from the outside layer of the embryo provide enough of an accurate measure to reveal what is happening inside the embryo?⁶

This concern was supported when the same researchers completed another study on 11 donated embryos that were deemed ‘abnormal’ and would have been discarded. Sending the embryos to another laboratory to be retested, researchers found that only 2 out of 11 embryos had the same reports across the two laboratories⁶. 4 out of 11 embryos that were previously reported as abnormal were now, normal and 2 out of 11 were now reported as being mosaic, having at least one normal fragment and hence a chance of a successful outcome. What is even more concerning is that even the gender identified varied between the two laboratories. Again, these results are only a very, very small sample size and is NOT statistically significant but does suggest a false positive rate for PGS as high as 55%⁶.

55% does seem extraordinarily high and some laboratories claim an accuracy rate of 99%. Quite a discrepancy. This 99% accuracy rate however, is thought to reflect accuracy in a clinical validation study and not necessarily the accuracy in true clinical matters that actually happen on a day to day basis in women doing IVF. Some estimates of the actual misdiagnosis rate sit around 5%⁴.

Time to Change?

To take into account the phenomenon of mosaicism, instead of reporting embryos as being euploid or aneuploid, or normal or abnormal, it has been suggested that embryos with less than 20% mosaicism are reported ‘normal’ and those over 80% mosaicism are reported as ‘abnormal’. This leaves those in the 20 – 80% as mosaic and depending on the advice and recommendations of the IVF Clinic, in the absence of any normal embryos potentially a consideration for transfer. Obviously though, this suggests radical change as previously any abnormality was discarded².

Putting it together

For some women, typically those who have a good IVF prognosis anyway, with normal ovarian reserve and the funds to do so, PGS testing could very well be a reliable and valid way forward. Particularly for those who have been on the IVF ‘journey’ for a considerable time and want to give themselves the very best chance of a live birth per transfer.

For others though, there is the need to stop and think. This is particularly for those who get a high number of ‘abnormal’ results and for those who are of advanced maternal age or who are unable to grow embryos to day 5.

The cost per birth for an IVF PGS cycle is estimated at being $45,300⁷. So whilst some of the evidence is promising it isn’t without its critics and until further evidence can be produced that supports a significant increase in live birth rates, you might be better off redirecting some that money into another IVF cycle. Or not. There is no clear cut answer and only through careful conversation and discussion with your fertility specialist regarding your individual situation can a decision be made as to if PGS is for you.

Reference

Twisk, M., Mastenbroek, S., van Wely, M., Heineman, M.J., Van der Veen, F. and Repping, S. (2006) Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2006, 1. Art. No.: CD005291.DOI: 10.1002/14651858.CD005291.pub2.
Gleicher, N. and Orvieto, R. (2017). Is the hypothesis of preimplantation genetic screening (PGS) still supportable? A review. Journal of Ovarian Research 10 (21). DOI 10.1186/s13048-017-0318-3
Dahdouh, E., Balayla, J. and García-Velasco, J.A. (2015). Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertility and Sterility 104(6) 1503 – 1512.
Brezina, P., Kutteh, W., Bailey, A. and Ke, R. (2016). Preimplantation genetic screening (PGS) is an excellent tool but not perfect: a guide to counselling patients considering PGS. Fertility and Sterility Reflections 105(1) 49 – 50.
Kushnir, V., Darmon, S., Albertini, D., Barad, D. and Gleicher, N. (2016). Effectiveness of in vitro fertilization with preimplantation genetic screening: a reanalysis of United States assisted reproductive technology data 2011–2012. Fertility and Sterility 106 (1) 75–79.
Gleicher, N., Vidali, A., Braverman, J., Kushnir, V., Barad, D., Hudson, C., Wu, Y.G., Zhang, L., Alberini, D. and the International PGS Consortium Study Group (2016). Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryo. Reproductive Biology and Endocrinology 14(54). DOI 10.1186/s12958-016-0193-3
Murugappan, G., Ohno, M., Lathi, R. (2015). Cost effectiveness of preimplantation genetic screening and in vitro fertilisation versus expectant management in patients with unexplained recurrent pregnancy loss. Fertility and Sterility 103 (5) 1215 – 1220.

Which is better: A day three or day five embryo transfer?

For some the answer will lie in the standard protocol of the clinic; for others it might be dictated by how many embryos they have. Regardless of how you get to your answer, it seems there are costs and benefits for both. Whilst there appear to be the seemingly obvious advantages of a day five transfer – that being the embryo has already grown and survived five days instead of three and therefore theoretically healthier, there are some distinct disadvantages. Plus if it was simply that conclusive that a day five transfer is the gold standard, than surely all the fertility clinics would be doing them as standard?

What happens during a day three transfer…

A day three transfer is when the embryo is transferred back into your uterus on the third day after fertilisation (with egg pick up and fertilisation happening on day zero). A day three embryo is considered to be in cleavage stage and the cells are still small in number and easy to count. There are all sorts of different grading systems but ideally a day three embryo has eight cells (though this number can vary between seven to nine cells and I am sure there are some stories out there of a four cell, day three embryo successfully implanting). According to the Centre for Disease Control (CDC) who publishes a huge amount of data on IVF success rates, in the U.S. in the year 2012 45.9% of non donor embryo’s were transferred on day three. For the record, 44.5% were transferred on day five, 4.5% on day two, 2.3% day four and 0.1% on day one.

…and a day five transfer

A transfer on day five, or sometimes day six means that the embryo is transferred on day five or six post fertilisation. An embryo at this stage has turned into a blastocyst and is getting ready for implantation. Cell differentiation is also beginning meaning that is there are now two different types of cells – one that will become the placenta and one that will become the fetus. Embryos cannot be grown in the lab for longer than this because the embryos are soon start hatching out of their shell and need your endometrium for implantation.

The case for a day five transfer

One of the main arguments for doing day five transfers is that only the strongest embryos have survived until this point and therefore are more likely to be chromosomally normal and hence develop into that take home baby. That is a fair point. According to data collected by the CDC, across all age groups, and particularly in women under 40, there were higher success rates for day five embryo transfers when compared with day three embryos – and not an insignificant amount. In their 2012 report, for women under 40 a day five transfer typically had about a 12% improved success rate than a day three transfer (interestingly though, a recent Cochrane review didn’t put the improved success rates so high, reporting that for the limited amount of studies that reported such figures, they only found there was only an increase in live birth rate of between 1 – 11% and no difference in miscarriage rates (1)) .

This means that for any one transfer, you can be more confident that your embryo will implant, which in turn means that lower numbers of embryos should be transferred, ideally one at a time. This carries the added benefit of theoretically reducing the chance of twins and triplets. Although multiples seem, and for many women still would be, a blessing, it does carry with it its own set of risks such as premature birth, higher chances of preeclampsia and lower birth weights which in turn can impair the overall health of the baby. Therefore if transferring on day five means that less embryo’s will be transferred each time, this ultimately results in better outcomes for both mum and baby.

Another reason some clinics prefer to complete a day five transfer is so that when the transfer is completed and the embryo is your uterus it is in a location more aligned with where the embryo would be expected to be in a natural cycle. Although fertilisation can happen anywhere along reproductive tract, most of the time it happens in the fallopian tube at the end closest to the ovary. The embryo then spends the next few days travelling down the fallopian tube, not reaching the uterus until day five. It is believed that when transfers occur on day two or three that the embryo is placed in the uterus too prematurely. These two different locations of the fallopian tube and the uterus also provide a different nutritional environment to the embryo catering to its differing developmental needs (1).

Day 3 or Day 5 - different paths to the same place? — Day 3 or Day 5 – different paths to the same place?

The case against a day five transfer

Whilst reading the above you are probably already drafting up arguments for your doctor on why they should be doing a day five transfer, it is important to remember that there are two sides to every coin.

A recent Cochrane review found that women who are waiting for a day five embryo transfer have lower transfer rates then women who have day three transfers (1). That is, ‘success rates’ aside, for a significant proportion of women, embryos arrest on day four which means that they would have been able to have a day three transfer, but unfortunately none survived to the blastocyst day five stage. Whilst it has been suggested that this may be better on a woman’s mental health because women don’t have to survive through the two week wait with an ‘inferior’ embryo that may not implant at all, surely most women would rather be ‘in the game’ and still with very reasonable chances of a BFP than not make a transfer at all? And as they say, just because the embryo wasn’t able to grow in a laboratory who is to say that it wouldn’t have grown ‘in vivo’, or in you to be less latin about it.

Women who complete day five transfers also generally have less embryo’s to freeze (1). Athough as we previously discussed, per transfer there may be up to around 12% higher success rates for a day five transfer, you are still far from being guaranteed that take home baby and may need to do subsequent frozen embryo transfers. Unfortunately for some though, by growing embryos to day five, several may have been lost getting them to grow in the laboratory to that stage. This in turn means that you have to go through the financial expense, emotional exhaustion and physical discomfort of going through the whole IVF process rather than ‘just’ a frozen embryo transfer.

The above two points (not making to transfer and having less embryos to freeze) contributes to the interesting point also highlighted in the Cochrane Review. That is although the pregnancy rate of each transfer may be higher for day five transfers the cumulative pregnancy rates for day three transfers were in fact higher. The cumulative pregnancy rate is the overall pregnancy rate when all the embryos produced have been used. Although the chances of success per transfer is lower, per cycle they are in fact higher for women who transfer on day three. This is an interesting point and one that is hard to take a step back and appreciate when each transfer feels like it is taking everything from you and you just want that positive result NOW.

Day five transfers have also been associated with higher rates of monozygotic twinning (when the one embryo splits and implants as two foetuses) and is also associated with higher rates of males being born (not that I’m attributing that to being a negative per se, but it lends itself to the fact that some sort of artificial elimination process is occurring, though I am aware that in mother nature slightly more males are born also). Day five transfers have also been associated with premature births when compared to day three transfers with the researchers hypothesising that by growing the embryos in culture for longer periods of time that this is possibly associated with subsequent placental development and functioning (2)

Additionally, it is women who are typically ‘good responders’ who are able to grow large numbers of embryos to day five. These women seem to produce good embryos regardless of what developmental stage they are at.

With the development of better monitoring systems for early embryo development the need to ‘wait it out’ for a day five embryo also reduces. The embryoscope for example enables laboratory staff to check that embryo development is ‘normal’ at every minute of the day. Who knows, perhaps by having these milestones noted it may one day prove to be more useful to predicting an embryos health than if it was able to develop into a blastocyst in the laboratory.

The Rebutal

However, just like the theory that day five embryos are inherently superior than day three embryos is the main reason to try for a blastocyst transfer, the theory that embryos thrive better inside you than in a laboratory is the main reason to support a day three transfer. This still may be so, though there are no guarantees of this and if an embryo is chromosomally abnormal it is not going to survive regardless of where it is.

The argument that embryos are better in your uterus rather than in a laboratory dish is also becoming less convincing as technologies develop. For instance, the culture that laboratories grow embryos in are becoming more tailored and there are now two different types of culture that can be used and changed depending on the age and hence nutritional requirements of the embryo (1). This should mean that fewer embryos perish at around that day three stage in the laboratory. Similarly, incubators are becoming more and more advanced and capable of maintaining the ideal temperature, gas composition and pressure for growing the embryos to day five removing the need for them to be transferred back into a living uterus as soon as possible.

To sum it up…

Whilst day five transfers have higher per transfer success rates, this needs to be weighed up against lower cumulative success rates and less embryos available for use in the future. But perhaps the biggest factor that women need to accept is the ‘what if’ factor. For despite all the advances in fertility treatments there is still a lot that is unknown. For a woman that had no embryos to transfer on day five, or only one or two, who is to say that any number of embryos wouldn’t have implanted if transferred on day three?

The answer as to which day is better to transfer on isn’t cut and dry and as patients we rely on the specialised skills of the laboratory staff and our doctors to make that decision for us. As improved monitoring techniques mean that healthier day three embryos can be selected and better culture means that more embryos survive to day five perhaps the answer to the question isn’t as polarising as first thought.

If you are doing IVF don’t forget to download your free IVF guide. With 19 evidence based ways designed to increase your egg quality, implantation rates and ultimately IVF success it’s a must see!

References

1. Glujovsky, D., Blake, D., Bardach, A., Farquhar, C. (2012). Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology (Review). The Cochrane Library, Issue 7.

2. Dar, S., Librach, C., Gunby, J., Bissonnette, F. and Cowan, L. (2013). Increased risk of preterm birth in singleton pregnancies after blastocyst versus Day 3 embryo transfer: Canadian ART Register (CARTR) analysis. Human Reproduction, 28 (4) 924–928.

Eating pineapple to aid in implantation? Read on…

Many women undergoing fertility treatments would have at some stage come across theory of eating pineapple to aid in implantation. But there seems to be some confusion as to why pineapple and can eating canned pineapple or drinking pineapple juice be of any benefit also?

Why Pineapple?

There are many forum posts and blogs written by ladies TTC who report that pineapple, or Ananas comosus, to use the scientific name, is said to aid in implantation as it contains bromelain. Bromelain is an enzyme is found in the core, juice and skin of pineapple but is most plentifully found in pineapple stem (2). Therefore bromelain is likely to be found in low levels in pineapple juice, however, if you are buying canned or carton pineapple juice the pasteurisation and sterilisation processes it needs to go through to preserve the pineapple juice in a can or carton most likely reduces the effectiveness of any naturally occurring bromelain. That is not to say though that firstly, there is any scientific evidence supporting the theory that bromelain is beneficial in aiding implantation and secondly, even if it was that there are sufficient levels found naturally in pineapple stem for it to be of therapeutic value.

Extracted bromelain is also available as a tablet form, though the dose varies considerably according to the reason for use and it would not be advisable to self medicate.

Uses of bromelain

Bromelain is believed to have properties that can assist the human body in many ways including the prevention of blood clots, swelling and inflammation. Due to these properties it has been indicated as being useful in preventing transient ischaemic attacks or mini-strokes and angina (1). It is also beneficial for those with osteo and rheumatoid arthritis due to its anti-inflammatory and pain relieving properties and is also suggested for people with chronic, inflammatory immune conditions and also as a method of assisting in the debridement of burns, in the relief of diarrhoea and with future research may also become an adjunct cancer therapy (1). Finally, bromelain has also been administered to people who have had sports injuries in order to control the swelling and bruising (2)- is there anything it can not do?!

Bromelain and pregnancy

As this is a fertility blog though we will assume that we want to know how bromelain can assist in supporting a pregnancy. I have been unable to find any control trial experiments or scientific research that indicates that bromelain is effective in the implantation of embryos. This does not necessarily mean that bromelain has no benefit just that it has not been researched and hence its efficacy can not be determined.

Due to its anti-inflammatory and anticoagulant properties though there might be a couple of pathways in which bromelain may be effective.

Due to its anticoagulant (stops blood clots) properties it could possibly facilitate blood flow to the uterus. With improved blood flow to the uterus the lining and health of the uterus may be improved which provides a better environment for which implantation can occur. Possibly.
Due to its anti-inflammatory properties bromelain has been found to benefit those who have autoimmune conditions such as rheumatoid arthritis. Further research may one day suggest that bromelain can assist women with autoimmune conditions and markers who’s condition is resulting in infertility. There have been studies done that indicates that bromelain was able to modulate how cells binded with T cells and natural killer cells (1), two types of cells also implicated in infertility.

Well, it can’t hurt anyway?

The mechanisms of bromelain are clearly under researched, particularly with reference to fertility. Therefore any benefits and also any costs of using bromelain are unknown and hence taking bromelain tablets should be avoided without proper medical advice. Although bromelain found naturally in pineapple is likely to be in doses that are relatively low, some people advise against eating too much pineapple too early in your cycle. This is as if it is eaten before ovulation some believe that the acidity of the pineapple may increase the acidity of cervical mucous making it a hostile environment for sperm and hence fertilisation (2).

However, due to the assumed relatively low levels of bromelain existing naturally in pineapple, as long as you eat it as recommended (no more then a couple of slices a day) and after confirmed ovulation, or embryo transfer, it is unlikely to do any harm. If you are looking at taking bromelain tablets, I would definitely recommend you speaking to a health professional before doing so, particularly due to bromelains blood thinning properties and especially if your fertility specialist has put you on low dose aspirin. It has also been found to increase the effectiveness of antibiotics so again seek medical advice before commencing bromelain but especially if you are on any other medications.

If you are thinking of, or doing, IVF don’t forget to get your free IVF guide with 18 other evidence based ways that will hopefully increase your egg quality, implantation rates and ultimately, IVF success.

References

1.Pavan, R., Jain, S. & Kumar, A. (2012) Properties and Therapeutic Application of Bromelain: A Review. Biotechnology Research International, published online 2012 Dec 10. doi: 10.1155/2012/976203

2. Meschino, J. Meschino Health Comprehensive Guide to Herbs. Available from meschinohealth.com

3. Campbell, L http://natural-fertility-info.com/bromelain-pineapple-for-implantation.html

Does bed rest help after an embryo transfer?

As if there isn’t enough to worry about after an embryo transfer, worrying that you are ruining any chance of a BFP as you have to get up and go straight after an embryo transfer is up there. This is especially so for women who need to go straight back to work after taking all that time off for blood tests and monitoring, the egg collection and the transfer itself.

Everyone has an opinion on how much bed rest you need and it ranges from none at all, to 10 minutes straight after the transfer to up to three days (who has time for that?). Saying that though, who amongst us wouldn’t lie flat on our backs for three weeks if it was proven to increase the probability of a successful embryo transfer?

When I searched ‘bed rest embryo transfer’ in a medical search engine I found less than 10 articles directly related to this topic in the last 10 years. Needless to say more research would be useful. Or would it? I only say this for I couldn’t find one piece of evidence that indicates that bed rest is beneficial – has this conclusion already been drawn?

The JURY IS IN

If it were to be summed all up in one sentence, Abou-Setta et al in their 2014 Cochrane Review (1) report

there is insufficient evidence to support any specific length of time for women to remain recumbent, if at all, following embryo transfer

So it seems as if there is no evidence to support the need to rest after a transfer. To reach this conclusion they did a thorough search for all trials that had been conducted and found two studies that they thought were appropriate, consisting of 594 patients. When we think of how many embryo transfers get done every day and the amount of money that changes hands, I think that this indicates a disproportionately small number of research articles being produced. But hey.

Abou-Setta et al (1) also highlight that the research done is of low quality and recognises that more research is definitely needed in this area which may help to change future thinking.

Well at least it doesn’t do any harm…?

Gaikwad et al (2) report that even 10 minutes of bed rest following embryo transfer can be detrimental. They report on one study where there were two groups of women – one who had been told to rest following transfer and one who didn’t rest. Ultimately this study had to be abandoned for ethical reasons because it became evident early on that the women who rested following a transfer had a lower chance of a successful outcome then those who did not. Gaikwad speculates on other investigators thoughts as to whether or not the seemingly detrimental effect of bed rest is due to the position of the uterus when lying down as well as speculating that continuing on with every day living helps manage our coping strategies and anxiety levels which has previously been researched to have an impact on success rates.

The amount of time women are recommended to rest in bed also varies. This has also been researched and regardless of whether the bed rest is for 10 minutes (2), 30 minutes (3), one hour (4) or one day (5) it seems that the less time that is spent in bed post embryo transfer the better the chances of pregnancy and ultimately a take home baby. It should be noted that there is some conflicting evidence and not all researchers say that bed rest is detrimental (though they do all seem to concur that it is at the very least not beneficial).

Why is bed rest recommended?

Whilst I am sure that they exist (surely?!) I have been unable to find any articles, proper research articles or internet articles that support the need for bed rest, despite the chat rooms and forums being full of women who report that their specialist advised them to do so. Whilst these articles are also not saying to go run a marathon (who would with ovaries the sizes of oranges) why are a lot of women undergoing embryo transfers still be advised to do so? Remember though if your specialist has recommended a period of rest for you, query it with them, there could be something in your particular medical history that makes it a worthwhile pursuit… maybe…

Other reasons why bed rest is not required

Placement of embryo

Personally, despite the fact that whilst I try and linger horizontally in the ‘transfer room’ as long as possible after a transfer, the rational side of me believes that rest is not required and the embryo isn’t going to ‘fall out’ as soon as you stand up. When you look at the thousands of years of natural conceptions that happened prior to IVF, I am pretty sure that not one of those fertile women even thought to have a lie down on day 3 or 5. Especially for those ladies who do the day 5 transfers the location in your uterus where your Specialist places the embryo during the transfer is pretty much exactly where it would be by day 5 in nature, ie typically towards the top of uterine cavity after traveling through the fallopian tube. And for those ladies who don’t do day 5 transfers, embryos can move and fertilise at any point in the fallopian tube or uterus so again, no stress required! Those ladies who really do think about things a lot, yes transferred embryos can move around, but they are pretty well supported once they are in they are in there (its not as if there is just a totally empty space) and the incidence of ectopic pregnancy in IVF gestations is around 1.3% (Australian Doctor, 27th March 2015) which when you think about the overall success rates is relatively low and putting yourself on bed rest because you think the embryo is going to move around doesn’t really outweigh the reasons for NOT going on bed rest.

Circulation and blood flow

Additionally, when we are moving around the circulation through out body is improved, this includes circulation to the uterus. The longer that we are immobile or resting in bed, our circulation system slows meaning that less blood is being pumped around the body and to the uterus. One of the reasons some of us take low dose aspirin or visit the acupuncturist is to try and increase blood flow to the uterus so why would we want to do anything that inhibits this. By increasing blood flow some believe that this can increase the quality of the lining which ultimately supports implantation. When you look at it from this point of view, we really should be making sure that we are doing light exercise and improving circulation throughout the cycle.

Over thinking time

When we are on bed rest it gives us too much time to think. Whilst for a short time we may be secretly quite happy to finish off the Orange is the New Black boxset our mind will pretty soon start turning back to the little ball of cells that has been placed inside of you. One thing that fertility patients tend to do very well is think, which inevitably leads into a dangerous cycle of self blaming, stress and anxiety. No thank you. And this theory is also supported by Küçük (7) and by Gaikwad (2) as briefly mentioned above. More on the impact of stress and anxiety in future posts.

I am sure there are many other reasons why bed rest could be detrimental to embryo transfer success, but these are just to name a few.

But please tell me if have you been instructed to rest after embryo transfer and for what reasons?

And as always, the above is just for information purposes, please discuss with your treating specialist to decide what is best for your individual situation.

References

1. Abou-Setta, AM, Peters LR, D’Angelo A, Sallam HN, Hart RJ, Al-Inany HG. Post-embryo transfer interventions for assisted reproduction technology cycles (Review). Cochrane Database of Systematic Reviews 2014. Issue 8

2. Gaikwad, S., Garrido, N., Cobo, A., Pellicer, A. & Remohi, J. (2013) Bed rest after embryo transfer negatively affects in vitro fertilization: a randomized controlled clinical trial. Fertility and Sterility Vol 100 (3) 730- 735

3. Purcell, K., Schembri, M., Telles, T., Fujimoto, V. & Cedars, M. (2007) Bed rest after embryo transfer: a randomized controlled trial. Fertility and Sterility Vol 87 (6) 1322 – 1326

4. Bar-Hava I, Kerner R, Yoeli R, Ashkenazi J, Shalev Y, Orvieto R. (2005) Immediate ambulation after embryo transfer: a prospective study. Fertility and Sterility 83 (3) 594–597.

5. Amarin, Z. & Obeidat, B. (2004) Bed rest versus free mobilisation following embryo transfer: a prospective randomised study. BJOG: An International Journal of Obstetrics and Gynaecology Vol 111(11) 1273-6.

6. Australian Doctor

7. Küçük, M. (2013) Review Bed rest after embryo transfer: is it harmful? European Journal of Obstetrics & Gynecology andReproductive Biology Vo (167) 123–126