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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.

Mosaic of a different kind

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

  1. 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.
  2. 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
  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.
  4. 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.
  5. 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.
  6. 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
  7. 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.

Filed Under: Uncategorized Tagged With: Cost of IVF, embryo transfer, improve ivf success rates, IVF success rates, ovarian reserve, PGD, PGS

ICSI IVF… What Is It About?

For some ICSI is just that next step down the fertility path when traditional IVF fails.  For others their clinic ONLY fertilises eggs by using ICSI and there is no way around it.  One thing is apparent though and that is that ICSI is gaining ground on IVF and becoming more and more common.  Here are some answers to those common questions regarding ICSI.

What is ICSI?

ICSI, pronounced ‘ick-see’ stands for intra-cytoplasmic sperm injection.  It is when the embryologist selects one sperm from the semen sample that has been provided and this single sperm is then injected directly into the egg.  There are different methods and techniques that the embryologist can use to select the best sperm such as using an extra high magnification microscope or putting the sperm into substances that mature sperm then bind to and then picking one of these.  For the purposes of this article we will just lump all these different methods together (as is mostly done in the literature).

There are strict rules set by various overseeing bodies that dictate which sperm is suitable for ICSI.  For example sperm must be mature and of a particular size and shape.  This is reassuring as it again attempts to ensure that only healthy, mature sperm are injected – though if they weren’t healthy, mature sperm the egg probably wouldn’t fertilise rather than having adverse outcomes for your baby.

Although it is a different procedure ICSI comes under the umbrella of IVF and sometimes your lab might interchange the term ICSI with IVF.

ICSI is different to IVF, which as you are likely to know is where the egg and the sperm are placed together in a dish and the sperm are left to their own devices to penetrate the shell of the egg and fertilise the egg that way.  As a new patient in the fertility world IVF can seem a little bit more natural then ICSI because at least some sort of natural selection is taking place, right?  That is in traditional IVF the best sperm still has to win at the end of the day, albeit in a manufactured environment.  On top of injections and ‘harvesting’ your eggs ICSI can seem like yet another intervention.

Why is ICSI used?

ICSI has been traditionally used when there is significant male factor infertility and we can’t really go further without first briefly touching on sperm count. You might remember that the normal sperm count in a healthy man is around 40 million per ‘go’ (or ejaculate in case I wasn’t clear).  Don’t forget though that sheer numbers is not enough and the sperm themselves need to be healthy with good motility, that is the need to have the ability to move around and get to where they need to and good morphology, meaning that they look the part with one tail and one head, for example. When a semen sample is provided, the embryologist will prepare the sperm, taking out all these stragglers leaving behind only the best of the best. Or as I have heard one consultant say SAS sperm.

Low Sperm Count

It has previously been mentioned that in instances of male factor infertility if the SAS sperm count is greater than 10 million it might be worth attempting IUI, if the count is between 5 – 10 million try IVF and anything less than this just use ICSI as the likihood of fertilisation without it would be relatively low.  It is in these very low sperm counts that ICSI was first intended.

Previous Zero Fertilisation Rate

In addition to the reason of having low sperm count, another reason that ICSI might be used is if you have previously completed a cycle where there was zero fertilisation.  This can happen in 10 – 20% of couples (Chen et al as cited in 1).  Instead of having to live that one again, your embryologists may recommend that you skip plain old IVF and head straight to ICSI in order to give the egg and sperm the best chance to meeting and the egg fertilising.  Remember though, that just because the sperm has been injected right into the egg, a little something special still has to happen and it doesn’t automatically guarantee fertilisation.  It can in some instances improve it though which is why some clinics opt for ICSI as standard, though other clinics believe that with normal, healthy sperm ICSI is just not required and with mother nature not actually intending for a needle to necessarily be shoved in her eggs side they are quite possibly correct.

Rescue ICSI

Rescue ICSIICSI may also be performed in ‘rescue’ situations.  That is when traditional IVF has been attempted but no fertilisation has occurred after a certain amount of time.  In this case the embryologist will inject the egg with sperm in an attempt to make it easier for fertilisation to occur.  When rescue IVF is needed research shows that the sooner it is done the better.  One small study shows that fertilisation rates for rescue ICSI performed after 6 hours has a fertilisation rate of 70%, compared with only 48% when rescue ICSI was performed after 22 hours (1).  This 70% fertilisation rate is in line with the general fertilisation rates of standard IVF (Nagy et al as cited in 1) so this is a very good outcome.  The 6 hour rescue ICSI, as opposed to 22 hour rescue ICSI also has better implantation, pregnancy and live birth rates.  It should be noted that in some instances clinics do not always like to practice rescue ICSI due to the risk of more than one sperm being inserted into the egg and the complications this can cause (though there are ways technician can try and see if an egg has fertilised to reduce this from happening, for example by looking at the polar body of an egg, so this doesn’t happen very often).

Extra Testing or Surgical Collection

ICSI can also be recommended if you are planning on doing embryo testing or if sperm has needed to be collected surgically through means such as Percutaneous Epididymal Sperm Aspiration (PESA), Micro-Epididymal Sperm Aspiration (MESA) or Testicular Sperm Extraction (TESE).

Does ICSI cause higher rates of birth defects?

Generally speaking, the news is good.  It seems that if you are comparing IVF to ICSI there is no correlation between the use of ICSI over IVF and birth defects.

This was recently covered in a metaanalysis completed by some researchers in Europe (2). They reassuringly found that there was no difference between ICSI conceived babies and IVF conceived babies and this has also been reported elsewhere (3).

Although this study is getting a little old now (Bonduelle et al 2003, as cited in 3) research was also done assessing children’s development at two years of age which is a welcome study to have given that a lot of research stops following the babies at birth.  By completing standardised testing it was found that at two years the psychomotor and cognitive development of children were the same irrespective of whether the child was conceived using IVF or ICSI.

The Centre for Disease Control reports nearly 70,000 ICSI cycles were completed in America in the year 2012.  This is a number that has been steadily increasing since the introduction of ICSI and we can be forgiven for thinking that there may be some safety in numbers.  With all the checks and scrutiny that IVF clinics are rightfully held to, if ICSI was causing an increase in children with birth defects it would have come to light by now.  And with the first ICSI babies being conceived in the early 90’s, this provides around 25 years of longitudinal data to have had scrutinised.

There was one study however, that again studied babies born following ICSI conception or IVF conception (4).  They found that ICSI babies generally were at higher risk of preterm birth and lower gestational weight and age (even accounting for the fact they were born earlier).  It seems though that ICSI babies were more likely to be part of multiples which could very well account for this outcome as when they assessed just singletons the ICSI babies were no longer at a disadvantage.  This was only one very small study however with flaws in its own methodology, but in the interests of presenting both sides of the story, I mention it briefly.

Interestingly some researchers hypothesise that it sometimes can be the reverse, that is children of IVF conceived births can fare worse off than ICSI (2).  One theory of why this is is because IVF is used predominantly when the sperm is of sufficient quality and quantity, but there are still difficulties with fertility.  This infers that it is due to maternal factors that infertility is experienced.  That is IVF is traditionally used when there is female factor infertility and ICSI when there is male factor infertility.  If this is the case and if there are slightly poorer outcomes for IVF babies, it would seem that it is more important to have a healthy mother producing good quality eggs which may be able to compensate in some way for poorer sperm quality.  I should also stress that when comparing birth outcomes the researchers are generally looking at things like birth weight and gestational age and not major disabling defects, therefore if not totally ideal is most likely to be so insignificant to not change your decision to complete one procedure over another.  Though like everything, your doctor will be the best person to walk you through the pros and cons.

Whilst we have established that there is no differerence between IVF conceived and ICSI conceived babies, in the course of researching I did find that it has been mentioned that ART babies in general have higher risk of birth defects.  There are a number of possible reasons for this and one is that it may be that the reason couples have difficulty conceiving is the risk factor for the defect rather than the technology itself.  Alternatively, it may be one or more then one of the steps involved in the IVF/ICSI process that causes  this.  For example it may be the medication used to stimulate cycles, growing embryos in a culture or transferring embryos into the uterus that possibly increases the risk of birth defects (though IUI is also included under the ART umbrella and in IUI the embryo is not created in the lab so this doesn’t necessarily explain it all).

These same researchers also suggests that babies that are the result of a frozen embryo transfer are generally at less risk of preterm birth and lower birth weight.  This is good news for women who are already less then thrilled to be completing a frozen transfer due to the slightly lower success rates.  It is suggested that this occurs because in frozen embryo cycles there is not the same amounts of medication being used and in the luteal phase (that is the phase after ovulation/ transfer) the hormones in your body more accurately reflect those in nature.   But don’t worry fresh cycle ladies, there is some evidence that suggests that there is actually no relationship between the total dose of medication taken, number of eggs harvested and the health of your baby (this is low grade evidence though and further research is needed).

Remember, take all this with a pinch of salt and there is no point in getting concerned over this without discussing your individual situation with your doctor.  Although when you are in the moment it may seem like the be all and end all, for example  ART children are possibly more likely to have certain defects, the overall number of children experiencing these remain a very, very small number.  It is up to you to determine what you are comfortable with but for most women the risk of not having a child far outweighs the relatively very small risk of a child with an abnormality.  But again the exact numbers and percentage will vary according to your particular situation so it is best to discuss this with your clinic.

How much does ICSI cost?

Cost of ICSIDepending where in the world you live the cost of ICSI over IVF can be significant. Resolve, which is a leading information and support network for all things fertility related report that ICSI can cost up to an extra $1500 to the cycle for those women living in the United States of America.  If you are in Australia, where there are already excellent Medicare rebates for IVF, the extra out of pocket expense for doing ICSI over IVF can be around $300 depending on your clinic.

References

1. Chen, C. & Kattera, S. 2003. Rescue ICSI of oocytes that failed to extrude the second polar body 6 h post-insemination in conventional IVF. Human Reproduction Vol.18, No.10 pp. 2118-2121

2. Pinborg A, Wennerholm UB, Romundstad LB, Loft A, Aittomaki K, Söderström-Anttila V, Nygren KG, Hazekamp J, Bergh C: Why do singletons conveived after assisted reproductive technology have adverse perinatal outcome? Systematic review and meta-analysis. Human Reproduction Update 2013, 19:87–104

3. Devroey, P. and Van Steirteghem. A. 2004. A review of ten years experience of ICSI. Human Reproduction Update, Vol.10, No.1 pp. 19±28, 2004

4. Nouri, K., Ott, J., Stoegbauer, L., Pietrowski, D., Frantal, S. and Walch, K. 2013 Obstetric and perinatal outcomes in IVF versus ICSI-conceived pregnancies at a tertiary care center – a pilot study. Reproductive Biology and Endocrinology 2013, 11:84

Filed Under: Uncategorized Tagged With: Birth defects, Cost of ICSI, Cost of ICSI Australia, Cost of IVF, Cost of IVF Australia, Fertilisation Rate, Fertilisation Rates, ICSI, IVF success rates, Rescue ICSI

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