becja, Author at Fertility Fact Checker

Assisted hatching & embryo glue – Do they work?

Fertility treatments are quickly evolving. It is no longer just a matter of egg meets sperm and waiting for the magic to happen.

Now there is the choice of doing preimplantation genetic screening (or PGS – we’ve covered that one pretty well here), assisted hatching, using timelapse imagery, autoimmune protocols, endometrial receptivity array (ERA), endometrial scratching… the list continues…

Unfortunately, not all of these ‘add-ons’ have the research to indicate that they will increase IVF birth rates or the evidence to say that they do not impact the future health of the baby (1). That is not to say that they won’t in the future, but for now, for some of these treatments, the research just hasn’t been done. If you are keen to use the latest technologies available though, sometimes you have to take the risk of it not being an evidence based treatment yet. Most clinics are upfront in saying ‘it may or may not work’ but if they are misleading with the evidence that is available or the treatment has actually been shown not to work and is still being recommended, well, that is another story – especially when it comes with a price tag with more zeros behind it than what you would like.

As the British Human Fertilisation and Embryology Authority (HFEA) state ‘The most important thing you can do when making decisions about fertility treatment is to ensure you are well informed.’

Never a truer word said.

Read on for a review on just two of the add-on treatments that is currently available (more reviews to follow).

Assisted Hatching

As summarized by HFEA, the early embryo is surrounded by a thick layer of special proteins called the zona pellucida. Before an embryo can implant in the womb it has to break out or ‘hatch’ from its zona pellucida. It is thought that by assisting this hatching – using acid, lasers or other tools to thin or make a hole in the zona pellucida – it helps the embryo to hatch and therefore implant (2).

The Evidence

The National Institute for Clinical Excellence (NICE) is the British national body advising doctors on treatments. It says: “Assisted hatching is not recommended because it has not been shown to improve pregnancy rates.” Although it has been used since the late 1980’s there is still insufficient evidence to determine its impact on live birth rate and relevance to use today.

A Cochrane review, which is a very comprehensive and respected scientific review, pooled the data of 31 studies on assisted hatching which included over 5700 women doing IVF (3). When examining live birth rate of IVF cycles that used assisted hatching (and after all, this is the only outcome measure that really matters) they found that there was insufficient evidence to suggest that assisted hatching increases the chances of a take home baby.

Interestingly, there may be a slight increase in the clinical pregnancy rate for those women doing assisted hatching (3). It only just reaches statistical significance though and may only be useful in a certain subset of women doing IVF – such as those with repeated failures or traditionally considered to have a ‘poor prognosis’. Additionally, it appears that this result may only be valid when the zona pellucida was completely removed (as opposed to having a small hole made in the shell or the shell being made thinner by chemical means).

What also needs to be considered when deciding with your fertility team whether or not assisted hatching is appropriate for you, is assisted hatching increases the risk of multiples as well as the chance of monozygotic twinning (where the embryo splits in two)(3). Pregnancies with more than one baby in the womb carry risks to both the babies and the mother and should be avoided where possible.

In summary, until a proven beneficial effect of assisted hatching on live birth rates is established, it should not be offered (4).

Embryo Glue

Embryo glue is another IVF add-on with the goal of assisting the embryo to implant.

The use of embryo glue is when the embryo is placed in a substance that is believed to help it attach and implant better to the uterine lining. Traditionally, clinics used a fibrin sealant to this; however, this does not appear to have been studied recently and the focus has shifted to those substances containing hyaluronan, which are considered more effective (1). Hyaluronan is a substance that is naturally found in the reproductive tract of women and is believed to form a viscous solution that helps with the embryo transfer process (1).

The Evidence

A Cochrane review of nearly 4000 women found that it increased live birth rates and clinical pregnancy rates by up to 10% (5). This finding has been reported in other papers (1,4), however, as the HFEA highlights there was only one study of high quality (with others being of moderate quality) that contributed to this finding and therefore more high quality studies are needed before it can be a generalized recommendation.

Although the evidence does seem to favor the use of embryo glue, The Cochrane Review did note that the incidence of a multiple pregnancy is higher. Unlike in the use of assisted hatching, the phenomenon of the embryo splitting into twins does not seem to be a contributing factor. Instead, it is simply because the success rates of using this treatment is higher and therefore when more than one embryo is transferred they are more likely to implant. This again highlights the preference to only do single embryo transfers in order to avoid a highrisk multiple pregnancy.

In Summary

There is likely to always be some guilt or wondering ‘what could have been’ when choosing whether or not to use add-ons. As fertility patients you need to know that you have done your very best to make this cycle successful. If you are looking at just comparing these two treatments though, in my opinion, it does seem conclusive that embryo glue using hyaluronan has the evidence based edge over assisted hatching with some good emerging data to support it. We are all different though with unique medical histories so, if nothing else, make sure you speak to your treating team to see what the best treatment might be for you.

Harper, J., Jackson, E., Sermon, K., Aitken, R., Harbottle, S., Mocanu, E., Hardarson, T., Mathur, R., Viville, S., Vail, A. & Lundi, K. (2017) Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions? Human Reproduction, 32 (3): 485–491.
Human Fertilisation and Embryology Authority. Accessed 27^th August 2018 https://www.hfea.gov.uk/treatments/explore-all-treatments/treatment-add-ons/
Carney, S., Das, S., Blake, D., Farquhar, C., Seif, M. & Nelson, L. (2012) Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)). Cochrane Database of Systematic Reviews Issue 12. Art.No.: CD001894. DOI: 10.1002/14651858.CD001894.pub5.
Datta, A., Campbell, S., Deval, B., Nargund, G. (2015) Add-ons in IVF programme – Hype or Hope? Facts Views vis ObGyn, 7 (4): 241-250.
Bontekoe, S., Johnson, N., Blake, D. (2014) Adherence compounds in embryo transfer media for assisted reproductive technologies. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD007421. DOI: 10.1002/14651858.CD007421.pub3.

Does acupuncture increase IVF success rates? An update.

You don’t have to look far to find stories of women doing IVF reporting that acupuncture was the reason they got their take home baby. Acupuncture has many possible benefits to an IVF cycle including increasing egg quality, uterine blood flow and implantation(1) as well as reducing stress and it is certainly worth considering.

The research

Back in 2014 Nandi and colleagues summed it up perfectly when they said

basically, the evidence regarding the efficacy of acupuncture to improve clinical pregnancy rate is controversial. In spite of 40 clinical trials and nine systematic reviews, the debate still continues.’

If you are going to stop reading now, overall, that still stands.

If you are thinking about spending your hard earned cash on acupuncture, it pays to drill down a little more.

>>>If you are about to do an IVF cycle and are looking for evidence based ways to increase your success rates, make sure you check out Eat Think Grow.

Is it a sham?

In randomized control trials, when researchers are trying to ‘prove’ that a treatment, such as acupuncture, has an effect, it will often be compared to a control. The control could be receiving no treatment at all or in this case it could be the use of sham or placebo needles.

When placebo or sham needles are used the person receiving the treatment, in this case the woman doing IVF, really thinks they are having proper acupuncture. It might be that the needles just don’t penetrate the skin the same way or they are put in just slightly away from known acupoints and therefore aren’t doing what they should.

One recent systematic review looked at all the studies that examined the difference in IVF outcomes (such as clinical pregnancy or live birth) depending on whether they had placebo or actual acupuncture around the day of embryo transfer. What they found was that there was no statistical difference in clinical pregnancy rate, ongoing pregnancy rate or live birth rate between placebo or sham acupuncture and real traditional acupuncture.

When the control though was changed from being placebo to having no treatment at all there was a significant difference, in this case there was an increase in the live birth rates of those women having acupuncture when compared to those that did not. Those women that had the acupuncture were 1.15 times more likely than those that did not have the acupuncture to have a live birth (1). Interestingly it was not associated with clinical pregnancy rate or ongoing pregnancy rate.

Before rushing out to have acupuncture there are a number of things to consider.

Firstly, an odds ratio of 1.15 is still kind of small in the scheme of things. But hey, if that was a definite, I’d try it. Secondly, it’s not a definite. The research is not water tight and there remains lots of conflicting studies and also sometimes the studies they use to get to such numbers can be of low quality.

What is interesting though is that it may not be the actual acupuncture – that is the insertion of needles on the acupoints making the difference- it may be the experience. It might be the stress relieving properties of lying down for 30 minutes while the needles are in, or the placebo effect of really feeling as if you are making a difference to your next cycle or even just the chat with the practitioner.

Who knows.

Building on this theory, if you are thinking about acupuncture but aren’t so sure or can’t afford it, in the first instance I would a) find an activity that you genuinely enjoy and relaxes you and b) find an activity that you genuinely feel is going to make a difference to your cycle (you may find the mindfulness activities in Eat. Think. Grow! fits this bill ;)) It can’t hurt and just might get you some of the side benefits of acupuncture without the actual acupuncture. It would be interesting to see studies in the future that compared the IVF success rates between those that used acupuncture and those that used general relaxation strategies and determine what the difference to IVF success rates is.

It should be noted that other reviews have evaluated the impact of acupuncture in comparison to no treatment and found that it statistically increased the chances of an ongoing pregnancy but not clinical pregnancy rate or live birth rate to any statistical significance (Manheimer as cited in 3). Just to further highlight the fact that the evidence around this one really is conflicted.

Timing and dosage of acupuncture

Embryo Transfer
Many women doing acupuncture will typically go to the acupuncturist once or twice around embryo transfer and call it a day. Generally speaking this is insufficient to increase the possibility of live birth rates – though they are associated with reducing stress (3). This finding was also supported when a systematic review was completed of studies that when combined looked at the cycles of over 6300 women (4).

Egg Retrieval
This finding was similar when studies looked at women who had acupuncture around the time of egg retrieval – there was no difference in live birth rates between those that had acupuncture around the time of egg retrieval and those that didn’t (4). To be fair though, acupuncture done around the time of egg retrieval is generally more focused on pain relief being the goal of the treatment rather than increasing live birth rates, so that is reasonable.

First two weeks of cycle
The next grouping when looking at the timing of acupuncture and its impact on take home baby rates looks at women who have acupuncture during ovarian hyperstimulation – so those having acupuncture in the first half of their cycles while on gonal f, menopur or whichever follicle stimulating drug you are taking. These ladies typically had at least four sessions and it was found that overall, the pooled pregnancy rates were higher for those having acupuncture than those that were not. Specifically those that had the acupuncture throughout ovarian hyperstimulation where 2.41 times more likely to have a live birth than those that did not (4). To reach this figure there was only three studies that used the data from 435 women so it is not a large pool of women in the scheme of things and therefore, again, should be interpreted with caution. But it’s still interesting.

Entire cycle
When looking at how many treatments you would need to during a cycle, one study suggested that eleven acupuncture treatments during an IVF cycle was associated with significantly improved IVF birth outcomes and fewer miscarriages and another suggested 13–14 sessions was associated with significantly more live births compared with no treatment or embryo transfer day only acupuncture (3).

14 sessions in one cycle though is a lot! That is nearly once session of acupuncture every two days. I wonder if there are other forces at play in this group that weren’t measured in the study. For example, it would take a particular type of woman to go to acupuncture every second day during an IVF cycle. Presumably she wouldn’t work (or have a very flexible work situation), has the finances to attend all these sessions and clearly has some firm beliefs that acupuncture and/ or Chinese medicine is going to make an impact and therefore might also engage in other beneficial health practices also. Maybe these other hypothetical situations are also contributing to the increased success rates?

Like all things in fertility, it seems likely that the ultimate dosage will differ person to person (3), from what I have read though, highlighting the ineffectiveness of acupuncture on transfer day only towards live birth rates does seem more or less consistent across the research.

Types of acupuncture

The type of acupuncture can also make a difference to the likelihood of success. There is traditional acupuncture which is where needles are inserted into acupoints (usually around 4 to 10) along meridians in your body (this is the type you are probably most aware of). When these needles are stimulated by a small electrical current it then becomes electroacupuncture. There is also auricular acupuncture and laser acupuncture, which as the name suggests uses small laser beams to effect the acupoints instead of needles (4).

Essentially, out of all these types, electroacupuncture seemed to have the most affect. Those women that had electroacupuncutre in comparison to a control group were statistically more likely to have a clinical pregnancy and live birth. But noteworthy, they did not have higher ongoing pregnancy rates.

Possible harm

As stated earlier, acupuncture is generally believed to do no harm to an IVF cycle. I am only aware of one study where they found acupuncture to lower IVF success rates when done around transfer day. One theory for the reason for this result was that the acupuncturist was not ‘on site’ where the embryo transfer was being completed. It is thought that driving to this extra appointment timed just before and just after the transfer, added stress in an already stressful day and this extra stress helped explain this difference (5). It should also be noted that the group not receiving acupuncture had a freakishly high success rate – nearly double of what it would be expected to be. This in turn would make anything in comparison look bad.

Another point to take into consideration, and this assumes that you believe acupuncture does have the potential to have an impact, is that there are some acupoints that are believed to be associated with miscarriage or at the very least contra-indicated to pregnancy (3). This serves as another reminder to make sure that you are visiting an experienced practitioner.

Things to keep in mind

You can see the research is mixed. Although it may be simply that acupuncture does not work, one of the other reasons the research didn’t indicate any benefit (assuming there is one to reflect in the first place!) is that there was is so many differences in the methodology of administering acupuncture. There is simply too many variances in the methods acupuncture practitioners would use including acupuncture point selection, number of sessions, timing of when sessions are administered, type of needling control and location of treatment (1).

The Final word

As I started off saying the evidence is controversial. I believe that it is an all or nothing thing. If you are only going to go on transfer day because a friend of a friend did and she got a positive result on a pregnancy test, I’d probably give it a miss. If though you believe in Chinese medicine philosophy and are willing to integrate it into your life as well as attend as many as 14 sessions over the course of your cycle, then I think it might be worth a shot.

Also, just because the evidence that says acupuncture increases IVF success rates isn’t necessarily solid, that also doesn’t necessarily mean it doesn’t and with further study, well, who knows?

Reference

1. Cheong, Y.C., Dix, S., Hung Yu Ng, E., Ledger, W. & Farquhar, C. (2013). Acupuncture and assisted reproductive technology (Review). The Cochrane Library, Issue 7
2. Nandi, A., Shah, A., Gudi, A. & Homburg, R. (2014). Acupuncture in IVF: A review of current literature. Journal of Obstetrics & Gynaecology 34 (7) 555-561
3. Hullender Rubin, L., Anderson, B. & Craig, L. (2018). Acupuncture and in vitro fertilisation research: current and future directions. Acupuncture Medicine 36 (2) 119 – 122.
4. Qian, W, Xia, X-R., Ochin, H., Huang, C., Gao, C., Gao, L., Cui, Y-G., Liu, J-Y. & Meng, Y. (2017). Therapeutic effect of acupuncture on the outcomes of in vitro fertilization: a systematic review and meta-analysis. Archives of Gynecology and Obstetrics 295, 543–558.
5. Stener-Victorin, E. & Manheimer, E. 2011. Commentary on the Cochrane Review of acupuncture and assisted conception. Explore (NY). 2011 ; 7(2): 120–123. doi:10.1016/j.explore.2010.12.01

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.

Stress and anxiety: does it really matter to IVF?

For some of us, anxiety feels like your brain can’t stop calculating. Calculating outcomes, calculating consequences, calculating alternatives. All bad obviously. And all meaningless. After all when does an anxious person ever think an unknown outcome is going to be positive? Never, that’s when.

There are times when I have been so, so far into my wave of anxiety, I just couldn’t see out. The triggers for my anxiety are so inconsequential that a ‘normal’ person wouldn’t understand. But if you have ever had anxiety, fertility related or not, you will get what I mean.

When your friends short text message has you obsessing all day that you have somehow offended her (when the logical part of your brain, which is taking a back seat at the moment, knows you couldn’t have), when an exchange with a colleague has you literally sick to the stomach and the thought of a team meeting has your chest tightening.

I know some people won’t know what I mean by that, but I know a lot of you will.

A barrier to IVF

Stress, anxiety, fear of uncertainty, the feeling of your life constantly being on hold, the emotional cost, having ‘had enough’ and thinking that you have a poor IVF prognosis (without doctors actually stating this) are all major reasons why women don’t continue with IVF when the issue of money has been taken out of the equation¹.

A recent small study showed that for women in the US who chose not to continue with IVF despite being insured for more cycles, 39% stated that stress was the reason why they couldn’t continue treatment. Specifically, these women stated that the toll fertility treatments took on their relationship was too much as well as simply being too anxious and depressed to continue¹.

In fact, stress and anxiety being the reason women do not continue with IVF when money isn’t the issue (because their cycles are funded by researchers or government programs) is likely to be higher than 39% with the authors citing a Swedish study where the number is thought to be around 65% and an Australian study where the number was thought to be around 54%.

Women don’t start IVF and fertility treatments lightly. That take home baby is very much wanted and much sacrifice and consideration has already gone into making it happen. Therefore if it is the stress and anxiety associated with fertility treatments that is making women stop it must be HUGE, unbearable. And if so, why isn’t it talked about more and more done to help women before they get to that point?

Impact of stress on IVF success rates

I know that some of the information out there looking at stress and IVF success rates talks about cortisol and the hypothalamic pituitary adrenal (HPA) axis and how this links with our ovaries. But ultimately, at the end of the day is this impacting our chance of a take home baby with IVF?

The impact of stress and anxiety on IVF success rates is mixed, to say the least. One meta analysis reports that emotional stress is unlikely to have an impact on IVF pregnancy rates² and that feelings of tension, worry or depression experienced as a result of a woman’s fertility problems, its treatment, or other co-occurring life events are unlikely to further reduce chances of pregnancy. *phew*

On the other hand, there is a study that suggests that women who experience emotional distress and receive psychological intervention are twice as likely to become pregnant than those that do not³. Whilst there is a number of reasons to NOT take this statistic as a fact it highlights the potential untreated anxiety can possibly have. Although the authors report that the effect size of psychological treatments may not be as big as doubling success rates, they do nonetheless believe that larger reductions in anxiety are associated with improved pregnancy outcomes.

Whether or not stress and anxiety does hinder IVF success rates is yet to be determined. Personally, I think it is not as straight forward as just being ‘anxious’ or not and there are far more significant factors that possibly impact the success of an IVF cycle.

Regardless of whether or not anxiety does impact success rates, I think we are all agreed that when stress and anxiety are better managed, quality of life improves along with the quality of our relationships and just the general ability to feel a little bit ‘normal’.

To sum it up, although its impact on IVF success rates is conflicted, overall, better managing our stress and anxiety can only be a good thing.

What is the best way to manage stress and anxiety when doing IVF?

Mind body interventions, such as yoga, web based interventions, cognitive behavioral therapy, acupuncture, online support groups, education sessions, guided relaxation and mindfulness classes are just some of the ways that have been studied in an effort to try and determine what best helps women doing IVF to reduce their stress and anxiety⁴. On top of this there is the more traditional methods such as exercising and eating a healthy diet.

Just as we all have different triggers and symptoms of stress and anxiety the ‘best’ way to manage it is likely to be unique to everyone.

For me, and many women, mindfulness does the trick to providing that small gap to disrupt the never ending thoughts that run around and around your mind. There has been some early studies that show that women who participated in a particular mindfulness course had improved quality of life measures and also increased pregnancy rates (44% of women in the mindfulness group had a pregnancy versus 26% of women from the control group who did not do mindfulness activities)⁵.

DIY Mindfulness

Although we cannot always be lucky enough to be asked to participate in a mindfulness based study for women doing IVF (!) we can embrace the mindful way of thinking and incorporate it into our everyday lives. We can get the benefits of unwinding and slowing our mind without the need to spend hours lying down to relax or taking time to attend particular courses and classes.

Next time you are in your anxiety wave, try this. When you have a shower (or are doing the tidying or waiting for your train or any number of mundane tasks where you notice your thoughts running away from you), list five things.

Five things that you can see (such as the soap sitting on the soap dish or the tap being twisted slightly off center). Five things that you can hear (such as the water going down the drain or the exhaust fan going around) and five things that you can feel (the tiles under your feet or the water on your back). As you get more practiced at doing this you will start to notice the details in what you are doing more, becoming more absorbed in the task that is at hand and more distanced from the ruminating thoughts in your head.

Mindfulness. Try it. And if you want additional mindfulness exercises have a look at this previous post. If nothing else, at least for a couple of minutes you will have the head space to feel just a little clearer, breaking that negative thought cycle and have the weight lifted from your chest. It does for me. And who knows, it may even improve IVF success rates.

** As always though, this article is just for general information. If your feelings of stress or anxiety is preventing you from living your life and you just don’t find enjoyment in things the way that you used to or if you have ANY feelings of self-harm or harming others, speak to your health professional immediately. They will be able to help you access treatments that you didn’t even know about so it is well worth the conversation**

References

Domar, A., Smith, K., Conboy, L., Iannone, M. & Alper, M. (2010). A prospective investigation into the reasons why insured United States patients drop out of in vitro fertilisation treatments. Fertility and Sterility. 94 (4) 1457 – 1459.
Boivin, J., Griffiths, E. & Venetis, C. (2011) Emotional distress in infertile women and failure of assisted reproductive technologies: meta-analysis of prospective psychosocial studies. British Medical Journal. 342:d223 doi:10.1136/bmj.d223
Frederkisen, Y., Farver-Vestergaard, I., Skovgård, N., Ingerslev, H. & Zachariae, R. (2010) Efficacy of psychosocial interventions for psychological and pregnancy outcomes in infertile women and men: a systematic review and meta-analysis. BMJ Open ;5:e006592. doi:10.1136/bmjopen-2014006592
LoGiudice, J. & Massaro, J. (2018). The impact of complementary therapies on psychosocial factors in women undergoing in vitro fertilization (IVF): A systematic literature review. Applied Nursing Research 39 220 -228.
Li, J., Long, L., Liu, Y., He, W. and Li, M. (2016). Effects of a mindfulness based intervention on fertility quality of life and pregnancy rates among women subjected to first in vitro fertilisation treatment. Behaviour Research and Therapy 77 96 – 104.

5 easily overlooked things to check before your IVF cycle

Your anti-müllerian hormone (AMH) is checked, you can tell to the hour when you are ovulating and you are pretty sure you’re the only one of your friends who uses acronyms such BFP, DPO and CD* in their every day life. You are just about ready to go for your next IVF cycle.

But here are 5 tests that may significantly impact on your fertility and IVF success.

As always though, don’t just start supplementing and self treating these things without medical advice as if your levels are already spot and you start self-prescribing, supplementation could do more harm than good. But they are definitely worth chatting to your fertility specialist about if you are concerned or have had recurrent failures.

Vitamin D

Like everything in fertility the research is mixed, but low levels of Vitamin D has been associated with endometriosis, the development of insulin resistance in women with PCOS and uterine fibroids¹. When the vitamin D in follicular fluid (the fluid surrounding each of your eggs) was measured in a group of women doing IVF, it was found that when women were deficient in vitamin D, for every one unit increase in vitamin D there was a 6% increase in the chances of an ongoing pregnancy rate². I’d take that.

Speak to your fertility specialist to see what your levels are (when you are pregnant they will test you for it anyway) and in the meantime focus on absorbing vitamin D from the sun – in a completely sunsmart way of course.

Thyroid function

That pesky thyroid has a big role to play and if it isn’t working properly can impact pretty much everything you can think of to do with reproducing life. This includes impaired ovulation, fertilization, implantation, miscarriage, and late pregnancy complications³. The acceptable levels of thyroid hormones can vary and there is some debate whether or not things like thyroid autoimmunity even matters enough to need to be tested³; though a recent meta-analysis suggests that although it does not impact number of eggs retrieved, fertilisation, implantation or clinical pregnancy rate thyroid autoimmunity may be implicated in miscarriage rates (this is still overwhelmingly unlikely to happen though and certainly not something to add to your worries – I have high thyroid antibodies and still got a take home baby. Two, infact.)⁴. What it does highlight though is that completing thyroid testing is a worthwhile activity, especially because depending on your medical history thyroid problems can often be treated.

Immunology issues

The role of autoimmunity in fertility is becoming more accepted and many doctors may test for immunology issues as standard when you start treatment. Some autoimmune tests include anti-nuclear antibodies, anti-DNA/ histone antibodies, antiphospholipid antibodies, antisperm antibodies, natural killer assay and cardiolipin antibodies. That is a lot of antibodies and only the tip of the iceberg.

Not all these markers are always a direct reason for infertility and some women can have them and oops! just happen to fall pregnant accidentally. They all are implicated in infertility though and it is certainly worth another blood test or two to ensure that they aren’t a hiding passenger on your fertility journey. Again, if something is found, depending on your circumstances, your fertility specialist may have a suitable treatment.

Melatonin

Melatonin is a powerful antioxidant and may benefit fertility by helping to keep oxidative stress in ovaries and eggs to a minimum which in turn improves egg quality. Several studies have been conducted investigating melatonin as a supplement for women undergoing IVF and found that when the optimal level of melatonin was reached that it was associated with a higher number and quality of mature eggs at harvest⁵. It has also been found to support the production of progesterone in women with luteal phase defect (though don’t even think about stopping those progesterone suppositories if you doctor has prescribed them; although a significant difference was found the impact on actual progesterone levels was still relatively small)⁵.

As always, do not go self-medicating, as although melatonin has not been found to be poisonous, supplementation is not always recommended in women undergoing IVF for a number of reasons. Supplements can sometimes interact with the prescribed medications taken and in women with autoimmune conditions melatonin supplements can have immune-stimulatory capabilities. Speak to your doctor before starting any supplements and in the meantime try to balance your melatonin levels by ensuring you get adequate sleep and natural daylight.

Sperm fragmentation

This isn’t a blood test but rather a sperm test for the men. Ideally it should be done as part of your initial work up at your clinic but it can easily get overlooked – particularly if you and your partner already have an obvious reason for your difficulty with fertility. In fact one study suggests that for couples with unexplained infertility, 80% of these couples later had their reason ‘explained’ as being due to sperm defragmentation when the appropriate tests were done⁶. That does seem a little amazing…

After a sperm sample is provided, in a sperm fragmentation test, the sperm is looked at to see if the DNA is healthy and intact. If DNA fragmentation is high this means that a high percentage of sperm is damaged. The treatment options are limited, though Menevit supplements may be of assistance (your doctor may have recommended this anyway), and it may mean that ICSI will have a greater chance of success for you than standard IVF.

Please note that this list is not exhaustive. They are just a few points designed to open up the conversation with your fertility specialist. Iron, zinc and magnesium levels are just a few others you might want to discuss.

*If you’re not quite there with the acronym thing BFP means big fat positive, DPO is days post ovulation and CD is cycle day.

Vanni, V., Vigano, P., Somigliana, E. , Papaleo, E., Paffoni, A., Pagliardini, L. & Candiani, M. 2014 Vitamin D and assisted reproduction technologies: current concepts. Reproductive Biological Endocrinology. 2014; 12: 47. Published online 2014 May 31. doi: 1186/1477-7827-12-47
Ozkan, S., Jindal, S., Greenseid, K., Shu, J., Zeitlian, G., Hickmon, C. & Pal, L. (2010) Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertility and Sterility. Vol 94 (4) 1314–1319.
Unuane, D., Velkeniers, B., Deridder, S., Branvenboer, B., Tournaye, H. and De Brucker, M. (2016) Impact of thyroid autoimmunity on cumulative delivery rates in in vitro fertilization/intracytoplasmic sperm injection patients. Fertility and Sterility. 106 (1) 144 – 150.
Busnelli, A., Paffoni, A., Fedele, L. &, Somigliana, E.(2016). The impact of thyroid autoimmunity on IVF/ICSI outcome: a systematic review and meta-analysis. Human Reproduction Update. 22(6) 775-790.
Fernando, S. & Rombauts, L. (2014) Melatonin: shedding light on infertility? – a review of the recent literature. Journal of Ovarian Research 7 98
Lewis, S. (2013) The place of sperm DNA fragmentation testing in current day fertility management. Middle East Fertility Society Journal. 18 (2) 78 -82