Blog - Fertility Fact Checker

Is IUI the best choice for women with unexplained infertility?

Up to 25% of women with fertility difficulties are ‘unexplained’. So there are certainly a few ladies who will be interested to know that a comprehensive literature review evaluating the success of intra-uterine insemination (IUI) for women with unexplained fertility has confirmed its findings (1).

In an attempt to determine if IUI (both with and without medication) is more successful at achieving higher birth rates than timed intercourse or ‘expectant management’, the findings from 14 studies including 1867 women were combined and analysed. ‘Expectant management’ by the way is letting nature run its course with no intervention. I find the term quite ironic in the fertility setting because that is the whole point – fertility patients are not ‘expectant!’

Remember, this review was completed to examine the impact of IUI for women with unexplained infertility. Not women with PCOS, not women who has a partner with low sperm count, just unexplained.

Interestingly, the authors included studies that examined women with mild endometriosis. Mild endometriosis was presumably not considered troublesome enough of a diagnosis to be the cause of preventing a woman getting pregnant. Women who had a diagnosis of moderate endometriosis however, were not included in the study. It seems that having moderate endometriosis was a reason for being unable to conceive and hence these women were not categorised as ‘unexplained’. You with me? Whilst we can appreciate why this distinction was made, I wonder if in years to come, as more research is completed if this distinction will change. From what I understand, how the reproductive system works – both in isolation and when interacting with our other systems such as the endocrine and immune system – it is in such a delicate balance. Perhaps one day even mild endometriosis will be found to have, for example, a very subtle immunological response that means it is widely recognised as a cause for fertility problems. Ultimately this may change the diagnosis and label of ‘unexplained’. But for now and the purposes of this review, I digress.

Using IUI

In some instances of unexplained infertility IUI is considered the first port of call. It is financially less expensive and places less physical stress on the woman trying to conceive than IVF. Though if you ask me, and anyone else who has had a two week wait after an IUI, psychologically it is just as hard. IUI can be completed either with ovarian hyperstimulation or without. Ovarian hyperstimulation is when medications are administered to stimulate the ovaries to produce and release an egg. When there is no ovarian hyperstimulation, this is also referred to as a ‘natural cycle’.

Benefits of IUI with ovarian hyperstimulation

IUI with ovarian hyperstimulation is thought to have a few added benefits when compared to IUI without ovarian hyperstimulation. One of these is that with the hCG trigger shot (such as pregnyl or ovidrel) doctors theoretically can more accurately pin point the time of ovulation (1). This means that you can be more sure that when the sperm is inseminated, it is at the right time to fertilise the egg and hopefully get that BFP.

Another reported benefit is that IUI with ovarian hyperstimulation enables some subtle abnormalities with follicle and endometrial lining growth to be ironed out (1). I kind of see this as your reproductive system getting ‘hijacked’ and being coerced into do the ‘right thing’ through the administration of medications.

Costs of doing IUI with ovarian hyperstimulation (and not the financial kind)

From what I read, the main negative is that there is a risk of ovarian hyperstimulation syndrome (OHSS). Presumably though this would be much less of a risk than women undergoing IVF as the quantities of medication being taken and the amount of follicles and eggs that are being grown are in much smaller quantities.

Another negative is the risk of a woman falling pregnant with multiple children. If during ovarian hyperstimulation a woman has three follicles growing there is a chance that all three follicles contain eggs and could fertilise (If you have more then two follicles growing in an IUI cycle sometimes your clinic will cancel your cycle for this reason). This risk would have been a little better controlled in IVF as most often only one or two embryos are actually transferred. It is also because of the risk of multiples that NICE fertility guidelines states that ‘ovarian hyperstimulation should not be offered to women with unexplained infertility.’

Regardless of the NICE guidelines though and the very real risk of complications to yourself and your future children, I am willing to bet that most women experiencing infertility would certainly take take their chances if it meant that an IUI with ovarian hyperstimulation would mean higher success rates…am I right?

Well, does IUI in unexplained infertility have good success rates?

Remember this is only the results from this literature review (1). There may be very real reasons why your odds are better (or worse) for a particular treatment and only a conversation with your doctor about all the alternatives can clarify that.

What this literature review did was compare a number of the different protocols of IUI against each other. These were:

IUI versus timed intercourse where both were done in a natural cycle – that is without ovarian hyperstimulation
IUI versus timed intercourse, both using ovarian stimulation
IUI in a natural cycle versus IUI in a stimulated cycle
IUI in a stimulated cycle versus timed intercourse in a natural cycle (similar to expectant management)
IUI in a natural cycle versus timed intercourse in a stimulated cycle.

The findings were:

1. IUI without stimulation when compared with timed intercourse, also without stimulation was found to have no evidence of a difference in cumulative live births between the two groups. The evidence suggested that if the chance of a live birth with timed intercourse was assumed to be 16%, that of IUI would be between 15% and 34% (remember the results are reporting cumulative birth rates, not birth rates per cycle).

2. IUI versus timed intercourse, both in a stimulated cycle – again the study reported that there was no evidence of a difference between the two treatment groups with the evidence suggesting that if the chance of achieving a live birth in timed intercourse was assumed to be 26%, the chance of a live birth with IUI would be between 23% and 50% (though I can see what you are thinking, it looks like the IUI was still better, though remember that this is cumulative birth rates and the difference may not have been statistically significant)

3. IUI in a natural cycle versus IUI in a stimulated cycle – there WAS an increase in live birth rates for women who were treated with IUI in a stimulated cycle compared with those who underwent IUI in natural cycle (without stimulation). The evidence suggested that if the chance of a live birth in IUI in a stimulated cycle was assumed to be 25%, the chance of a live birth in IUI in a natural cycle would be between 9% and 21%.

4. IUI in a stimulated cycle versus timed intercourse in a natural cycle– there was no evidence of a difference in live birth rate between the two groups The evidence suggested that if the chance of a live birth in timed intercourse or expectant management in a natural cycle was assumed to be 24%, the chance of a live birth in IUI in a stimulated cycle would be between 12% and 32%.

I find this one particularly interesting as surely an IUI in a stimulated cycle would be better than just letting nature do run it’s course? What it does say though, is that in the context of this particular study, for women who are experiencing unexplained infertility, there is still just as much of a chance that a pregnancy may still occur by trying through the ‘old fashioned way’ than by having a full blown IUI!

5. IUI in a natural cycle versus timed intercourse in a stimulated cycle – There was evidence of an increase in live births for IUI. The evidence suggested that if the chance of a live birth in timed intercourse in a stimulated cycle was assumed to be 13%, the chance of a live birth in IUI in a natural cycle would be between 14% and 34%

In Summary

Personally, I find it is difficult to see any rhyme or reason as to the above results. In some cases it is the IUI itself that seems to improve success rates but sometimes it doesn’t. Other times medication might be key to success but then this is not continued. And then in another scenario a stimulated IUI had no statistically significant improvement over ‘expectant management’! It did appear though that if you had decided that you needed to take action and see if an IUI was going to work for you, IUI with medication was the way to go.

The author of the study came to the conclusion that:

There was no conclusive evidence of a difference between most treatment groups in cumulative live birth rates (i.e. rates at conclusion of a course of treatment)… for couples with unexplained subfertility undergoing IUI when compared with timed intercourse, both with and without ovarian hyperstimulation

Before you ask your fertility specialist why you are doing one set of protocol over another, remember the following:

As always in fertility research more evidence is required. In this instance more studies examining each of the different situations would have led to stronger quality of evidence.
Your past medical history or individual set of circumstances may have led your fertility specialist to recommend one intervention of another which may seemingly contradict these findings.
The above findings are for cumulative birth rates – which in this instance means that when this treatment has stopped for one reason or another, then that is the outcome. It should not be confused with the success rates for each cycle ie each monthly treatment.
There is obviously a wide discrepancy in success rates across the studies which again reflects individual circumstance as well as highlighting a need for larger more precise studies.
The mean or median age (depending on the study reporting) was 30 – 33 and the findings shouldn’t necessarily be extrapolated out of this age range
Donor insemination was excluded from the study and it only included men with an average sperm sample.

Finally

As said previously, although this was a comprehensive review of the literature done to date these results are not necessarily the be all and end all and there is definitely room for the results to change in the future with more research.

At the moment it may appear that IUI for couples with unexplained infertility IUI isn’t necessarily the best evidence based approach to take, but does that necessarily mean that IVF is? IUI is cheaper and often physically easier for many women. For those reasons it still may be a very worth while first port of call when entering the world of fertility treatments.

Reference

Veltman-Verhulst SM, Hughes E, Ayeleke RO, Cohlen BJ. Intra-uterine insemination for unexplained subfertility. Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No.: CD001838. DOI: 10.1002/14651858.CD001838.pub5.

A spoonful of sugar… not exactly ‘delightful’ for IVF success

We have heard many, many times about the disastrous effects of sugar on our natural fertility. ‘Disastrous’ sounds quite dramatic, but it is the current bad thing in nutrition circles right? Sarah Wilson, ‘I Quit Sugar’ author, Pete Evans, general paleo champion and a whole host of trainer-slash-tv-show-celebrities will be back me up here.

And it seems rightfully so.

For natural fertility, sugar is frequently cited as being responsible for increasing inflammation (especially in women with endometriosis), altering hormone levels such as progesterone, estrogen and androgens and increasing insulin resistance which has its own collection of negative consequences.

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Not exactly helping the medicine that's going down. — **Not helping the medicine that’s going down.**

But what about the impact of sugar on IVF success? Unsurprisingly there is only an incredibly limited number of randomized control trials looking at the impact of sugar on IVF success rates. Is that because it’s generally understood that of course sugar negatively impacts IVF? If so, why isn’t that information fed to us (pardon the pun) in the fertility clinics in a very clear way? Or is it because there are no funding bodies willing to pay for such a trial? Or perhaps it’s thought to play very little of a role at all. Regardless of the reason the outcome is still the same. More evidence is needed.

For those of you who have read my free ebook (and those of you who haven’t, why not? Did I mention it was free?) you will know that I am a big believer that despite all the medications, medical procedures and laboratory techniques that IVF utilizes as ‘patients’ we are still active in that process. That is despite the fact that your body is about to be highjacked by all sorts of medications you still have control over what you eat, drink and the way you live your life.

That is NOT to say that if we have a bad cycle with skyrocketing estrogen, 50 antral follicles developing and only one lead follicle that eating the right food is going to save the day, but in a more moderate situation modifying diet and lifestyle factors have been shown to have a significant impact on IVF success rates (1). As we know Lady Luck also has her hand to play in the IVF cycle – so perhaps modifying those lifestyle factors can be considered a bit like buying extra lines in the lottery rather than just the standard ticket.

Its not just monkey business

So back to sugar and IVF.

It wasn't a winner. And I don't know why I had a lotto ticket from 2009 in my purse. — Removing some of the ‘luck’ from an IVF cycle.

Like I said, there is insufficient information examining the exact impact of sugar on IVF success. Interestingly though in 2014 a study conducted on rhesus monkeys was completed (2). I know, a human study would have been preferable but don’t we share over 90% of the same DNA with primates?

What the scientists did was get a group of monkeys and divide them into two separate groups. Over a period of six months one group was given extra sugar in their diet and the other group was not. I know, try and suspend that part of your brain that is telling you this is a step back for animal rights.

They then did a stimulated cycle, very similar to that of an IVF cycle and compared the outcomes of the monkeys that were given sugar against those that were not. What they found was that when they did an egg collection, after six months of eating extra sugar, although overall the number of eggs collected was similar between the two groups, significantly less mature eggs were able to be collected in monkeys that had been given extra dietary sugar versus those that were not (18.5% of eggs were mature in the sugar group versus 86% mature in the non-sugar group). It is believed the sugar interfered with how the eggs were able to mature. This is obviously concerning as fertilisation and production of a viable embryo is not possible without eggs first developing to maturation. And because I know you are thinking it, the extra sugar that these primates were taking wasn’t even that high with researchers reporting that it was in fact the equivalent of less than half of what most women in the U.S. would consume.

Although this is only a small, elementary study completed in monkeys it is one of the first to particularly look at the direct relationship between sugar and IVF cycle outcomes. It is therefore absolutely worth noting and women undergoing IVF could do worse than to simply reduce the amount of sugar they intake.

A human study this time

Another study was also done (3), this time in humans, looking at the relationship between carbohydrate intake (and as we know, sugar is a simple form of a carbohydrate), protein intake and IVF outcomes. Although this was only a small study – only twelve women participated, so yes, there is plenty of room for these results to be skewed – they found huge differences when women aged 35 or younger and with a BMI of 26.5 or less modified these two food groups.

After being unsuccessful for one of their IVF cycles, these women waited at least two months before commencing another cycle. In between these IVF cycles the women focused on reducing their carbohydrate intake and increasing their protein intake (these women had dietary support and were guided on how to do this) and found that blastocyst formation increased significantly as did clinical pregnancy rates – from 16% to a whopping 83%.

All in all, this led the authors to summarise that

Seemingly young healthy patients with poor embryo development can possibly increase the percentage of blastocyst formation by increasing their daily intake of protein and lowering their daily carbohydrate intake 2 months prior to their IVF cycle. – Russell et al 2012

And for ladies over 35…

Sugary donuts: High in carbohydrate, low in protein. Just bad all round.

Dr Russell repeated this kind of study on 120 ladies who were aged 36 and 37. As reported by Kate Johnson for Medscape, these ladies were categorised depending on whether their diet consisted of high amounts of protein (over 25% of their food intake) or low amounts of protein (under 25%). It was found that ladies who were in the ‘high protein’ group had better rates of blastocyst formation (64% vs 34%), clinical pregnancy rates (66% vs 32%) and the holy grail of IVF treatments, live birth rates (58% vs 11%) .

Additionally, when protein was greater than 25% coupled with carbohydrate being less then 40% the clinical pregnancy rate skyrocketed to 80%. I think that is AMAZING.

Dr Russell concedes that although from the data presented here it seems as if a high protein, low carbohydrate (and that includes sugars) diet is the way to go, the underlying mechanisms is unknown. Is it the actual grains that causes this change or is it another factor such as a possible inflammatory effect of gluten (have a look at my post on gluten if you haven’t already)?

Before you start throwing out all the pastas, breads and cookies from your pantry remember that changing your diet when imminently about to commence an IVF cycle is not necessarily about weightloss (you don’t want to drastically alter your weight without your fertility doctor being aware of it as it may change your medication regime) but is about making sure you are eating the optimal foods to assist in the production of healthy eggs and ensuring that there is a healthy environment to welcome any little embryos. The women in these studies also had help from nutritionists to help them get their balance just right. Likewise, before you make any drastic changes to your diet it would be prudent for you also to get this type of advice – or even just speak about it with your doctor or fertility nurse. In the meantime though, it is safe to say that I would definitely rethink that afternoon Mars Bar.

References

Gormack, A., Peek, J., Derraik, J., Gluckman, P., Young, N. & Cutfield, W. (2015) Many women undergoing fertility treatment make poor lifestyle choices that may affect treatment outcome. Human Reproduction, 30 (7) 1617–1624
Chaffin, C., Latham, K., Mtango, N., Midic, U. & VandeVoort, C. (2014) Dietary Sugar in Healthy Female Primates Perturbs Oocyte Maturation and In Vitro Preimplantation Embryo Development. Endocrinology 155 (7)
Russell, J., Abboud, C., Williams, A., Gibbs, M., Pritchard, S. & Chalfant, D. (2012) Does changing a paitents dietary consumption of proteins and carbohydrates impact blastocyst and clinical pregnancy rates from one cycle to the next? Fertility and Sterility. Sup 47 O-153.
http://www.medscape.com/viewarticle/803821

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.

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…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.

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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.

Is a Gluten Free Diet for Fertility Tin Hat Thinking?

Tin hat thinking is when you do something which you can see might be worth a try even though the hard scientific backing isn’t necessarily there. Things that can’t hurt to try and there seems to be loads of qualitative evidence on the internet though the quantitative evidence seems a bit lacking. You know the general sort of things – eating organic, not wearing perfume or cosmetics and perhaps eliminating dairy. They might be things that your naturopath prescribes, but what your fertility specialist doctor might say makes no difference. I realize this sounds quite dismissive to naturopaths and it is really not meant to. The more and more I research into fertility treatments the more and more I can see that sometimes some of the answers are in the way we live our lives rather than being solely dependent on how many units of Gonal F we are injecting into our stomach.

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For me, eating a gluten free diet was one of those tin hat thinking moments. After several failed cycles I felt the need to attempt to take some control back and try something different. So amongst a couple of other things I tried eating gluten free diet starting from cycle day one. I did happen to get a BFP on the cycle I went gluten free, though I was also on some additional medication which also would have made an impact. Saying that though, I also know of others who have also experienced a BFP when eating gluten free (and there is that qualitative evidence again). But was it just coincidence and would it have been ‘our time’ regardless? Who knows. For a significant number of people though, particularly those with unexplained infertility, eating a gluten free diet may be much more than tin hat thinking and might just well be the real underlying cause of their infertility.

Celiac Disease

Celiac disease occurs in up to 1% of the population, but only 20- 50% of those may experience symptoms. As you are probably aware, traditionally people who have celiac disease are required to eat a gluten free diet. This is because celiac disease is an autoimmune condition which is triggered by gluten which is the protein fraction of wheat, barley and rye. There is a bit of a complex biochemistry reaction but essentially the gluten causes a number of chain reactions which results in an inflammatory response in the body and the production of some specific antibodies. It is perhaps the presence of these antibodies that may contribute to difficulty conceiving, recurrent miscarriages and once you are finally pregnant with one that sticks, intrauterine growth restriction, which can result in your baby being born with a significantly lower birth weight and other difficulties.

The evidence for associating gluten with infertility

There has been a bit of research around celiac disease and just last year a meta-analyisis was completed investigating the association between celiac disease and issues of the reproductive system in women (Tersigni, 2014). The meta-analysis included 24 studies that had been completed on this area and here are what I consider the five essential things to know:

1. Women with unexplained infertility or recurrent miscarriage have a 5 or 6 fold, respectively, increased risk of being affected from celiac disease compared with the general population.

2. Classic celiac symptoms are often absent, or at most the symptom may be the very general fatigue associated with iron deficiency anaemia. This means that it can be a significant length of time before diagnosis, and hence treatment is initiated.

3. Before and after studies have been done on women with celiac disease and the number of children they were able to have before and after diagnosis. Before diagnosis women with celiac disease were found to have less numbers of children than women without celiac disease. After diagnosis and treatment this number returned to similar numbers. This indicates that treatment of celiac disease and eating a gluten free diet is beneficial to aiding fertility in women with celiac disease and seemingly reverses the destructive mechanisms.

4. There are two suggested mechanisms by which celiac disease limits fertility: firstly causing malabsorption and nutrient deficiency and secondly, the accompanying automimmune reactions.

It is believed by preventing the absorption of nutrients an imbalance in the reproductive hormones such as luteinising hormone and follicle stimulating hormone is experienced. This in turn prevents normal ovarian functioning and hence causes infertility. Deficiency of nutrients such as folic acid also ultimately leads destruction of the rapidly growing embryo as it needs this acid to develop neurons and develop normally.

The second mechanism being autoimmune factors effects fertility in two ways. One possible way is that the antibodies produced by women with celiac disease destroy the outer layer of the blastocyst. This prevents the embryo from implantation and forming the placenta as it is this outer layer of the blastocyst that gives rise to the developing placenta. Another possible way is that the antibodies prevent the endometrium from growing new blood vessels, again preventing implantation resulting in a BFN once again.

5. Women with celiac disease also show an increased risk of miscarriage, intra-uterine growth restriction, low birth weight and preterm delivery. This indicates that the implications for having celiac disease go far beyond difficulties at conception and that a long term gluten free is essential in women with celiac disease who achieve preganancy.

Take action!

Especially if you have ‘unexplained’ infertility or recurrent miscarriage, at your next appointment ask your doctor if you have been screened for a sensitivity to gluten. The symptoms are not always the typical responses and can easily be missed. One of the first screens to do is to test for endomysial and anti-TG antibodies (Tersigni, 2014)

Check out the possibility of eating a gluten free diet. Although on the one hand it has never been easier to knowingly eat gluten free – there is pretty much a gluten free substitute for EVERYTHING these days, on the other hand it is nearly impossible to cut out all the hidden gluten – it sometimes seems gluten is everywhere… there is wheat syrup and hence gluten in that Cadbury’s chocolate bar you have just eaten!

If you are just starting out to eat gluten free the big things to avoid are foods containing wheat. That includes pretty much all cereals, baked goods, bread, cakes, pastry, noodles and pasta. Vegetables, fruit and meat are fine as is rice and some other non-wheat grains. Like I said though, the ‘hidden’ gluten is in a lot of things including salad dressings, soups and beer. If you are serious about going gluten free it is therefore essential to check the back of the pack before eating.

As for me, although I did decide to stop eating gluten I have not yet been tested for the specific antibodies that often present with a gluten sensitivity. I will request these at my next appointment but in the mean time I found it ‘worthwhile’ eating gluten free if for no other reason than knowing that I had given things my ‘best shot’. Anyway, as previously discussed, for a significant number of women with infertility the idea of eating a gluten free diet is perhaps based in science and not so ‘tin hat’ as what I first thought.

Reference

Tersigni, C., Castellani, R., deWaure, C., Fattorossi, A., De Spirito, M., Gasbarrini, A., Scambia, G. & Di Simone, N. (2014) Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Human Reproduction Update. 20 (4) 582–593

PCOS: New research on an old question

OK, so this girl doesn't have the stereotypical weight problems but the message is still the same: lifestyle changes — OK, so this girl doesn’t have the stereotypical weight problems but the message is still the same: lifestyle changes

Some researchers in America have again put to test the theory that if a woman with PCOS loses weight than she is more likely to get pregnant. Yes, this isn’t anything new, but the research is new and has compared the effectiveness of losing weight on fertility to one of the old favourites of fertility specialists out there, the oral contraceptive pill.

There has been a lot of information published on polycystic ovary syndrome (PCOS) both on the internet in general and in peer reviewed journal articles in specific. And this is probably because there seem to be a lot of women who have it with incidence reported at being up to 15% in women of child bearing years (1).

THE STUFF YOU PROBABLY KNOW ABOUT PCOS

Most of the ladies here will be familiar with the diagnostic criteria for PCOS but just to give a quick recap, PCOS is a syndrome that is diagnosed when a woman has 2 out of the following:

High levels of androgens (male hormones). This is why women with PCOS can have too much body of facial hair, thinning on the scalp or acne
Ovulation that is either absent, irregular or takes its sweet time. Generally menstrual cycles longer than 35 days are counted as fulfilling one of the diagnostic criteria
Enlarged ovaries with many small cyst, often forming a ‘chain’ around the ovary, obviously you would generally only find this if you have a scan… and you are likely to only of had a scan if something has already aroused your suspicion to seek medical advice (2)

THE VISCOUS CYCLE

The characteristics of PCOS mean that women can be overweight and can have insensitivity to insulin (but not always). You may recall that insulin is the hormone that helps the cells absorb glucose from our blood. When insulin resistance occurs this means that more insulin is needed to absorb the same amount of sugar, this gets into a vicious cycle that means sugar levels and insulin levels climb and climb (as does your weight and stored fat) ultimately leading to metabolic changes and an imbalance in your sex hormones such as estrogen. This stops ovulation whilst at the same time the insulin stimulates your ovaries to over produce male hormones. It’s like a double whammy and in there the extra fat you have laid down also starts to produce androgens again adding to the viscous cycle (2)

Treatment for PCOS will often focus on treating the symptom that the presenting woman is concerned about and doesn’t really tend to focus on fixing the underlying hormonal changes. When the presenting issue is infertility (why else are we here?!?) there can be a number of suggestions. Following the medical model (and there are many natural, complementary therapy alternatives out there) the first line of treatment is ovulation induction (3). The problem with this though is that women with PCOS can fail to ovulate at all and underlying mechanisms of insulin resistance is not addressed. IVF is another option though women with PCOS can be very sensitive to injectable hormones meaning that it can be difficult to find the ideal quantity that will produce a good quantity and quality of mature eggs on collection day. For example, you may be doing an IVF cycle and be prescribed 100 units of Gonal F. On day 7 when you have your first lot of bloods taken your estrogen may not really be moving, say the Gonal F gets increased to 125 units, which is still a small increase this may be over the tipping point for you and your oestrogen may have increased much more than anticipated which potentially puts the quality of the eggs in jeopardy… see the balancing act that is needed?

WHATS WITH THE NEW RESEARCH THOUGH?

Because of these reasons, and many others, attention is often, but perhaps not often enough, turned to improving precycle health. That is it is much better to try and improve your health before going into a cycle to try and level out those hormone levels, reduce the number of antral follicles that are ready to go (and muck up oestrogen levels) and ultimately get a few good quality eggs. And lets face it a few good quality eggs are much much better then the 10 plus eggs that women with PCOS can easily get sometimes. AND THAT IS WHERE THE NEW RESEARCH COMES INTO IT. I took too long to get there huh? I knew it. Legro and his colleagues completed this study to compare the effectiveness of two of the main preconceptive treatments out there for women with PCOS. That is comparing weight loss against the oral contraceptive pill (OCP).

Women with PCOS are often placed on the pill in order to suppress the ovaries, get those pesky antral follicles under control and lower the levels of androgens in the blood. Additionally, women are also often recommended to lose weight for many reasons , one being to try and improve insulin resistance and attack the vicious cycle that way. But which is better? It may come as no surprise but in this study hands down the women in the group that modified their lifestyle and lost weight had better outcomes than those that were taking the pill. And what was this outcome? LIVE BIRTH RATES! The holy grail of fertility treatments and an outcome measure that is not used anywhere near enough (researchers tend to settle for ‘ongoing pregnancy rates’ a lot of the time it seems). Although it was a small study with only 149 participants, these women were randomly categorised into one of three preconception arms for 16 weeks:

Life style intervention with the goal of achieving 7% weight loss reduction. Interestingly, as well as implementing calorie limitation (between 1200 to 2000 calories depending on weight) and physical exercise they also implemented orlistat (generic name Alli) for women with a BMI of over 30. Whilst in a perfect world a healthy diet and physical exercise would do the trick for larger women the reasons for their increased weight can be multifactorial, insulin resistance makes it harder to lose weight, it is often more difficult for larger ladies to do physical exercise and sometimes there are also psychological reasons for putting weight on. Implementing the weightloss drug in this way stimulates weightloss and gives the ladies help to lose weight which also increase motivation and compliance to the regime. Who doesn’t get inspired to continue on the weight loss path when you can see the number on the scales actually going down?
Oral contraceptive pill taken continuously over the 16 weeks
Both. That is they received a lifestyle intervention AND the oral contraceptive pill

After only four cycles of timed intercourse, of the 49 women on the contraceptive pill only, five gave birth. This was in comparison to 13 out of 50 women in the lifestyle intervention and 12 out of 50 in the combination category.

What this shows is what we really deep down already know and that is that by exercising and reducing your weight by the targeted 7% its going to increase your chances of a live birth over taking the oral contraceptive pill. It is definitely easier said than done but what I liked about this study was the openness the researchers had to alternatives in helping women lose the weight. As we said, in a perfect world diet and exercise would be enough but sometimes a helping hand is needed and when the outcome is one of those take home babies then the more help the better!

References

Agency for Health care Research and Quality http://www.ahrq.gov/news/newsletters/research-activities/13sep/0913RA34.html
Chevarro, J. & Willett, W. 2009. The Fertility Diet. McGraw Hill Publishers.
Legro, R., Dodson, W., Kris-Etherton, P., Kunselman, A., Stetter, C., Williams, N., Gnatuk, C., Estes, S., Fleming, J., Allison, K., Sarwer, D., Coutifaris, C. & Dokras, A. 2015 Randomized Controlled Trial of Preconception Interventions in Infertile Women With Polycystic Ovary Syndrome. Journal of Clinical Endocrinology and Metabolism.