unexplained infertility Archives - Fertility Fact Checker

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

3 things YOU can do to improve your chances of IVF success

If you have downloaded the FREE IVF Guide you may already know about these methods... and even if you have, they each have so much potential to impact your next cycle that a quick reminder can't hurt!

I've been reading a lot of fertility books lately and a lot of the information in the books crosses over with the IVF guide... except the IVF guide is 100% free!

Anyway, check out the video and let me know what you think!

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.

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

Antinuclear Antibodies and Infertility

Antinuclear antibodies (ANA’s) is a grey area in infertility. Some doctors will tell you testing positive for ANA’s it doesn’t make any difference to your fertility, some believe it may be the reason why you still don’t have that take home baby and others may try you on some medication, just…because.

Testing for ANA’s comes under the umbrella of testing for ‘immune problems’ and seems to be a growing area of interest. And whilst for some a diagnosis of ‘unexplained’ is exactly that, for others ‘unexplained’ may sometimes become explained when immunological issues are investigated.

Without sounding too hippie, there seems to be many more allergy suffers today then there was of days gone by. An allergy is ‘a damaging immune response by the body to a substance, especially a particular food, pollen, fur, or dust, to which it has become hypersensitive.’ Especially with today’s chemicals, sprays, laundry detergents! and extreme levels of cleanliness in general it is difficult to know exactly what allergens people may be allergic to and what impact it is having on the body. Having these allergies can trigger immune responses in the body which can also be associated with infertility.

The doctors willing to consider immune issues in infertility seems to be growing. There is also a growing amount of research and literature further investigating immunology problems and its negative impact on fertility. Regardless of this though, it still seems as if it is not necessarily routine to have all your immunology tests completed at the outset. If you take nothing else out of this blog post, take away this:

make sure you discuss immunology problems as a possible source of infertility with your doctor and that they have requested the relevant blood tests.

Sometimes in fertility, the problem you initially thought that was the cause of your infertility spirals and spirals until you don’t know what is going on. For the sake of a blood test, it is well worth ruling this one out.

There are lots of different markers and factors to consider in immunology. There are antisperm antibodies, antiphospholipid antibodies, natural killer cells and leukocyte antibodies and a whole heap more that I haven’t even heard of. Each of these should be tested and evaluated by your doctor. Then there is my favourite: antinuclear antibodies.

A…N… what??

For some women, including myself, having high levels of antinuclear antibodies (ANA’s) can be the, or one of the, reasons behind difficulty conceiving. Although many people can have higher ANA’s then normal and be completely healthy it can also be an indicator of an autoimmune response where your body is producing a type of antibody that starts attacking the nuclei in the cells of your normal tissue. As my specialist described it, its like your immune system is constantly switched on and is possibly considering an embryo as a foreign body that needs to be eliminated. But there are different levels of ‘high’ ANA’s, or ANA positives.

You may get a ANA positive result of 1:160 and because ANA results are reported in titres, what this means is that when 1 part of your blood was mixed with 160 parts of a diluting substance laboratory staff are still able to detect the ANA’s. Different labs have different ways of reporting when is considered ‘positive’ and when they stop diluting. For me, I had ANA of 1:2560 which means that when 1 part of my blood is mixed with 2560 parts of another substance they can still detect the antinuclear antibody, which as far as I am aware is as high as the scale goes. Mixing your blood with so much of the other substance you would expect to not see any of the ANA’s at this point. This is going to sound contradictory to what I have said, but being ANA positive in itself is not a diagnosis or an indicator that anything is necessarily wrong. In a review done in 2009 (1) it was found that having low titre antibodies (for example around 1:160) does not impact IVF success rates. Depending on your clinical symptoms, what being ANA positive can be though is an indicator to do further immunological testing for things such as lupus or connective tissue conditions, like rheumatoid arthritis. Positive ANA’s can also be present in a healthy population as well so just because you receive a positive result does not necessarily mean anything is wrong per se.

When getting your results back regarding ANA’s there may also be information on what pattern is present, such as homogenous or speckled. Different patterns can be associated with different autoimmune conditions and your own situation needs further discussion with your specialist or GP.

ANA +ve + TTC = ?

Despite it seemingly being a bit of a ‘Wild West’ topic to some fertility specialists and the fact that it does not necessarily always mean something is wrong, there does seem to be a link between being ANA positive and experiencing infertility issues.

One study investigating the presence of immunological markers in IVF patients noted that in the general population 5% of people have elevated ANA’s where as in their infertile cohort, 30% of patients undergoing IVF were ANA positive (2).

That is there are a lot more ANA positive people in those that are known to be reproductively challenged then those in the general population. Another study looked at 560 Iranian women who had experienced 3 or more miscarriages. They found that 13% of women who had experienced recurrent miscarriage were ANA positive and only .9% of their control group, that is the healthy population who did not experience recurrent miscarriage, were ANA positive (3). It should be noted that about half of these ANA positive women also had antibodies associated with Lupus – so when you get your test results back, make sure you aren’t jumping to conclusions or worrying without getting more of the picture.

From the above studies it appears that there does seem to be some association with being ANA positive and having difficulty either conceiving or continuing a pregnancy (at least in the early stages of pregnancy).

The different areas of fertility ANA’s can impact

Premature Ovarian Failure

ANA’s can possibly have an impact fertility at various stages – whether that be by affecting implantation rates to having an impact on oocyte, or egg, quality. Carp and colleagues (4) speculate that autoimmune conditions can be responsible for premature ovarian failure to implantation failure and pregnancy loss. And the boys aren’t ‘immune’ either by the way, with Carp also mentioning that autoimmune conditions could be responsible for testicular failure as well. Carp mentions that 10 – 30% of women with premature ovarian failure (when the ovaries fail before the age of 40) have some type of concurrent autoimmune condition. There are many other reasons for premature ovarian failure and often a reason is not found. When it is associated with an autoimmune condition however, it is usually associated with high levels of follicle stimulating hormone, anti-muellerian hormone and inhibin – measurements that many women with infertility will be familiar with (4). The good news here is that if you do experience premature ovarian failure due to autoimmune conditions then with addressing the autoimmune conditions at play, along with any subsequent hormonal conditions such as diabetes, then recovery of ovarian function may occur (4). Unfortunately though it is not the magical answer and even if your autoimmune complications are resolved, if the damage has already occurred and there are no eggs remaining then it is suggested, in this study at least, that donation is the only option in the cases of severe premature ovarian failure (4), but like always discuss your options with your doctor.

Follicular Fluid and oocyte (egg) quality

Just as ANA’s can show up in your blood, they can also show up in follicular fluid. Follicular fluid is the fluid that surrounds the oocyte, or the egg, in its follicle. You will recall that when you have an egg collection, follicles are extracted from your ovaries and from the follicles eggs are extracted. Recently follicular fluid has been recognised as being a key indicator of the environment that eggs are housed in and the substances that are in the fluid can impact egg quality and hence subsequent fertilisation and pregnancy rates (5). For women where ANA’s have been detected in follicular fluid, this has been associated with typically producing smaller amount of embryos. Not only is there less quantity produced but it seems that those that are produced are generally also of lower quality than ladies who are ANA negative (ie have normal levels of antinuclear antibodies.

Implantation and pregnancy rates

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Assuming that by running the gauntlet so far you have kick started your ovaries into action as well as produced some fantastic quality embryo’s. So far so good. Before we get too ahead of ourselves unfortunately elevated ANA’s can also influence implantation and overall success rates even where good quality embryo’s are produced. One study done in 2012 (2) compared the overall implantation and success rates of women experiencing infertility who were ANA positive (ie had more antinuclear antibodies then normal) to those that were ANA negative. Although there sample size was quite small only comparing 96 cycles for the ANA positive women to 285 cycles of ANA negative women it was enough to significantly indicate that women who were ANA positive had lower numbers of embryo’s and a lower proportion of good quality embryos. Additionally in this group the pregnancy rate for ANA positive group was 28% compared to 46% in the ANA negative group. This understandably lead the authors to conclude that the

‘presence of ANAs significantly interfere with the oocyte and embryo development, as well as reduce implantation and pregnancy rate in patients undergoing IVF treatment’ (2).

Some good news

Although this study was done back in 2003 and was only a small sample size it had some interesting findings (6). Essentially what the researchers did was assess the IVF success rates of women testing positive for ANA’s and for those testing negative. In the first cycle women testing positive achieved lower pregnancy rates then those that were ANA negative. This is what we would expect given all of the above. The cumulative pregnancy rates though were not significantly different. AND that’s without the ANA positive women even taking specific medications to address their ANA. As the authors note

This indicates that the mechanisms of implantation failure by ANA could be solved, and effective and safe medication should be developed for better implantation rates

The treatment for ANA’s seems to vary and if you look at the notice boards you will find women taking different medications. Treatment will depend on your lab results and the type of patterning found. Prednisolone together with aspirin before conception and into pregnancy seems to be common treatment; however, again, discuss what will be best for you with your doctor.
INTERPRET IN CONTEXT OF OTHER TESTS

It is important to be mindful that when interpreting your ANA results that is only in the context of a ‘bigger picture’ taking into account other symptoms you may or may not be having and other blood tests that your practitioner completes. For example, in my case the fact that the ENA Panel (extractable nuclear antigen test) was negative, and the anti-DNA was also negative was an indicator that there were not necessarily any other autoimmune conditions under the surface and that by treating the impact of the ANA’s themselves that success may be just around the corner. And it was.

Being ANA positive is only one of many other antibody tests out there that may or may not impact on fertility. These can include antiphospholipids and immunoglobulins (IgA, IgG and IgM) and are also worth discussing with your specialist.

It is also important to remember that as previously highlighted being ANA positive can come in varying degrees. For example 1:80 indicates that there are far few antibodies in the blood then a result of 1:640. Having only ‘mildly’ positive ANA result may be less of an issue then a very high result and may influence you and your specialists decision as to whether or not the side effects of any treatment is more detrimental then not treating at all.

THE TAKE HOME ANA MESSAGES

Being ANA positive does NOT necessarily indicate that you have an underlying autoimmune condition or that anything is wrong, perfectly healthy, fertile people can be ANA positive
There is some research though that indicates being ANA positive is more common in women that need to receive fertility treatments
The presence of excessive ANA’s may be implicated in premature ovarian failure, embryo quality, implantation and recurrent miscarriage.
More research in this area is required and many fertility specialists do not believe that the presence of ANA’s on their own are worth treating

I am always worried about ‘scare mongering’ when I mention to my friends who are having fertility treatments to get their ANA’s (and other autoimmune markers) checked. There are so many things to worry about in the fertility world and just because this was one of my problems, it may not be yours. But given that the presence of excessive ANA’s does appear in a significant proportion of women yet to conceive, for the inconvenience of a blood test and a chat with your doctor its certainly something worth considering.

Finally, for those women who are interested in exploring ANA’s and other immunology issues there is a book by Dr Alan Beer entitled ‘Is Your Body Baby Friendly’. Dr Beer was an incredibly respected fertility specialist in California and assisted many women who had given up their fertility dreams to go on and get that take home baby. In his book it states that there is no such thing as ‘unexplained’ infertility and for everyone there is a reason. The book goes into some details about the different immunological problems that exist and also have some very inspiring case studies. A word of caution though the book is not necessarily for the faint hearted and may get you self diagnosing all sorts of issues! If you have run out of conversation or options with your fertility specialist though it may just very well give you a few things to discuss with them and for that reason is very well worth a look.

If you are doing or are thinking about doing IVF, don’t forget to get your free IVF guide with 19 evidence based ways that are designed to increase egg quality, implantation rates and hopefully IVF success!

References

1. Cline, A. & Kutteh, W. 2009. Is there a role of autoimmunity in implantation failure after in-vitro fertilization? Current Opinion Obstetrics and Gynecology. 21(3):291-5

2. Ying Ying, Yi-ping Zhong, Can-quan Zhou, Yan-wen Xu, Qiong Wang, Jie Li, Xiao-ting Shen, and Hai-tao Wu 2012. Antinuclear Antibodies Predicts a Poor IVF-ET Outcome: Impaired Egg and Embryo Development and Reduced Pregnancy Rate. 41 (5): 458-468 (doi:10.3109/08820139.2012.660266)

3. Molazadeh M., Karimzadeh, H. & Azizi M. 2014. Prevalence and clinical significance of antinuclear antibodies in Iranian women with unexplained recurrent miscarriage. Iranian Journal of Reproductive Medicine 12(3): 221 – 226.

4. Carp, H. Selmi, C. & Shoenfeld, Y. 2012. The autoimmune bases of infertility and pregnancy loss. Journal of Autoimmunity (38)J266 – J274

5. Revelli, A., Delle Piane, L., Casano, S., Molinari, E., Massobrio, M. & Rinaudo, P. 2009. Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics. Reproductive Biology and Endocrinology 7:40

6. Kikuchi, K., Shibahara, H., Hirano, Y., Kohno, T., Hirashima, C., Suzuki, T., Takamizawa, S. & Suzuki, M. 2003. Antinuclear antibody reduces the pregnancy rate in the first IVF-ET treatment cycle but not the cumulative pregnancy rate without specific medication. American Journal of Reproductive Immunology. 50 (4):363 – 7