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

1. 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
2. There is some research though that indicates being ANA positive is more common in women that need to receive fertility treatments
3. The presence of excessive ANA’s may be implicated in premature ovarian failure, embryo quality, implantation and recurrent miscarriage.
4. 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