As some of you may already know, I have not had the best of luck with IVF, especially in the past 12 months. Hopefully it’s about to turn around though as I’ve recently learned about a new up and coming theory in the IVF world that may explain what has been happening.
This article is about my recent personal introduction to natural killer cells.
There is a lot of excitement in the field of IVF research as NK cells are providing a plausible explanation as to why some women have unexplained failed implantations or recurrent miscarriages during IVF. While you may not be interested in IVF research just for the fun of it, I thought this might be of interest to those of you who have had two or more failed cycles like I have. Or for those who have had a string of miscarriages without any explanation.
IVF statistics and my bad luck
We all know that the odds of a single IVF cycle working are pretty low, even if you’re young and healthy (please check out my blog on misleading IVF success rates if this is news to you). But for someone like me who has had Day 5 embryos pass genetic testing, the statistical success rate should be upwards of 70% per transfer.
But instead of benefiting from this high statistical success rate, instead I’ve recently had two unsuccessful frozen embryo transfer attempts putting me amongst the 10% of people who would not fall pregnant after trying twice. (If this math seems strange to you, please check out my blog on calculating your IVF success rates over multiple cycles).
My introduction to uterine natural killer cells
Fortunately however, I have one of the best IVF specialists anyone could ever hope to see (in my view anyway). As some of you may know, 90% of fertility problems relate to issues with the embryo (whether that be sperm or egg related), and only about 10% relate to other potential causes, namely the uterus.
The genetic testing I did on my embryos prior to my last two transfers, led my doctor to believe that I may have a uterine problem so he recommended a hysteroscopy to investigate.
For all of those who don’t know what a hysteroscopy is, it’s essentially a short day-surgery where they use a small camera to inspect your uterine cavity and then take a biopsy.
As it turns out, the hysteroscopy revealed that I am one of a very small percentage of women with a high concentration of uterine natural killer (NK) cells, which may explain why I have had repeated failed embryo implantations, and which also puts me at a high risk of miscarrying if I am eventually able to fall pregnant, which has happened to me twice in the past.
What are natural killer cells in relation to pregnancy?
Natural killer cells are a healthy part of the immune system normally used by the body to destroy anything perceived to be “foreign” and/or harmful. They are a sub-type of white blood cell (cytotoxic lymphocyte) that provides a rapid response to infected cells and tumor formation.
Implantation is a really unusual situation for the immune system where these natural defenses need to be lowered.
If you think about what happens during implantation, the embryo (which is genetically different to us) penetrates the lining of the uterus to establish its own blood supply so that it can receive nutrients for further growth and then continues to grow rapidly. If this was any other organism trying to do this, our immune systems would totally freak out as this behavior resembles that of a parasite!
So it is essential that our natural killer cells have orders NOT to shoot this apparent invasion of our uterus in order for our pregnancy to succeed.
Natural killer cells cause failed implantation
The theory goes that the problem for people like me is that there is an abnormally high concentration of natural killer cells, specifically in the uterus, which fail to get the memo about not attacking the implanting embryo. Essentially implantation fails because of this “friendly fire”.
A critical detail about NK cell diagnosis
It is essential that women interested in being tested for NK cells understand the difference between the two types of NK cells typically involved in failed implantations and recurrent miscarriage. Not knowing the difference between uterine, and blood NK cells means you could be misdiagnosed by some doctors.
“Superbright” CD56 natural killer cells are known as uterine NK cells, as approximately 90% of NK cells found in the uterus are the “Superbright” CD56 type. “Dim” CD56 natural killer cells on the other hand form in the order of 90% of NK cells in the blood and hence are known as blood NK cells.
Blood NK cells are very different to uterine NK cells leading some experts to conclude that “measuring any parameter of NK cells in blood is not useful in trying to understand the cause of reproductive failure” (Moffett and Shreeve 2016; Ong 2016).
The important thing to know here is that you can only be properly diagnosed with high natural killer cells by having a uterine biopsy as a blood test may give you false positive results.
How do you treat natural killer cells when doing IVF?
At the time of writing I am about a week away from doing another frozen embryo transfer but this time I will be attempting a controversial new therapy for treating the high concentration of natural killer cells in my uterus in an attempt to prevent implantation failure.
This therapy, which was only first reported in 2012 (Krigstein and Sacks 2012) essentially involves suppressing my immune system through the oral administration of steroids, starting 2 weeks before the transfer, and should I get pregnant, for about 3 months after the day of transfer. I also will have a four hour intralipid infusion both on the day of the transfer and at the end of the first trimester should I fall pregnant, which will also aid in lowering my immune system.
The evidence (not) supporting NK cell therapy
The reason I say this therapy is controversial is because the research supporting this treatment is very thin. When I did my usual literature search I found that as of May 2016, no randomized controlled trials had been conducted on using immune suppression therapy along with IVF for women with high uterine NK cell counts.
The best paper I could find on NK cell therapy concluded that some NK cell therapies are beneficial on IVF outcomes however these treatments ‘could not be recommended due to the paucity, or poor quality of evidence currently available’ (Polanski and Barbosa et al. 2014).
Not very satisfying that’s for sure…
As my regular readers will know, I am a BIG fan of medical research to support any reproductive intervention, but in this situation, I have sided with my doctor. Please let me explain..
Why I chose to do NK cell therapy during my next frozen embryo transfer
Researchers criticize clinicians for offering immune-suppression therapy with insufficient scientific evidence, and indeed there are some doctors using this therapy irresponsibly for financial gain.
On the other side of the coin however, you have genuinely world-leading IVF specialists using this therapy to solve real-life infertility problems for couples like us who don’t have time to wait for the researchers to prove that this therapy works in the right circumstances.
So what got me over the line when considering this treatment? It was the case studies… While I know case studies are almost devoid of “scientific rigor”, they are still compelling. For example, Krigstein and Sacks (2012) reported the case where an otherwise healthy couple who had experienced three prior miscarriages, following 10 IVF cycles had a healthy baby boy on the 11th attempt after starting immune-suppression therapy. 2 years later, they were successful again on the first attempt after following the same protocol giving birth to a second healthy boy.
My own IVF specialist has had similar cases, so this does not appear to be a random event in my view.
My husband and I were faced with the choice to continue crossing our fingers and hoping that our next cycle would work, despite our ever decreasing probability of success, or we could try something new. Given the sound medical advice we received, and after independently informing ourselves of the situation we are getting ourselves into, NK cell therapy was the more rational option compared to blindly risking further precious embryos and hoping for better luck next time.
The side effects of NK cell therapy
So what about side effects? At this stage I don’t have a lot to report except for the side effects of the steroids which have included losing my appetite, regularly feeling nauseous, occasionally getting splitting headaches and struggling to sleep.
I’m also coming down with a case of tonsillitis, and have a terrible cough but I guess that means the steroids are being effective in lowering my immune system?
Another side effect to consider is the potential damage being done to my liver and adrenal glands by taking steroids for 3 months. The steroids may be considered relatively “safe” but 3 months is a long time and I already have major problems with managing my cortisol levels thanks to having PCOS and living most of my life with very high stress levels. So for me this is a big deal, but for now, I hope that the risks are worth it.
Things you should know before starting NK cell therapy
So for those of you, who are long-time followers, consider this blog-post the latest update on me and my journey through IVF.
And for those of you who have suffered multiple failed implantations, or recurrent miscarriages, I hope this article has been informative and given you food for thought.
If you’re going through something similar, I’d love to hear about it so please leave me a comment below.
But before you sign-off, and you go calling your IVF specialist to talk about you NK cell concentrations, I just want to remind you of these key things you need to know before exploring this path as a potential cause of your failure with IVF or for recurrent miscarriages:
1. The prevalence of women with high NK cells is overblown by many physicians who may be pushing this treatment for the wrong reasons. So BE SCEPTICAL!
2. Some specialists argue that blood testing for NK cells is effective, but this does not appear to be the case so don’t start treatment based on a peripheral blood test result. If your doctor suggests a blood test for NK cells, then this should be a massive red-flag, as this is a great way to get a false positive test result as I have explained above (see “A critical detail about NK cell diagnosis” above).
3. The only circumstance you will want to consider this therapy is after you have had a uterine biopsy to confirm your diagnosis.
Wishing you all the best with your journey as always,
Dr Kee Ong, Monash IVF, Personal correspondence, 2016.
Krigstein M, and Sacks G. Oral immune suppressants for repeated implantation failure associated with high natural killer cell levels. Journal of Obstetrics and Gynaecology, 2012.
Moffett A, Shreeve N, Reply: First do no harm: continuing the uterine NK cell debate. Human Reproduction, 2016.
Polanski L, Barbosa M, Martins W, Baumgarten M, Campbell B , Brosens J, Quenby S, and Raine-Fenning N. Interventions to improve reproductive outcomes in women with elevated natural killer cells undergoing assisted reproduction techniques: a systematic review of literature. Human Reproduction, 2014.