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Natural Killer Cells : an emerging possibility

Last year, at The Fertility Society of Australia’s annual conference in Auckland,  I presented some research into one of the currently controversial areas of reproductive medicine – the role of natural killer cells in pregnancy. 

Investigating an approach known as the Bondi Protocol, this research offers experimental immune therapy for women who test positive to high levels of natural killer (NK) cells in the blood or uterus. High NK cell activity has been associated with miscarriage and embryo implantation failure.  Further randomised trials are clearly needed to prove that treatment leads to better pregnancy outcomes.  However, the results of the research to date are promising, and there are exciting possibilities for the future.

I’ve been interested in this area of medicine since my PhD in reproductive immunology at the University of Oxford (UK) over 15 years ago.  But over the last decade the controversy and debate surrounding natural killer cells has grown.

The arguments for and against the use of immune therapy in pregnancy began as early as the 1950s, when it was first shown that the immune system is suppressed in normal pregnancy. This effect was thought to be essential for the embryo implant.  Whilst the use of therapy became widespread, studies carried out then, did not suggest many benefits.  Likewise, the use of immune therapy in IVF patients used in trials. years later would also show little benefit.

It wasn’t until the mid-1990s that ‘natural killer cells’ were first described in the uterus, and ‘ attracted worldwide attention.  It was then that the debate amongst the medical profession fired up.  As the main immune cell-type found in the uterus in pregnancy, the concept of testing natural killer cells in a new group of patients  - those suffering unexplained infertility, repeated miscarriages or IVF failure - was spawned by doctors in the United States.  Their theory was that high levels of natural killer cells prevented pregnancy from occurring, and thousands of women across the globe latched onto this news in the hope that this was the answer and solution they had been searching for, but evidence has been lacking.

The U.S doctors offered testing that measured the levels of natural killer cells without proper benchmarks, and charged thousands of dollars for immune therapy, which involved high dosages of drugs prescribed for long periods throughout the pregnancy (controversial in itself due to the slight increase in pregnancy complications). 

There was no question that they were good at marketing, but the lack of any solid scientific evidence concerned the medical profession, with conventional doctors claiming that those using the test were taking advantage of desperate women. 

When I moved to Australia 7 years ago, scepticism was rife amongst Australian specialists and not surprisingly.  At this time I set out to find more evidence, and create a reliable test.  It was important to identify the fundamental features of the test, such as what was a normal level of natural killer cells.  This was of vital importance, as some American clinics claimed, unrealistically, that extremely high numbers of women apparently have abnormal immune function. What was found was that 15% of women with recurrent miscarriage had high levels of natural killer cells by our definition. 

A treatment protocol was then developed to study the effects of using an immunosuppressant to reduce the number and activation levels of natural killer cells. Known as the Bondi Protocol, it involves the use of Clexane and Prednisolone, both previously used in this area of study .  However, unlike in the United States, the Bondi Protocol uses moderate dosages for short periods of time (during the first three months of pregnancy).  To date there has been no reported problems in the mothers or babies throughout this study. However, it is important to remember that these are still relatively small numbers and a low risk of adverse effects may still be present.

In the seven years the study has been running, over 2000 women have been tested, and over 100 babies have been born. In a recently presented analysis, 87 women with high blood NK cell levels were treated with the Bondi Protocol and followed up closely (58 women had repeated IVF failure, and 29 had repeated miscarriage).  This group of patients had particularly poor prognoses, with average age 38 and a history of 6 miscarriages or 6 failed IVF cycles. The overall cumulative live birth rate over several cycles was 52%. This success rate rose to 59% in those who had high levels of activated NK cells (using a marker called CD69), and 86% in those women aged less than 38. 80% of the miscarriage patients had a successful pregnancy within a year of the NK cell test, most occurring in the very first pregnancy treated. And 70% of the IVF patients had a successful pregnancy in the first 3 IVF cycles with the Bondi Protocol. It was also interesting to observe that the best outcomes occurred in couples with no other infertility factor (ie. ‘unexplained’), supporting the hypothesis that high NK cell levels may be itself an infertility factor.

What was interesting about this study is that it has shown higher than expected live birth rates in patients with an otherwise poor prognosis.  Many of these patients carried a successful pregnancy after many many miscarriages or failed IVF cycles.

Large randomised trials are still required to prove that any connection between natural killer cells and pregnancy is more than just chance.  However, it is my hope that natural killer cell testing will turn out to be a useful tool in helping women fulfil their desire to have a baby.

For further information about accessing Natural Killer Cell testing, contact the relevant IVF clinic in your state to find out how : IVFAustralia (NSW), Melbourne IVF (VIC) or Queensland Fertility Group (QLD).

Read an abstract presented by Associate Professor Gavin Sacks at the Fertility Society of Australia Conference 2012.

Read a transcript from a 60 Minutes interview with Associate Professor Gavin Sacks here: http://sixtyminutes.ninemsn.com.au/stories/919380/ending-the-heartbreak

 

Comments

Natural Killer cells and associated immune related issues can and do affect pregnancy. I have antiphophilipid Syndrome and higher than average NK cells. I was treated with steroids for five out of 8 IVF. I have a two year old son now. My NK cells were well within acceptable range when he was conceived. I was not taking steroids when he was conceived but was on low dose aspirin and LMW Herapin for the entire pregnancy. NK Cells and immune related diseases are routinely treated in the U.S. and U.K.
We continue to be amazed that we have a 2year old son after 6 years and 17 IVF attempts. After asking to be tested by our IVF specialist I was actually pleased with a higher than average presence of NK cells and a possible 'cause' for the unexplained infertility. We easily conceived our first child naturally 8yrs prior. We went on the Bondi protocol for the next cycle and got lucky! Thank you so much for your work! I just hope this option has now spread wider than it had when we were looking for answers.
I was recently diagnosed wit high natural killer cells, but they are only slightly elevated. What is the normal range for NK cells? I have read so many different things on the internet. What is the normal range???
Dear Prof. Gavin Sacks, My names gandes & 6 yaera married. At May 19th Ive Inseminasi and its failed. My ASA was normal, my dokter said to cek my NK Cell, Result was 680 tan average. I'm so sad & distraught.. Pleas give some advise for natural cure & what sould i have to do... Thank you very much.. Regrads Gandes. ..
Dear Gandes,We recommend you please call 1800 111 483 to discuss your individual situation and make an appointment with A/Prof. Sacks.Regards,Virtus Health
My wife and I have been experiencing unexplained miscarriages and unsuccessful pregnancy attempts. Ive never heard of this being a factor but apparently we aren't the only ones. We have a 6 year old after a normal pregnancy. Now we have been trying for 4 years without success. We recently lost twins at 12 weeks that were done thru IVF. Anyone know if this type of treatment is done in the US? Or can be medicated to subdue NK cells? thanks in advance