Immunology – is it behind your implantation dysfunction?

Immunologic implantation dysfunction (IID) has a very real impact on thousands of pregnancies, IVF cycles and fertility strategies. It’s a highly complex area, and nowhere near high enough on the agenda for many doctors and clinics. But immunology – is it at the root of your implantation struggle?

In part two of our miniseries with Dr. Sher and the Sher Fertility Solutions (SFS) team, we’re covering all-things immunology, IID and autoimmune. Missed part one? Make sure you’ve covered our embryo implantation dysfunction 101 with Dr. Sher, before diving in.

Flick to our partnership with Sher Fertility Solutions and book a consultation, or keep reading for the low-down on immunologic implantation dysfunction (IID), in part two of our implantation dysfunction mini-series. 

Over to Dr. Sher – 

Diagnosing immunologic issues

In part one of our implantation dysfunction miniseries, we finished off with Immunologic Implantation Dysfunction (IID), what it is an its connection to IVF failure, repeat miscarriage (or recurrent pregnancy loss) and ‘unexplained infertility’.

Today, let’s cover diagnosis. 

Because immunologic problems can lead to implantation failure, if a woman does have risk factors, it’s important to do an evaluation. Fertility-related immunologic risk factors include: 

• Unexplained or recurrent IVF failures
• Unexplained infertility
• Personal and/or family history of autoimmune disease (e.g rheumatoid arthritis, lupus erythematosus, or hypothyroidism/Hashimoto’s Disease, scleroderma, dermatomyositis, etc)
• Recurrent Pregnancy Loss (RPL)
• Endometriosis

If a woman comes to us with any of these risk factors, we’ll move to investigate IID.

Digging deeper into immunology and infertility, what factors can contribute to pregnancy loss, IVF failure and implantation dysfunction? Let’s un-pick a few that we look into, as a priority. 

Activated Natural Killer Cells (NKa)

Following ovulation and during early pregnancy, your natural killer (NK) cells and T-cells make up over 80% of the white blood cells in your uterine lining, or endometrium. 

These cells travel from your bone marrow to your uterus, and, under hormonal regulation, proliferate. Once exposed to progesterone, they start producing TH-1 and TH-2 cytokines. For optimal placental development, we need a fine balance between TH-1 and TH-2 cytokines. And excessive production or release of TH-1 can, via a complex toxicity process, lead to Immunologic Implantation Dysfunction (IID). 

Where’s the connection to implantation? Your functional NK cells peak in concentration – inside the endometrium – by about day 6-7 after they’re exposed to progesterone. And this timing matches up with when an embryo implants into the endometrium – usually, around day 6-7. 

It’s activation, not quantity

Getting technical, it’s worth noting that the concentration of your NK cells is pretty-much irrelevant here. It’s the NK cell activation which matters. In fact, certain conditions (like endometriosis) may feature below-normal NK cell concentration, but markedly increased activation. 

Assessment in the lab 

Laboratories use a few different methods to assess NK cell activation – also known as cytotoxicity. However, the K-562 Target Cell Blood Test is the gold standard. With this test, your NK cells are incubated alongside specific ‘target cells’. The lab will then calculate the percentage of target cells ‘killed’ – more than 12% suggests a higher level of NK cell activation, which usually requires treatment.

Currently, there are less than a half dozen reproductive immunology reference laboratories in the USA capable of performing a reliable K-562 target cell test. We’re in a privileged position at Sher Fertility Solutions, to provide patients with access to this gold standard of testing. 

Antiphospholipid Antibodies (APAs)

Many women who experience unexplained IVF failure, women with recurrent pregnancy loss (RPL), those with a personal or family history of autoimmune diseases, as well as women with endometriosis, test positive for APAs. 

More than 30 years ago, I led the ground-breaking proposal that women who test positive for APA’s get treated with a mini-dose heparin, to improve IVF implantation and birth rates. I based this approach on research suggesting that heparin repels APAs from the surface of the trophoblast (the embryo’s ‘root system’), reducing its anti-implantation effects.  

More recently, low dosage heparin therapy has been supplanted, using longer-acting low molecular weight heparinoids such as Lovenox and Clexane. 

It’s very possible that APAs alone do not cause Immunologic Implantation Dysfunction (IID). But their presence might help identify women who may be at risk, due to their associated risk for activated natural killer cells (see NKa above). 

We work on this basis because:

• The presence of female APAs in cases of male factor infertility appears to bear no relationship to IID
• Only APA-positive women who also test positive for abnormal NKa appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids 
• Most APA-positive women who have increased NKa also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies

I appreciate this is getting pretty technical – do flick through our free immunology eBook, for further detail, or book a consultation with Sher Fertility Solutions. My team are at the forefront, and passionate about, all-things immunology. 

Antithyroid Antibodies (ATAs)

There’s a clear relationship between ATAs and reproductive issues, (especially recurrent miscarriage and infertility). 

Between 2% and 5% of women of childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often encounter reproductive difficulties, from infertility and unexplained (often repeated) IVF failure to recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. 

In most cases, thyroid autoimmunity (Hashimoto’s disease) is caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  

However, we tend to see increased thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss. And, thyroid antibodies can be present asymptomatically in women. These antibodies may persist in women who’ve suffered from hyper or hypothyroidism, even after their thyroid function has been normalised. 

So, reproductive problems seem to be linked more to the presence of thyroid autoimmunity (TAI), than to clinical existence of hypothyroidism. Which may be why thyroid treatment alone doesn’t routinely result in better outcomes, for fertility. 

ATAs are useful markers

We see anti-thyroid autoantibodies as useful markers for predicting poor outcomes in patients undergoing assisted reproductive technologies, such as IVF.

Some years back, I reported that 47% of women who have anti-thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL). And, that these women often present with reproductive dysfunction. 

We demonstrated that, in these cases, appropriate immunotherapy with IVIG or intralipid (IL) and steroids often results in a significant improvements.

Join us next time with Dr Sher, for the guide to gold standard Immunologic Implantation Dysfunction treatment options.