Immunotherapy, infertility & treatment options for IID

Treatment for immunologic implantation dysfunction (IID) is on the pioneering edge of fertility care. Long-misunderstood and shunned by the medical community, it’s at the heart of many, many successful pregnancies following recurrent miscarriage. So how do immunotherapy, infertility and IID all link together?

In part three of our miniseries with Dr. Sher and the Sher Fertility Solutions team, we’re diving into the immunotherapy infertility connection, and evidence-based treatment solutions. Missed part one and two? Make sure you’ve covered our embryo implantation dysfunction 101 with Dr. Sher, plus his introduction to immunology, and its impact on fertility.

Keen to look at treatment options with Sher Fertility Solutions? Book a consultation, then read on for Dr Sher’s thoughts on treatment options for immunologic implantation dysfunction (IID) , in part three of our implantation dysfunction mini-series. 

Over to Dr. Sher – 

Treatment for immunologic implantation dysfunction (IID)

In the second part of our implantation dysfunction miniseries, we covered Immunologic Implantation Dysfunction (IID), diagnosis and what we mean by ‘activated natural killer cells’. 

Today, we’re exploring immunotherapy, infertility and treatment options for IID. 

The mainstay of treatment involves selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/Dexamethasone)
• Heparinoids (Lovenox/Clexane)

Your team may recommend one, a few, or all of these immunotherapy options to find a break-through in your infertility journey. 

Now, let’s run through each one in more detail. 

Intralipid (IL) therapy

What are intralipids? 

Intralipid (IL) is a suspension of soybean lipid droplets in water – it’s primarily used as a source of parenteral nutrition (where we’re providing nutrients in liquid form). When administered intravenously, intralipids provide essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid. 

How are intralipids used in infertility treatment? 

It’s thought that fatty acids within the intralipid emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs), expressed by the natural killer (NK) cells. 

This sounds very technical – and it is – but crucially, this process is believed to decrease NK cell cytotoxic activity, and enhance embryo implantation. 

Whatever the exact mechanism might be, intralipid acts primarily to suppress NK cell overproduction of TH-I cytokines. This is enhanced by administering corticosteroids (keep reading for more details on these) such as dexamethasone, prednisolone and prednisone, which augment immune modulation of T cells. 

The combined effect of intralipid and steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of two to three weeks. 

It is likely to be just as effective as IVIg therapy in this respect, but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for around four to six weeks, when administered in early pregnancy.

IVIg therapy

Until about a decade ago, the only effective and available way (in the USA) to down-regulate activated NK cells was through intravenous administration of a blood product, known as immunoglobulin-G (IVIg). 

Why did IVIg (and reproductive immunology) get such bad press?

The fear, while unfounded, that administration of this product might lead to transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIg, along with significant side effects in around 20% of cases, led to bad press and negative publicity for the entire field of reproductive immunology. 

It was easier for doctors to simply say “I don’t believe IVIg works”, and avoid risk and bad publicity, than to pioneer the treatment. But, the thousands of women who had babies because of NK cell activity being down-regulated through its use, attest to IVIg’s efficacy. 

Where are we at, today? 

Doctors (myself included) who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press (sadly caused by fear-mongering) took its toll and spawned a malicious controversy. 

It was only through the introduction of intralipid therapy (about 15-20 years ago), that the tide began to turn in favor of those patients who required low-cost, safe and effective immunotherapy to resolve their IID.

Corticosteroids

Corticosteroid therapy (e.g using Prednisone or Dexamethasone) has become a key factor in most IVF treatment programs. It’s believed by most to enhance implantation due to an overall immunomodulatory effect (activating or suppressing the body’s immune system function). 

Corticosteroids reduce TH-1 cytokine production (read up on part two of our miniseries for a run-through on TH-1). When given in combination with intralipids or IVIg they augment the embryo implantation process.

The Prednisone or Dexamethasone therapy must start (along with intralipids/IVIg) 10-14 days before egg retrieval and continue until a negative pregnancy test, or until the 10th week of pregnancy.

H2 Heparinoid therapy

There’s compelling evidence that injecting low molecular heparin (Clexane or Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birth rate in women who test positive for antiphospholipid antibodies (APAs). Also, that it might prevent later pregnancy loss when used to treat certain thrombophilias (e.g the  homozygous MTHFR mutation).

What about …

Baby aspirin?

In my opinion, aspirin has little (if any) value when it comes to immunologic implantation disorder (IID). In fact, it could even reduce the chance of success. 

The reason for this is that aspirin thins the blood, and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, potentially compromising IVF success.

Enbrel and Humira (TH-1 cytokine blockers)?

These are, in our opinion, relatively ineffective in IVF. As yet, there’s no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage, if thought to be due to activated NK cells and/or cytotoxic lymphocytes/T-cells, but not for IVF. 

This is because the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance, like with IL therapy) so very early on could compromise, rather than benefit, implantation.

Leukocyte immunization Therapy (LIT)

Injection of the male partner’s lymphocytes to the mother is thought to enhance the uterus’ ability to recognize the embryo as “self” or “friend”, and avoid rejection. LIT has been shown to up-regulate Treg cells and down-regulate NK cell activation, improving TH-1:TH-2 balance.

This could have a  therapeutic benefit,  but  the same can be achieved through use of intralipids, plus corticosteroids. 

Also, intralipids are much less expensive, and the use of LIT is prohibited by law in the USA.

There are a few other alternative approaches which, in my opinion, still lack confirmation of efficacy, including:

• The use of the endometrial receptivity array (ERA) to determine the ideal window of implantation
• Granulocyte Stimulating Factor (Neupogen)
• Uterine platelet-rich plasma (PRP) for uterine washes
• Endometrial flushing with hCG solution
• Endometrial scratch

Keen to explore immunotherapy, infertility and an expert program of care? Touch base with the team at Sher Fertility Solutions today for pioneering expertise.