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IS LYMPHOCYTE IMMUNIZATION THERAPY (LIT) EFFECTIVE IN TREATING RECURRENT PREGNANCY LOSS?

Mya Care Blogger 27 Feb 2024
IS LYMPHOCYTE IMMUNIZATION THERAPY (LIT) EFFECTIVE IN TREATING RECURRENT PREGNANCY LOSS?

Miscarriages are a heartbreaking reality for many couples trying to conceive. According to the American College of Obstetricians and Gynecologists, miscarriages occur in 10–25% of pregnancies, with the majority happening in the first trimester.

Recurrent Pregnancy Loss (RPL) refers to the occurrence of two or more consecutive miscarriages. It is estimated that about 1-5% of couples trying to conceive experience RPL. Unfortunately, the chance of RPL increases by about 20% per miscarriage, and many treatment options that tackle fertility are unable to address the issue.

For couples who experience RPL, the emotional toll can be devastating. However, there is a treatment option that may offer hope for those struggling with unexplained recurrent miscarriages: Lymphocyte Immunization Therapy (LIT).

In this article, we will explore what LIT is, its potential benefits and drawbacks for treating multiple miscarriages, and the controversy surrounding the use of LIT as a fertility treatment.

What is Lymphocyte Immunization Therapy (LIT)?

Lymphocyte immunization therapy, also known as LIT or Lymphocyte Immunotherapy, is a fertility treatment that involves injecting a woman with her partner's white blood cells (lymphocytes) to help her immune system accept the embryo and possibly prevent miscarriage. It is done 4-6 weeks before conception for the best result possible, yet a booster shot may be recommended during the first trimester of pregnancy.

This treatment is based on the theory that some women may have an immune response to their partner's sperm or the embryo, leading to implantation failure and recurrent miscarriages.

During a miscarriage, many events can go wrong. Most miscarriages are the result of spontaneous (non-inherited) genetic mutations that cause the body to reject the embryo or fetus. For women with RPL, the body rejects the embryo or fetus, irrespective of whether it is mutated or not.

Using Lymphocyte Immunotherapy for pregnancy can help prevent potential immune responses toward the embryo that may prevent it from staying implanted in the uterine lining. However, it is important to note that LIT is not a standard treatment for recurrent miscarriage and is classified as experimental by some authorities, although it has been a subject of study since 1980[1]. For instance, the procedure has remained suspended since 2002 in the United States, with the FDA restricting its use for study purposes only[2]. It is also a costly procedure with potential side effects, and its effectiveness is still unclear due to limited research and inconsistent findings.

How Does Lymphocyte Immunization Therapy Work?

The idea behind LIT is that by exposing the woman's immune system to her partner's lymphocytes, it will become more tolerant and less likely to attack the embryo. This is similar to how allergy shots work, where the body is exposed to small amounts of an allergen to build up immunity.

Results from women with recurrent miscarriages occasionally reveal immune abnormalities, such as increased reactivity, antibodies towards her partner's genetic material[3], and inflammation.[4] Aborted embryos or fetuses can also leave behind RNA fragments and other proteins that can stimulate a heightened immune response and detract from chances of success with each subsequent pregnancy loss.

It is theorized that LIT can help lower the sensitivity of the immune system to the future father's sperm and genetic material, which may play a prime role in some cases of RPL.[5]

The Controversy Surrounding LIT

The REMIS study refers to a specific study that was conducted in 1999 to evaluate the effectiveness of Lymphocyte Immunization Therapy in treating recurrent miscarriages. The controversy surrounding the REMIS study arises from the fact that it reported no success with LIT in improving pregnancy rates, contradicting findings from prior studies.

The study was performed on 86 women, with 85 other women forming the control group. In the United States, the FDA suspended LIT in 2002, citing research from the study that showed it was ineffective. The conclusion that LIT should not be offered as a treatment for RPL based on these findings has come under question in recent years.

Now, more than two decades later, there is some evidence supporting the safety and efficacy of LIT in helping some women overcome RPL.[6] However, despite there being more research available now than back in the late 90s, the evidence is still limited to results seen across several hundreds of women suffering from recurrent miscarriage (as opposed to a handful).

The success rate of lymphocyte immunotherapy varies, with some studies showing a significant improvement in pregnancy rates for couples who have undergone the treatment:

  • One study published in the Journal of Reproductive Immunology found that LIT improved live birth rates in women with unexplained recurrent miscarriages by as much as 20%.
  • Another study shows improvements as great as 31% for women with recurrent pregnancy loss.[7]
  • The same study reveals a modest 8% improvement for women with recurrent implantation failure.

According to a 2021 review, the overall efficacy of LIT in treating recurrent implantation failure is questionable, with a minimal success rate. Therefore, LIT may be unsuitable for treating this form of pregnancy loss.

With more time and testing, the efficacy of LIT might become clearer, especially as science begins to unravel more potential causes for RPL.

Lymphocyte Immunotherapy Procedure

The first step in LIT is to isolate lymphocytes from the partner's blood. This is typically done through a process called leukapheresis, where the blood is filtered through a machine to separate the white blood cells. The lymphocytes are then mixed with the woman's blood and injected into her upper arm.

To check whether the procedure is successful or not, a leukocyte antibody detection test can be performed. This measures how many antibodies the mother has in her blood that can prevent the embryo from implanting or successfully developing[8].

Is LIT Painful?

The pain experienced during LIT can vary from person to person. Some individuals may feel mild discomfort or pain at the injection site, similar to a regular shot. However, others may not experience any pain at all.

It is essential to discuss any concerns or possible side effects with your healthcare provider before undergoing LIT.

Who is a Good Candidate for Lymphocyte Immunotherapy?

LIT is typically recommended for couples who have experienced multiple miscarriages, especially those with unexplained recurrent miscarriages. It may also be recommended for couples who have had failed IVF cycles due to implantation failure.

As already mentioned before, LIT is not a standard treatment for recurrent miscarriage and is still considered experimental by many medical professionals. It is typically only offered by specialized fertility clinics and may not be covered by insurance.

LIT Pros and Cons

Like any medical treatment, Lymphocyte Immunization Therapy has its own set of potential benefits and drawbacks. Let us take a closer look at the pros and cons of LIT for treating multiple miscarriages.

Pros

Some potential LIT therapy benefits include:

  • May improve implantation rates: The main goal of LIT is to improve the woman's immune response to the embryo, potentially leading to a higher chance of successful implantation and pregnancy.
  • Non-invasive procedure: LIT is a relatively simple procedure that does not require surgery or anesthesia.
  • Maybe a viable option for unexplained recurrent pregnancy loss: For couples who have experienced multiple miscarriages with no known cause, LIT may offer a potential solution.
  • May improve IVF success rates: LIT may improve live birth rates in some cases, particularly for couples with implantation failure[9].

Cons

Some potential drawbacks of LIT are:

  • Limited research and evidence: LIT is still considered an experimental treatment, and there is limited research and evidence to support its effectiveness.
  • Not widely available: LIT is not a standard treatment for recurrent miscarriage and is only offered by specialized fertility clinics, making it less accessible for some couples.
  • Expensive: LIT is not typically covered by insurance and can be costly, with some clinics charging up to $10,000 for the treatment.
  • Potential side effects: As with any treatment, there is a risk of side effects, including fever, chills, and allergic reactions.

Potential Side Effects of LIT

LIT involves a risk of side effects, the same as with any medical treatment. The most common LIT side effects reported include fever, chills, and allergic reactions. In rare cases, more severe side effects, such as infections, have been reported.[10]

It is essential to discuss the potential risks and side effects with your doctor before undergoing LIT and to closely monitor any symptoms after the treatment.

Alternative Therapies to LIT for Miscarriage

Several alternative therapies with similar immune-enhancing benefits to LIT may benefit women with recurrent pregnancy loss.

Intralipid Therapy

Intralipid therapy involves the intravenous infusion of a fat emulsion, which includes anti-inflammatory lipids such as omega-3 fats and alpha-linolenic acid[11]. The proposed mechanism alters the activity of Natural Killer (NK) cells, a type of immune cell. Under ordinary circumstances, NK cells are thought to contribute to fetal development. In recurrent miscarriage, high levels of overactive NK cells may attack the fetus, leading to pregnancy loss.

Intralipid therapy suppresses the activity of NK cells, thus potentially improving pregnancy outcomes in women with suspected immune-related pregnancy loss.

However, its effectiveness remains controversial. In a review surveying 12 studies, researchers found that intralipid therapy can potentially increase the odds of successful implantation by almost three times, raise the chances of pregnancy by roughly 67%, and more than double the rate of successful live births in women with prior difficulties.[12]

However, more research is required to draw firm conclusions as results vary across studies, with some trials being uneventful. Intralipid therapy may help women with recurrent miscarriages who have high NK cell levels, inflammation, and for whom other treatments failed.

Intravenous Immunoglobulin (IVIg)

IVIg is a therapy derived from pooled human plasma containing a mix of antibodies (immunoglobulins). It modulates various immune system components, such as potentially lowering NK cell activity, reducing inflammation, correcting the balance of harmful antibodies (e.g., antithyroid antibodies), and promoting immune tolerance[13].

While off-label IVIg is used occasionally for immune-related pregnancy loss, its specific mechanism in miscarriage prevention isn't fully understood. As with intralipid therapy, studies have shown mixed results. One study suggests it may improve the odds of live birth by more than 20% in women with primary recurrent pregnancy loss, yet not in those with secondary pregnancy loss.[14]

More research is required to determine how it works, who might benefit, and to establish consistent protocols for its usage in this context.

Other Promising Therapies Under Investigation

In addition to the above alternatives, there are some promising areas of research into other options to LIT for managing recurrent pregnancy loss that target other immune factors:

  • Mesenchymal stem cells (MSCs): MSCs have immunomodulatory and regenerative properties. Animal studies suggest they might help create a more supportive uterine environment, reduce inflammation, and improve uterine tolerance.[15]
  • TNF-alpha inhibitors: Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory molecule. Researchers are investigating whether blocking TNF-alpha could be beneficial in specific cases of immune-mediated pregnancy loss. A small study shows promising results when treating women with TNFa inhibitors in the first trimester who displayed declines in human chorionic gonadotrophin, a marker of pregnancy loss.[16] 
  • Microbiome modulation: The gut and reproductive tract bacteria might play a role in maternal immune function during pregnancy. Studies are exploring how manipulating the microbiome could benefit pregnancy outcomes.[17]
  • Granulocyte colony-stimulating factor (G-CSF): This factor promotes the development of specific white blood cells. There is preliminary evidence suggesting it might improve implantation and pregnancy outcomes, yet results are contradictory, and more research is needed[18].

These are only a fraction of investigations. In time, we can expect to have a far more comprehensive understanding of all the possible immune-related causes of recurrent pregnancy loss, which might expand the scope of treatment.

Conclusion

Lymphocyte immunization therapy (LIT) is a fertility treatment that involves injecting a woman with her partner's white blood cells to help her immune system accept the embryo and prevent miscarriage. While it is still considered an experimental treatment, it may offer hope for couples struggling with multiple miscarriages.

Since the efficacy of the treatment has not been widely confirmed yet, it is not a standard treatment for treating recurrent pregnancy loss or failed IVF. Also, it is a costly procedure with potential side effects, the seriousness of which is yet to be determined by medical research.

If you are considering LIT as a treatment option, it is crucial to discuss your options with your doctor. With the right information and guidance, you can make an informed decision about whether LIT is the right choice for you.

To search for the best Fertility Healthcare Providers in India, Malaysia, Saudi Arabia, Singapore, Spain, Thailand, Turkey, the UAE, the UK and The USA, please use the Mya Care search engine.

To search for the best Fertility Doctors in Malaysia, Spain, Thailand, the UAE, the UK and the USA, please use the Mya Care search engine.

Sources:

  • [1] https://esmed.org/MRA/mra/article/download/4061/99193547059
  • [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862550/
  • [3]https://pubmed.ncbi.nlm.nih.gov/10601081/#:~:text=Anti%2Dpaternal%20antibodies%20directed%20towards,immune%20after%20paternal%20leukocyte%20immunization.
  • [4] https://www.sciencedirect.com/science/article/abs/pii/S0165037820301108
  • [5] https://rbej.biomedcentral.com/articles/10.1186/s12958-017-0315-9
  • [6] https://pubmed.ncbi.nlm.nih.gov/36351029/
  • [7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533392/
  • [8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589387/
  • [9] https://academic.oup.com/humrep/article/38/Supplement_1/dead093.872/7203352
  • [10] https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.15348
  • [11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933936/
  • [12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788620/
  • [13]https://www.researchgate.net/publication/229159512_Intravenous_Immunoglobulin_for_Repeated_IVF_Failure_and_Unexplained_Infertility
  • [14] https://pubmed.ncbi.nlm.nih.gov/37491929/
  • [15] https://pubmed.ncbi.nlm.nih.gov/31943723/
  • [16] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174430/
  • [17] https://pubmed.ncbi.nlm.nih.gov/35934639/
  • [18] https://academic.oup.com/humrep/article/34/3/424/5334616

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